Computed tomography-based radiomics combined with machine learning allows differentiation between primary intestinal lymphoma and Crohn's disease

BACKGROUND Due to similar clinical manifestations and imaging signs,differential diagnosis of primary intestinal lymphoma(PIL)and Crohn's disease(CD)is a challenge in clinical practice.AIM To investigate the ability of radiomics combined with machine learning methods to differentiate PIL from CD.METHODS We collected contrast-enhanced computed tomography(CECT)and clinical data from 120 patients form center 1.A total of 944 features were extracted singlephase images of CECT scans.Using the last absolute shrinkage and selection operator model,the best predictive radiographic features and clinical indications were screened.Data from 54 patients were collected at center 2 as an external validation set to verify the robustness of the model.The area under the receiver operating characteristic curve,accuracy,sensitivity and specificity were used for evaluation.RESULTS A total of five machine learning models were built to distinguish PIL from CD.Based on the results from the test group,most models performed well with a large area under the curve(AUC)(>0.850)and high accuracy(>0.900).The combined clinical and radiomics model(AUC=1.000,accuracy=1.000)was the best model among all models.CONCLUSION Based on machine learning,a model combining clinical data with radiologic features was constructed that can effectively differentiate PIL from CD.

Saccharomyces cerevisiae prevents postoperative recurrence of Crohn's disease modeled by ileocecal resection in HLA-B27 transgenic rats

BACKGROUND Postoperative recurrence(POR)after ileocecal resection(ICR)affects most Crohn's disease patients within 3-5 years after surgery.Adherent-invasive Escherichia coli(AIEC)typified by the LF82 strain are pathobionts that are frequently detected in POR of Crohn's disease and have a potential role in the early stages of the disease pathogenesis.Saccharomyces cerevisiae CNCM I-3856 is a probiotic yeast reported to inhibit AIEC adhesion to intestinal epithelial cells and to favor their elimination from the gut.AIM To evaluate the efficacy of CNCM I-3856 in preventing POR induced by LF82 in an HLA-B27 transgenic(TgB27)rat model.METHODS Sixty-four rats[strain F344,38 TgB27,26 control non-Tg(nTg)]underwent an ICR at the 12th wk(W12)of life and were sacrificed at the 18th wk(W18)of life.TgB27 rats were challenged daily with oral administration of LF82(109 colony forming units(CFUs)/day(d),n=8),PBS(n=5),CNCM I-3856(109 CFUs/d,n=7)or a combination of LF82 and CNCM I-3856(n=18).nTg rats receiving LF82(n=5),PBS(n=5),CNCM I-3856(n=7)or CNCM I-3856 and LF82(n=9)under the same conditions were used as controls.POR was analyzed using macroscopic(from 0 to 4)and histologic(from 0 to 6)scores.Luminal LF82 quantifications were performed weekly for each animal.Adherent LF82 and inflammatory/regulatory cytokines were quantified in biopsies at W12 and W18.Data are expressed as the median with the interquartile range.RESULTS nTg animals did not develop POR.A total of 7/8(87%)of the TgB27 rats receiving LF82 alone had POR(macroscopic score≥2),which was significantly prevented by CNCM I-3856 administration[6/18(33%)TgB27 rats,P=0.01].Macroscopic lesions were located 2 cm above the anastomosis in the TgB27 rats receiving LF82 alone and consisted of ulcerations with a score of 3.5(2-4).Seven out of 18 TgB27 rats(39%)receiving CNCM I-3856 and LF82 had no macroscopic lesions.Compared to untreated TgB27 animals receiving LF82 alone,coadministration of CNCM I-3856 and LF82 significantly reduced the macroscopic[3.5(2-4)vs 1(0-3),P=0.002]and histological lesions by more than 50%[4.5(3.3-5.8)vs 2(1.3-3),P=0.003].The levels of adherent LF82 were correlated with anastomotic macroscopic scores in TgB27 rats(r=0.49,P=0.006),with a higher risk of POR in animals having high levels of luminal LF82(71.4%vs 25%,P=0.02).Administration of CNCM I-3856 significantly reduced the levels of luminal and adherent LF82,increased the production of interleukin(IL)-10 and decreased the production of IL-23 and IL-17 in TgB27 rats.CONCLUSION In a reliable model of POR induced by LF82 in TgB27 rats,CNCM I-3856 prevents macroscopic POR by decreasing LF82 infection and gut inflammation.

