Simplified Histologic Mucosal Healing Scheme (SHMHS) for inflammatory bowel disease: a nationwide multicenter study of performance and applicability.

BACKGROUND: Assessment of mucosal healing is important for the management of patients with inflammatory bowel disease (IBD), but endoscopy can miss microscopic disease areas that may relapse. Histological assessment is informative, but no single scoring system is widely adopted. We previously proposed an eight-item histological scheme for the easy, fast reporting of disease activity in the intestine. The aim of the present study was to evaluate the performance of our Simplified Histologic Mucosal Healing Scheme (SHMHS). METHODS: Between April and May 2021 pathologists and gastroenterologists in Italy were invited to contribute to this multicenter study by providing data on single endoscopic-histological examinations for their IBD patients undergoing treatment. Disease activity was expressed using SHMHS (maximum score, 8) and either Simple Endoscopic Score for Crohn's Disease (categorized into grades 0-3) or Mayo Endoscopic Subscore (range 0-3). RESULTS: Thirty hospitals provided data on 597 patients (291 Crohn's disease; 306 ulcerative colitis). The mean SHMHS score was 2.96 (SD = 2.42) and 66.8% of cases had active disease (score ≥ 2). The mean endoscopic score was 1.23 (SD = 1.05), with 67.8% having active disease (score ≥ 1). Histologic and endoscopic scores correlated (Spearman's ρ = 0.76), and scores for individual SHMHS items associated directly with endoscopic scores (chi-square p < 0.001, all comparisons). Between IBD types, scores for SHMHS items reflected differences in presentation, with cryptitis more common and erosions/ulcerations less common in Crohn's disease, and the distal colon more affected in ulcerative colitis. CONCLUSIONS: SHMHS captures the main histological features of IBD. Routine adoption may simplify pathologist workload while ensuring accurate reporting for clinical decision making.

Diagnostic interobserver variability in Crohn's disease- and ulcerative colitis-associated dysplasia: a multicenter digital survey from the IG-IBD Pathologists Group.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis, two forms of inflammatory bowel disease (IBD), are chronic and relapsing conditions of the gastrointestinal tract both characterized by long lasting chronic inflammation and increased risk of dysplasia and colorectal cancer (CRC). The aim of our study was to evaluate the interobserver agreement about IBD-associated dysplasia among pathologists belonging to the Italian Group for Inflammatory Bowel Diseases (IG-IBD P). METHODS: The present multicenter survey was performed using telepathology, supported by an open source E-learning platform. Biopsy specimens from 30 colonoscopies and from 20 patients were included. The glass slides of any case, including clinical and endoscopic data, were digitalized and uploaded on the E-learning platform. All the digital slides were grouped in 54 diagnostic "blocks". Blinded histopathological evaluation on all the digital slides was performed by 20 gastrointestinal pathologists. Closed-ended questions about (1) the occurrence of IBD; (2) the classification of IBD (as UC or CD); (3) the presence of active versus quiescent disease; (4) the presence of dysplasia; (5) the possible association of dysplasia with the sites of disease (dysplasia-associated lesion or mass-DALM vs adenoma-like mass-ALM); (6) the grading of dysplasia according to the ECCO guidelines (negative, indefinite, low grade, high grade categories) and (7) the presence of associated serrated features, were proposed in each case. Inter-observer agreement was evaluated by mean agreement percentage and kappa statistic, when suitable. RESULTS: The diagnosis of IBD was confirmed in 19 of 20 patients, 17 of 19 being classified as UC, 2 as CD. The mean interobserver agreement percentages about (1) the evidence of IBD, (2) the presence of either UC or CD and (3) the activity grading resulted to be 80%, 69% and 86%, respectively. Dysplasia was detected in 8/20 patients, with moderate agreement between pathologists (mean 72%, k 0.48). Particularly, low grade dysplasia was found in 13 biopsies (combined k 0.38), whereas high grade dysplasia in 8 (combined k 0.47). When the endoscopic and histopathological data were combined, features consistent with DALM were found in 6 of 20 patients with low grade dysplasia and those consistent with ALM in 2 patients with low grade dysplasia in a single biopsy (mean agreement: 86%). An associated serrated pattern was discovered in 4 patients (7 biopsies). CONCLUSIONS: Our study showed moderate interobserver agreement about the histopathological detection and classification of IBD-associated dysplasia. Further efforts should be undertaken to integrate the histopathological data with both the ancillary tests and molecular investigations.

Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up.