Crohn's disease and clinical management today:How it does?

Crohn’s Disease(CD)is an Inflammatory Bowel Disease and is characterized by an immune-mediated nature.Its etiology results from the interaction between genetic,enviromental and microbial factors.Regarding pathophysiology,it involves high levels of interleukin(IL)-12,IL-17,and Th1 profile,along with loss of tolerance mechanisms,an increase in pro-inflammatory interleukins,beyond the possibility to affect any part of the gastrointestinal tract.Its symptoms include abdominal pain,chronic diarrhea,weight loss,anorexia,and fatigue,as well as blood in the stool or rectum.Additionally,conditions comprising musculoskeletal,cutaneous,ocular,hepatic,and hematological alterations may be associated with this scenario and extra-intestinal presentation,such as erythema nodosum,anterior uveitis,osteoporosis,and arthritis can also occur.Today,clinical history,exams as fecal calprotectin,ileocolonocopy,and capsule endoscopy can be performed in the diagnosis investigation,along with treatments to induce and maintain remission.In this sense,anti-inflammatory drugs,such as corticosteroids,immunomodulators,and biological agents,as well as surgery and non-pharmacological interventions plays a role in its therapy.The aim of this review is to bring more current evidence to clinical management of CD,as well as to briefly discuss aspects of its pathophysiology,surveillance,and associated disorders.

Moxibustion combined with acupuncture increases tight junction protein expression in Crohn's disease patients

AIM:To investigate the effect of herb-partitioned moxibustion combined with acupuncture on the expression of intestinal epithelial tight junction(TJ) proteins.METHODS:Sixty patients diagnosed with mild to moderate Crohn’s disease(CD)were allocated into the herb-partitioned moxibustion combined with acupuncture(HMA)group(n=30)or the mesalazine(MESA)group(n=30)using a parallel control method.There were 2 sets of acupoints used alternately for HMA treatment.The following points were included in Set A:ST25(Tianshu),RN6(Qihai),and RN9(Shuifen)for herb-partitioned moxibustion and ST36(Zusanli),ST37(Shangjuxu),LI11(Quchi),and LI4(Hegu)for acupuncture.The points for Set B included BL23(Shenshu)and BL25(Dachangshu)for herb-partitioned moxibustion and EX-B2 of T6-T1(Jiajixue)fo r acupuncture.The patients received the same treatment6 times a week for 12 consecutive weeks.The MESA group received 1 g of mesalazine enteric coated tablets4 times daily for 12 consecutive weeks.Intestinaltissues were stained and examined to compare the morphological and ultrastructural changes before and after the treatment session.Immunohistochemistry and in situ hybridization assays were used to detect the expression of intestinal epithelial TJ proteins zonula occludens-1(ZO-1),occludin,and claudin-1.The m RNA levels were also evaluated.RESULTS:After the treatment,both herb-partitioned moxibustion combined with acupuncture and mesalazine improved intestinal morphology and ultrastructure of CD patients;the patients treated with HMA showed better improvement.HMA significantly increased the expression of ZO-1(P=0.000),occludin(P=0.021),and claudin-1(P=0.016).MESA significantly increased the expression of ZO-1(P=0.016)and occludin(P=0.026).However,there was no significant increase in the expression of claudin-1(P=0.935).There was no statistically significant difference between the two groups for the expression of occludin and claudin-1(P>0.05).The HMA group showed a significant improvement in ZO-1 expression compared to the MESA group(2333.34±352.51 vs 2160.38±307.08,P=0.047).HMA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.017),and claudin-1 m RNA(P=0.017).MESA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.042),and claudin-1 m RNA(P=0.041).There was no statistically significant difference between the two groups in the expression of occludin and claudin-1 m RNA(P>0.05).However,the HMA group showed a significant improvement in ZO-1 m RNA expression compared with the MESA group(2378.17±308.77 vs 2200.56±281.88,P=0.023).CONCLUSION:HMA can repair intestinal epithelial barrier lesions and relieve inflammation by upregulating the expression of TJ proteins and their m RNAs.

Fecal microbiota transplantation cured epilepsy in a case with Crohn's disease: The first report

Fecal microbiota transplantation(FMT)is a promising strategy that involves reconstruction of gut microbiota.Recently,it has been considered as a treatment of Crohn’s disease(CD)and certain neurological diseases.Here,to the best of our knowledge,we report the first case that used FMT to achieve remission of intestinal and neurological symptoms in a girl with CD and a 17-year history of epilepsy.During the 20 mo of follow-up,FMT has proved its efficacy in preventing relapse of seizures after withdrawing the antiepileptic drugs.Furthermore,this finding highlights the role of microbiota-gut-brain axis and inspires a novel treatment for epilepsy through remodeling gut microbiota.

Differentiating Crohn's disease from intestinal tuberculosis

Differentiating Crohn's disease(CD) and intestinal tuberculosis(ITB) has remained a dilemma for most of the clinicians in the developing world, which are endemic for ITB, and where the disease burden of inflammatory bowel disease is on the rise. Although, there are certain clinical(diarrhea/hematochezia/perianal disease common in CD; fever/night sweats common in ITB), endoscopic(longitudinal/aphthous ulcers common in CD; transverse ulcers/patulous ileocaecal valve common in ITB), histologic(caseating/confluent/large granuloma common in ITB; microgranuloma common in CD), microbiologic(positive stain/culture for acid fast-bacillus in ITB), radiologic(long segment involvement/comb sign/skip lesions common in CD; necrotic lymph node/contiguous ileocaecal involvement common in ITB), and serologic differences between CD and ITB, the only exclusive features are caseation necrosis on biopsy, positive smear for acid-fast bacillus(AFB) and/or AFB culture, and necrotic lymph node on cross-sectional imaging in ITB. However,these exclusive features are limited by poor sensitivity, and this has led to the development of multiple multi-parametric predictive models. These models are also limited by complex formulae, small sample size and lack of validation across other populations. Several new parameters have come up including the latest Bayesian meta-analysis, enumeration of peripheral blood T-regulatory cells, and updated computed tomography based predictive score. However, therapeutic anti-tubercular therapy(ATT) trial, and subsequent clinical and endoscopic response to ATT is still required in a significant proportion of patients to establish the diagnosis. Therapeutic ATT trial is associated with a delay in the diagnosis of CD, and there is a need for better modalities for improved differentiation and reduction in the need for ATT trial.

Factors affecting recurrence after surgery for Crohn's disease

Although in Crohn's disease post-operative recurrence is common, the determinants of disease recurrence remain speculative. The aim of this study was to examine factors affecting post-operative recurrence of Crohn's disease. A Medline-based literature review was carried out. The following factors were investigated: age at onset of disease, sex, family history of Crohn's disease,smoking, duration of Crohn's disease before surgery,prophylactic medical treatment (corticosteroids, 5-amino salicylic acid [5-ASA] and immunosuppressants),anatomical site of involvement, indication for surgery (perforating or non-perforating disease), length of resected bowel, anast-omotic technique, presence of granuloma in the specimen, involvement of disease at the resection margin, blood transfusions and postoperative complications. Smoking significantly increases the risk of recurrence (risk is approximately twice as high), especially in women and heavy smokers. Quitting smoking reduces the post-operative recurrence rate. A number of studies have shown a higher risk when the duration of the disease before surgery was short. There were, however, different definitions of 'short' among the studies. Prophylactic cortic-osteroids therapy is not effective in reducing the post-operative recurrence. A number of randomized controlled trials offered evidence of the efficacy of 5-ASA (mesalazine) in reducing post-operative recurrence. Recently, the thera-peutic efficacy of immunosuppressive drugs (azathioprine and 6-mercaptopurine) in the prevention of post-operative recurrence has been investigated and several studies have reported that these drugs might help prevent the recurrence. Further clinical trials would be necessary to evaluate the prophylactic efficacy of immunosuppressants.Several studies showed a higher recurrence rate in patients with perforating disease than in those with non-perforating disease. However, evidence for differing recurrence rates in perforating and non-perforating diseases is inconclusive.A number of retrospective studies reported that a stapled functional end-to-end anastomosis was associated with a lower recurrence rate compared with other types of anastomosis. However, prospective randomized studies would be necessary to draw a definite conclusion. Many studies found no difference in the recurrence rates between patients with radical resection and non-radical resection. Therefore, minimal surgery including strictureplasty has been justified in the management of Crohn's disease. In this review, the following factors do not seem to be predictive of post-operative recurrence:age at onset of disease, sex, family history of Crohn's disease, anatomical site of disease, length of resected bowel, presence of granuloma in the specimen, blood transfusions and post-operative complications. The most significant factor affecting post-operative recurrence of Crohn's disease is smoking. Smoking significantly increases the risk of recurrence. A short disease duration before surgery seems, albeit to a very minor degree, to be associated with a higher recurrence rate. 5-ASA has been shown with some degree of confidence to lead to a lower recurrence rate. The prophylactic efficacy of immunosuppressive drugs should be assessed in future.A wider anastomotic technique after resection may reduce the post-operative recurrence rate, though this should be investigated with prospective randomized controlled trials.