BACKGROUND: Severe ulcerative colitis is a life-threatening disorder, despite i.v. glucocorticoids treatment. Infliximab has been proposed as a safe rescue therapy. AIM: To evaluate short- and long-term effectiveness and safety of infliximab in severe refractory ulcerative colitis. METHODS: Eighty-three patients with severe ulcerative colitis (i.v. glucocorticoids treatment-refractory) were treated with infliximab in 10 Italian Gastroenterology Units. Patients underwent one or more infusions according to the choice of treating physicians. Short-term outcome was colectomy/death 2 months after the first infusion. Long-term outcome was survival free from colectomy. Safety data were recorded. RESULTS: Twelve patients (15%) underwent colectomy within 2 months. One died of Legionella pneumophila infection 12 days after infliximab. Early colectomy rates were higher in patients receiving one infusion (9/26), compared with those receiving two/more infusions (3/57, P = 0.001, OR = 9.53). Seventy patients who survived colectomy and did not experience any fatal complications were followed-up for a median time of 23 months; 58 patients avoided colectomy during the follow-up. Forty-two patients were maintained on immunosuppressive drugs. No clinical features were associated with outcomes. CONCLUSIONS: Infliximab is an effective and relatively safe therapy to avoid colectomy and maintain long-term remission for patients with severe refractory ulcerative colitis. In the short term, two or more infusions seem to be more effective than one single infusion.

Endoscopic ultrasound-fine needle aspiration (EUS-FNA) for pancreatic lesions: effectiveness in clinical practice.

BACKGROUND: Diagnosis of pancreatic masses is often difficult. Endoscopic ultrasound-fine needle aspiration has been proposed as the best single-step strategy. AIMS: To prospectively evaluate feasibility, effectiveness and safety of endoscopic ultrasound-fine needle aspiration of pancreatic masses in a consecutive study of unselected patients. METHODS: Two hundred ninety-three patients were enrolled in two referral Hospitals in Northern Italy. All patients were referred either due to the presence of imaging test abnormalities (suspected or evident masses, or features indirectly suggesting the presence of a mass) or due to clinical or biochemical findings suggesting pancreatic cancer in the absence of positive imaging. All patients underwent linear array endoscopic ultrasound and, when indicated, fine needle aspiration. All procedures were recorded prospectively. The final diagnosis was established at the end of follow-up or when the patients underwent surgery or died. RESULTS: Fine needle aspiration was indicated in 246 of 293 cases (84%), considered technically feasible in 232 of 246 cases (94%) and gave adequate samples for histopathological diagnosis in 204 of 232 cases (88%). Endoscopic ultrasound sensitivity, specificity and accuracy were 79, 60 and 72%, respectively; the corresponding figures for endoscopic ultrasound-fine needle aspiration were 80, 86 and 82%. There was good agreement with final diagnosis for endoscopic ultrasound-fine needle aspiration (kappa 0.673, 95%CI 0.592-0.753), greater than that for endoscopic ultrasound alone (kappa 0.515, 95%CI 0.425-0.605). There was one case of intracystic haemorrhage and one case of transient hyperthermia (0.3%). CONCLUSIONS: Endoscopic ultrasound-fine needle aspiration of pancreatic masses seems to be feasible, effective and safe in this consecutive study of patients.

[Endoscopic ultrasound-fine needle aspiration (EUS-FNA) for pancreatic lesions: effectiveness in clinical practice]. / Agoaspirato con ago sottile sotto guida ecoendoscopica nelle lesioni pancreatiche: efficacia nella pratica clinica.

UNLABELLED: Endoscopic ultrasound-fine needle aspiration (EUS-FNA) was shown to be a highly reliable and a very effective diagnostic technique, both based on data from clinical trials and from large clinical practice studies. EUS-FNA results are reported to be in good-to-very good agreement with the final diagnosis, and the agreement significantly exceeded the chance agreement. The overall sensitivity and specificity of EUS and of EUS-FNA are very good. EUS-FNA is an effective diagnostic technique for the evaluation of pancreatic lesions, either reported with other imaging tests or suspected on the basis of clinical and biochemical features. EUS-FNA may be performed in most cases, and the results of EUS-FNA are particularly important for their excellent positive predictive value. Nonetheless, in a few cases EUS-FNA can not be feasible, or can give false negative or inconclusive RESULTS: The main practical consequence is that before referring patients to surgeons or oncologists, EUS-FNA should be considered as the best diagnostic strategy, since tissue is still the issue' . In a prospective two-centers consecutive series from Italy, FNA did not give any false positive diagnoses of malignancy, and reduced the number of indeterminate diagnoses; moreover, FNA significantly increased the specificity of diagnosis, while sensitivity was unchanged.

The hazardous burden of Herpesviridae in inflammatory bowel disease: the case of refractory severe ulcerative colitis.