Randomized controlled trial: Moxibustion and acupuncture for the treatment of Crohn's disease

AIM: To evaluate the clinical efficacy and safety of acupuncture and moxibustion for the treatment of active Crohn’s disease (CD).

Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: Phenotype-genotype correlations

AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD. METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP. RESULTS: NOD2/CARD15 mutations were found in 185 patients (35.1%) and in 33 controls (16.5%,P<0.0001). SNP8/R702W (10.8% vs 6%, P= 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P= 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vs controls: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet=1.71, 95%CI=1.12-2.6, P= 0.0001, ORtwo-risk alleles = 25.2, 95%CI =4.37- ,P<0.0001), early disease onset (carrier: 26.4 years vs non-carrier: 29.8 years, P=0.0006), ileal disease (81.9% (?) 69.5%, OR = 1.99, 95%CI = 1.29-3.08, P= 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs 64.8%), stricturing behavior (OR = 1.69,95%CI = 1.13-2.55, P= 0.026) and increased need for resection (OR=1.71, 95%CI: 1.13-2.62, P= 0.01), but not with duration, extra-intestinal manifestations, familial disease or smoking. TLR4 exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P = 0.06), in NOD2mut/wt: 26.7 years. CONCLUSION: These results confirm that variant NOD2/ CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4 mutation carriers tended to present at earlier age.

Response to strict and liberalized specific carbohydrate dietin pediatric Crohn's disease

AIM: To investigate the specific carbohydrate diet(SCD) as nutritional therapy for maintenance of remission in pediatric Crohn's disease(CD). METHODS: Retrospective chart review was conducted in 11 pediatric patients with CD who initiated the SCD as therapy at time of diagnosis or flare. Two groups defined as SCD simple(diet alone, antibiotics or 5-ASA) or SCD with immunomodulators(corticosteroids and/or stable thiopurine dosing) were followed for one year and compared on disease characteristics, laboratory values and anthropometrics.RESULTS: The mean age at start of the SCD was 11.8 ± 3.0 years(range 6.6-17.6 years) with five patients starting the SCD within 5 wk of diagnosis. Three patients maintained a strict SCD diet for the study period and the mean time for liberalization was 7.7 ± 4.0 mo(range 1-12) for the remaining patients. In both groups, hematocrit, albumin and ESR values improved while on strict SCD and appeared stable after liberalization(P-value 0.006, 0.002, 0.002 respectively). The majority of children gained in weight and height percentile while on strict SCD, with small loss in weight percentile documented with liberalization. CONCLUSION: Disease control may be attainable with the SCD in pediatric CD. Further studies are needed to assess adherence, impact on mucosal healing and growth.

Clinical significance of granuloma in Crohn's disease

AIM: Granuloma is considered the hallmark of microscopic diagnosis in Crohn's disease (CD), but granulomas can be detected in only 21-60% of CD patients. The aim of this study was to evaluate the frequency of granulomas by multiple endoscopic biopsies in patients with CD and to examine whether group of patients with or without granuloma exhibit a different clinical course. METHODS: Fifty-six patients with newly diagnosed CD were included in the study. Jejunoscopy, enteroclysis and ileo-colonoscopy were performed in all patients. At least two biopsy specimens from each examined gastrointestinal segment were examined microscopically searching granuloma. The clinical course was followed in all patients, and extraintestinal manifestations as well as details of any immunosuppressive therapy and surgical intervention were noted. RESULTS: Granuloma was found in 44.6% of the cases (25 patients). Patients with granuloma had higher activity parameters at the time of the biopsies. Extraintestinal manifestations were observed and surgical interventions were performed more often in the granuloma group. The need of immunosuppressive therapy was significantly more frequent in the patients with granuloma. Granuloma formation is mote often seen in younger patients, and mainly in the severe, active penetrating disease. CONCLUSION: The significantly higher frequency of surgical interventions and immunosuppressive therapy suggests that granuloma formation is associated with a more severe disease course during the first years of CD.

Circulating miR-125a but not miR-125b is decreased in active disease status and negatively correlates with disease severity as well as inflammatory cytokines in patients with Crohn's disease

AIM To determine the association of circulating mi R-125 a/b expression with the risk and disease severity of Crohn's disease(CD), and with inflammatory cytokines.METHODS Plasma samples were collected from patients with active CD(A-CD), or CD in remission(R-CD) and from healthy controls(HCs). The levels of the inflammatory cytokines interleukin-17(IL-17), tumour necrosis factor-α(TNF-α), and interferon-γ(IFN-γ) were measured by enzyme-linked immunosorbent assay. The expression of mi R-125 a/b was assessed by quantitative polymerase chain reaction(q PCR).RESULTS Twenty-nine A-CD patients, 37 R-CD patients, and 37 HCs were included in the study. Plasma mi R-125 a expression was decreased in A-CD patients comparedwith that in R-CD patients(P < 0.001) and HCs(P < 0.001). mi R-125 a expression levels enabled the differentiation of A-CD from R-CD patients [area under curve(AUC) = 0.854] and from HCs(AUC = 0.780), whereas mi R-125 b expression did not. mi R-125 a was negatively correlated with C-reaction protein(CRP)(P = 0.017), erythrocyte sedimentation rate(ESR)(P = 0.026), Crohn's disease activity index(CDAI)(P = 0.003), IL-17(P = 0.015), and TNF-α(P = 0.004) in A-CD patients. Furthermore, mi R-125 a was negatively associated with CRP(P = 0.038) and CDAI(P = 0.021) in R-CD patients. Regarding mi R-125 b, no association with CRP, CDAI, IL-17, TNF-α, or IFN-γ was found in A-CD or in R-CD patients. mi R-125 a levels gradually increased in A-CD patients who achieved clinical remission(P = 0.009) after 3-mo treatment, whereas they remained unchanged among patients who failed to achieve remission. No changes in mi R-125 b expression were detected in remission or non-remission patients after treatment. CONCLUSION Circulating mi R-125 a but not mi R-125 b is decreased in patients with active disease status and negatively correlates with disease severity and inflammatory cytokines in patients with CD.

Oral immune regulation using colitis extracted proteins for treatment of Crohn's disease: Results of a phase Ⅰ clinical trial