BACKGROUND: Herpesviridae infection or spread may be a hazard in immunodepressed patients. In the field of inflammatory bowel disease, refractory severe ulcerative colitis is a challenging condition, closely associated to immunosuppression both for inanition due to the disease activity and for immunosuppressive treatments. Cytomegalovirus (CMV) has been proposed as a major cause of refractoriness, while other Herpesviridae may be a risk factor in the long-term follow-up. AIM OF THE STUDY: To evaluate the positivity rates of CMV, Epstein-Barr (EBV) and Human herpes virus-8 (HHV8) in a consecutive group of ulcerative colitis patients who underwent colectomy for refractoriness to medical treatment compared to a control group, using state of the art methods. PATIENTS AND METHODS: Colonic specimens from 24 consecutive patients with ulcerative colitis submitted to colectomy for refractoriness and from 20 controls (submitted to colectomy for colorectal cancer) were studied. Standard histology and immunohistochemistry (IHC) for CMV and specific polymerase chain-reaction (PCR) for CMV, EBV and HHV8 were carried out. RESULTS: Regarding CMV, 1 case (4%) was positive at histology and IHC, whereas 3 cases (13%) were positive at PCR, compared to none in the control group (p=0.239). For EBV 2 cases (8%) and 2 controls (10%) were positive at PCR. None of the cases or of controls was positive for HHV8. The only clinical characteristic independently associated to CMV positivity was the white blood cell count at admission, higher among CMV positive patients (p<0.001). At the end of the post-surgery follow-up (median 7.3 years) none of the CMV positive cases experienced pouchitis, compared to 3/21 (14%) of the CMV negative cases (p=1.000). DISCUSSION: Our data suggest that CMV is uncommon (13%), even though PCR techniques, considered to be the most sensitive tools, were used for virus detection and the study population is made by highly selected patients with definite refractoriness. EBV and HHV8 may represent a theoretical risk of immunosuppressive therapy because of their potential role as cancer triggers; however in our study, results seem to be reassuring that UC patients undergoing immunosuppressive therapy are not exposed to an excessive risk of viral infection.

Therapeutic ERCP in paediatric patients.

BACKGROUND: Major limitations of endoscopic retrograde cholangiopancreatography in paediatric populations are a low incidence of biliopancreatic disease among children, the equipment dimensions (size of endoscopes and devices) and the increasing role of MR-cholangiopancreatography in the field of diagnostic indications. Aim of this study was to evaluate the diagnostic and therapeutic yields of endoscopic retrograde cholangiopancreatography for biliopancreatic diseases in a paediatric population. METHODS: Between 1996 and 2002, 48 endoscopic retrograde cholangiopancreatographies were performed in 38 children aged 4 weeks to 17 years as part of the diagnostic evaluation for suspected pancreatic or biliary tract disease. Endoscopic retrograde cholangiopancreatography was carried out under general anaesthesia, using prototype paediatric duodenoscopes or standard duodenoscopes in children younger or older than 18 months, respectively. RESULTS: The indications to perform endoscopic retrograde cholangiopancreatography were common bile duct stones (14 children), biliopancreatic abnormalities (8), primary sclerosing cholangitis (2), Wirsung disruption (1), biliary leakage (1), cholestasis (4) and pancreatitis (8). Cannulation was successful in all patients but one. Sphincterotomy together with stone extraction or stent insertion was performed in 30/38 patients. Immediate complications were mild and treated conservatively. CONCLUSIONS: Diagnostic and therapeutic endoscopic retrograde cholangiopancreatography can be used safely and effectively in the management of biliopancreatic diseases in childhood as well. Indications, endoscopic techniques and complications are similar to those reported for adult patients.

Review article: medical treatment of severe ulcerative colitis.

Approximately 15% of patients with ulcerative colitis have a severe attack requiring hospitalization at some time during their illness. This treatment leads to a remission in 60-80% of patients and non-responders may require a total colectomy. Mortality in severe episodes of ulcerative colitis decreased from 31-61% in the 1950s to 5-9% in the 1960s thanks to the introduction of steroids and to a policy of early colectomy. Recently, some new drugs have been shown to be effective in the treatment of severe steroid-refractory ulcerative colitis. This review concentrates on the clinical evaluation, prognostic factors and new developments in medical therapy in severe ulcerative colitis. A retrospective evaluation of a consecutive series of patients with severe ulcerative colitis admitted to a Gastroenterology Department in Torino, Italy, is also reported.

Review article: Crohn's disease: monitoring disease activity.