AIM: To evaluate safety and possible efficacy of induction of oral immune regulation using colitis extracted proteins (CEP) in Crohn's disease (CD) subjects. METHODS: Ten CDs were treated orally with autologous CEP thrice weekly for 16 wk. Subjects were monitored for CDAI and IBDQ. Immune modulatory effect was assessed by T-lymphocyte FACS analysis, CEP-specific IFNγ ELISPOT assay and cytokine levels. RESULTS: Induction of oral immune regulation significantly ameliorated disease activity. All (10/10) subjects had clinical response (CDAI≤70) and 7/10 achieved clinical remission (CDAI≤150). Significant increase in mean IBDQ score was noted (134±9 vs 164±12). No treatment-related adverse events were noted. High levels of CEP-specific IFNγ spot forming colonies were detected in five subjects prior to treatment and in all five, a marked decrease was observed. The CD4+/CD8+ lymphocyte ratio and peripheral NKT cell numbers increased significantly, in 7/10 and in 5/10 subjects, respectively. Significant increase in serum IL-10 and IL-4 levels was observed in 7/10 subjects during treatment period. CONCLUSION: Immune regulation via oral administration of CEP is a safe and possibly effective treatment for subjects with moderate CD and may provide means of antigen-specific immune modulation.

Ephrin-B2 is differentially expressed in the intestinal epithelium in Crohn's disease and contributes to accelerated epithelial wound healing in vitro

AIM:Eph receptor tyrosine kinases and their membrane bound receptor-like ligands, the ephrins, represent a bi-directional cell-cell contact signaling system that directs epithelial movements in development. The meaning of this system in the adult human gut is unknown. We investigated the Eph/ephrin mRNA expression in the intestinal epithelium of healthy controls and patients with inflammatory bowel disease (IBD). METHODS: mRNA expression profiles of all Eph/ephrin family members in normal small intestine and colon were established by real-time RT-PCR. In addition, differential expression in IBD was investigated by cDNA array technology, and validated by both real-time RT-PCR and immunohistochemistry. Potential effects of enhanced EphB/ephrin-B signaling were analyzed in an in vitro IEC-6 cell scratch wound model. RESULTS: Human adult intestinal mucosa exhibits a complex pattern of Eph receptors and ephrins. Beside the known prominent co-expression of EphA2 and ephrinAl, we found abundantly co-expressed EphB2 and ephrin-B1/2. Interestingly, cDNA array data, validated by real-time PCR and immunohistochemistry, showed upregulation of ephrin-B2 in both perilesional and lesional intestinal epithelial cells of IBD patients, suggesting a role in epithelial homeostasis. Stimulation of ephrin-B signaling in ephrin- B1/2 expressing rat IEC-6-cells with recombinant EphB1-Fc resulted in a significant dose-dependent acceleration of wound closure. Furthermore, fluorescence microscopy showed that EphB1-Fc induced coordinated migration of wound edge cells is associated with enhanced formation of lamellipodial protrusions into the wound, increased actin stress fiber assembly and production of laminin at the wound edge. CONCLUSION: EphB/ephrin-B signaling might represent a novel protective mechanism that promotes intestinal epithelial wound healing, with potential impact on epithelial restitution in IBD.

Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn's disease

AIM:To investigate the correlation between interleukin-18(IL-18) gene polymorphisms and the risk of developing Crohn's disease(CD).METHODS:The PubMed,CISCOM,CINAHL,Web of Science,EBSCO,Cochrane Library,MEDLINE,EMBASE and CBM databases were searched without any language restrictions using combinations of keywords relating to CD and IL-18 for relevant articles published before November 1st,2013.Screening of the published studies retrieved from searches was based on our stringent inclusion and exclusion criteria and resulted in seven eligible studies for meta-analysis.A metaanalysis was conducted using a random-effects model with STATA 12.0 software.Crude odds ratios(ORs) with95%confidence intervals(95%CI) were calculated.RESULTS:Seven case-control studies,with a total of1930 CD cases and 1930 healthy subjects,met our inclusion criteria.The results of our meta-analysis indicated that the IL-18 rs1946518 A>C and rs187238G>C polymorphisms may correlate with an increased risk of CD under five genetic models(all P < 0.05).Furthermore,we observed positive associations between the IL-18 rs360718 A>C polymorphism and CD risk under three genetic models(C allele vs A allele:OR = 2.03,95%CI:1.20-3.43,P = 0.008;CC vs AA+AC:OR = 2.39,95%CI:1.2-4.43,P = 0.006;CC vs AC:OR = 2.31,95%CI:1.22-4.38,P = 0.010).However,such associations were not found for the IL-18 rs917997 C>T,codon 35 A>C and rs1946519G>T polymorphisms(all P> 0.05).A subgroup analysis was conducted to investigate the effect of ethnicity on an individual's susceptibility to CD.Our results revealed positive correlations between IL-18 genetic polymorphisms and an increased risk of CD among Asians and Africans(all P < 0.05),but not among Caucasians(all P> 0.05).CONCLUSION:This meta-analysis indicated that the IL-18 rs1946518 A> C,rs187238 G>C and rs360718A>C polymorphisms may contribute to susceptibility to CD,especially among Asians and Africans.These polymorphisms are known to reduce IL-18 mRNA and protein levels.

Treatment of peri-anal fistula in Crohn's disease

Anal fistulas are a common manifestation of Crohn's disease(CD). The first manifestation of the disease is often in the peri-anal region, which can occur years before a diagnosis, particularly in CD affecting the colon and rectum. The treatment of peri-anal fistulas is difficult and always multidisciplinary. The European guidelines recommend combined surgical and medical treatment with biologic drugs to achieve best results. Several different surgical techniques are currently em-ployed. However, at the moment, none of these tech-niques appear superior to the others in terms of healing rate. Surgery is always indicated to treat symptomatic, simple, low intersphincteric fistulas refractory to medi-cal therapy and those causing disabling symptoms. Ut-most attention should be paid to correcting the balance between eradication of the fistula and the preservationof fecal continence.

Mycobacterium avium subspecies paratuberculosis causes Crohn's disease in some inflammatory bowel disease patients

Crohn’s disease(CD)is a chronic inflammatory condition that plagues millions all over the world.This debilitating bowel disease can start in early childhood and continue into late adulthood.Signs and symptoms are usually many and multiple tests are often required for the diagnosis and confirmation of this disease.However,little is still understood about the cause(s)of CD.As a result,several theories have been proposed over the years.One theory in particular is that Mycobacterium avium subspecies paratuberculosis(MAP)is intimately linked to the etiology of CD.This fastidious bacterium also known to cause Johne’s disease in cattle has infected the intestines of animals for years.It is believed that due to the thick,waxy cell wall of MAP it is able to survive the process of pasteurization as well as chemical processes seen in irrigation purification systems.Subsequently meat,dairy products and water serve as key vehicles in the transmission of MAP infection to humans(from farm to fork)who have a genetic predisposition,thus leading to the development of CD.The challenges faced in culturing this bacterium from CD are many.Examples include its extreme slow growth,lack of cell wall,low abundance,and its mycobactin dependency.In this review article,data from 60 studies showing the detection and isolation of MAP by PCR and culture techniques have been reviewed.Although this review may not be 100%comprehensive of all studies,clearly the majority of the studies overwhelmingly and definitively support the role of MAP in at least30%-50%of CD patients.It is very possible that lack of detection of MAP from some CD patients may be due to the absence of MAP role in these patients.The latter statement is conditional on utilization of methodology appropriate for detection of human MAP strains.Ultimately,stratification of CD and inflammatory bowel disease patients for the presence or absence of MAP is necessary for appropriate and effective treatment which may lead to a cure.

Treatment of Crohn's disease in pregnant women: Drug and multidisciplinary approaches

Inflammatory bowel disease affects a substantial number of women in their reproductive years. Pregnancy presents a number of challenges for clinicians and patients; the health of the baby needs to be balanced with the need to maintain remission in the mother. Historically, treatments for Crohn&#x02019;s disease (CD) were often discontinued during the pregnancy, or nursing period, due to concerns about teratogenicity. Fortunately, observational data has reported the relative safety of many agents used to treat CD, including 5-aminosalicylic acid, thiopurines, and tumor necrosis factor. Data on the long-term development outcomes of children exposed to these therapies in utero are still limited. It is most important that physicians educate the patient regarding the optimal time to conceive, discuss the possible risks, and together decide on the best management strategy.

Clinical literature review of 1858 Crohn's disease cases requiring surgery in China

AIM: To summarize the clinical characteristics of Crohn's disease(CD) patients who underwent surgery in China.METHODS: We searched four main Chinese electronic databases: CBM, VIP, CNKI, and Wanfang(from January1990 to October 2013). Then, we selected and carefully read 97 studies and extracted the surgical data for CD. We found that 1858 patients with CD underwent surgery between 1961 and 2012. The patients were stratified into two groups according to the year of surgery: 1961-2000 and 2000-2012. The clinical characteristics of these CD cases were compared between the two groups.RESULTS: The mean age at the time of surgery was 38.13 years. The most common locations of disease were the small intestine(40.84%), the colon(33.60%) and the ileocolon(23.09%). The primary indications for surgery were intestinal obstruction or stricture(23.84%), failure of drug therapy(14.80%), acute abdominal disease(13.46%), abdominal mass(10.93%), intestinal fistulae(9.90%), intestinal perforation(8.45%), perianal disease(6.73%), gastrointestinal bleeding(4.79%), and abdominal abscess(4.04%). The rate of diagnosis of CD before surgery was low(34.78%), and the misdiagnosis rate was 20.49%. The predominant surgical procedure for CD was bowel resection(69.54%). The rate of surgical complications was 20.34%, and the primary complications of surgery were infection(39.44%) and intestinal fistulae(26.09%). The relapse rate after surgery was 27.71%. For the periods of 1961-2000 and 2000-2013, the rates of both misdiagnosis before surgery and surgery related-death decreased(34.90% vs 12.10%, P < 0.001, and 23.53% vs 5.26%, P < 0.001, respectively). CONCLUSION: The rates of surgical complications and misdiagnosis were higher, whereas the rate of CDassociated tumor and the relapse rate were lower in China than in West countries.

Routine diagnosis of intestinal tuberculosis and Crohn's disease in Southern India

AIM:To investigate whether routinely measured clinical variables could aid in differentiating intestinal tuberculosis(ITB)from Crohn’s disease(CD).METHODS:ITB and CD patients were prospectively included at four South Indian medical centres from October 2009 to July 2012.Routine investigations included case history,physical examination,blood biochemistry,ileocolonoscopy and histopathological examination of biopsies.Patients were followed-up after 2 and 6 mo of treatment.The diagnosis of ITB or CD was re-evaluated after 2 mo of antituberculous chemotherapy or immune suppressive therapy respectively,based on improvement in signs,symptoms and laboratory variables.This study was considered to be an exploratory analysis.Clinical,endoscopic and histopathological features recorded at the time of inclusion were subject to univariate analyses.Disease variables with sufficient number of recordings and P<0.05 were entered into logistic regression models,adjusted for known confounders.Finally,we calculated the odds ratios with respective confidence intervals for variables associated with either ITB or CD.RESULTS:This study included 38 ITB and 37 CD patients.Overall,ITB patients had the lowest body mass index(19.6 vs 22.7,P=0.01)and more commonly reported weight loss(73%vs 38%,P<0.01),watery diarrhoea(64%vs 33%,P=0.01)and rural domicile(58%vs 35%,P<0.05).Endoscopy typically showed mucosal nodularity(17/31 vs 2/37,P<0.01)and histopathology more frequently showed granulomas(10/30vs 2/35,P<0.01).The CD patients more frequently reported malaise(87%vs 64%,P=0.03),nausea(84%vs 56%,P=0.01),pain in the right lower abdominal quadrant on examination(90%vs 54%,P<0.01)and urban domicile(65%vs 42%,P<0.05).In CD,endoscopy typically showed involvement of multiple intestinal segments(27/37 vs 9/31,P<0.01).Using logistic regression analysis we found weight loss and nodularity of the mucosa were independently associated with ITB,with adjusted odds ratios of 8.6(95%CI:2.1-35.6)and 18.9(95%CI:3.5-102.8)respectively.Right lower abdominal quadrant pain on examination and involvement of≥3 intestinal segments were independently associated with CD with adjusted odds ratios of 10.1(95%CI:2.0-51.3)and 5.9(95%CI:1.7-20.6),respectively.CONCLUSION:Weight loss and mucosal nodularity were associated with ITB.Abdominal pain and excessive intestinal involvement were associated with CD.ITB and CD were equally common.