A global measurement of Crohn's disease activity, comprising clinical, endoscopic, biochemical and pathological features is not available yet and perhaps is unobtainable. In this review we analyse the most used and validated clinical indices (Crohn's Disease Activity Index [CDAI], Perianal Disease Activity Index [PDAI], fistula drainage assessment), quality of life scores (Inflammatory Bowel Disease Questionnaire [IBDQ]), sub-clinical markers (C-reactive protein, faecal calprotectin, intestinal permeability) and endoscopic indices (Crohn's Disease Endoscopic Index of Severity [CDEIS]/Simple Endoscopic Score for Crohn's Disease [SES-CD], Rutgeeerts' score for postsurgical recurrence). We also review the main advantages and disadvantages of each of these scoring systems. All these indices are rather complex and time-consuming, therefore their use is limited to clinical trials. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision-making.

Anti-tumour necrosis factor alpha (infliximab) in the treatment of severe ulcerative colitis: result of an open study on 13 patients.

BACKGROUND: Conventional treatment options for patients with severe steroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently burdened by toxicity, or colectomy. Preliminary data suggest a benefit from anti-tumour necrosis factor alpha (Infliximab) therapy in patients with steroid refractory ulcerative colitis. AIM: To evaluate the efficacy of Infliximab in the treatment of severe ulcerative colitis refractory to conventional therapy PATIENTS AND METHODS: A series of 13 patients with severe ulcerative colitis, refractory to therapy with methyl-prednisolone, 60 mg daily for seven or more days, were treated with a single intravenous infusion of Infliximab 5 mg/kg. RESULTS AND CONCLUSIONS: Of these 13 patients, 10 (77%) had a clinical response to therapy defined by a clinical activity index 10 on two consecutive days. In 2 patients (15%) total colectomy was necessary on account of clinical worsening whilst one patient refused surgery and was lost to follow-up. All patients who responded showed very rapid clinical improvement, within 2 to 3 days of infusion. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 10.1 months (range 5-12; during this time, 9 out of 10 patients (90%) maintained clinical remission and were able to discontinue corticosteroid therapy. Infliximab appears to be an effective agent for inducing long-standing remission in refractory patients with severe ulcerative colitis.

Outcome of a conservative approach in severe ulcerative colitis.

BACKGROUND: Severe ulcerative colitis is potentially life threatening even though a policy of intensive medical management and early colectomy in recent years reduced mortality to almost zero. However, colectomy, with or without ileal-anal anastomosis, has its own problems (morbidity, pouchitis, cuffitis) and no reliable prognostic index of surgical outcome has been developed. Intravenous steroids are still the mainstay of medical therapy but their maximal duration before stating a 'treatment failure' has not been defined. AIM OF THE STUDY: To evaluate the effectiveness, safety and outcome of an intensive medical approach in a series of patients with severe ulcerative colitis. PATIENTS AND METHODS: One hundred and forty-nine episodes of severe ulcerative colitis in 115 patients admitted to a Gastroenterology Unit in a 7-year period were retrospectively evaluated. Intravenous glucocorticosteroids--methylprednisolone 1 mg/kg/day--and topical steroids were administered, and supportive treatments with intensive monitoring were extended to all the patients. Second-line strategies for steroid-refractoriness were prolonged glucocorticosteroids treatment, oral ciclosporin, infliximab or surgery. RESULTS: The median number of Truelove criteria at admission was 3 (range 2-5), median CRP 34 mg/l (range 10-196). Median follow-up after discharge was 49 months. In 84 (57%) episodes an early response was noted, while 65 (43%) did not respond within 10 days to the standard steroid treatment. In the non-responders group, 28 patients went into remission with a prolonged steroid treatment (slow responders); 15 patients were treated with ciclosporin (eight responders) and 6 with infliximab (four responders). A total of 24 colectomies was performed in this group of patients (in 21 cases within 30 days from admission). Slow responders showed lower albumin levels (P = 0.02), higher cumulative dose of glucocorticosteroids in the year prior to admission (P = 0.02) and higher age (P = 0.03), in comparison with early responders. Major complications were noted in four episodes which responded to medical treatment. Disease-related mortality was zero. CONCLUSIONS: Medical treatment and use of second-line therapies were effective in the present series of patients. A group of slow responders has been identified and, if an intensive medical monitoring is guaranteed, steroids can be safely prolonged after the first 10 days of treatment. Cumulatively, about 80% of the patients responded to short-term medical treatment, only 5% of the patients underwent colectomy in the follow-up period. Major adverse events were recorded in four patients, who had recovered completely after adequate medical treatment.

Detection of anti-Saccharomyces cerevisiae antibodies in Crohn's disease: is it a reliable diagnostic and prognostic marker?

BACKGROUND: In the past few years, serologic markers have been proposed in inflammatory bowel disease. Anti-Saccharomyces cerevisiae antibodies showed high specificity for Crohn's disease. A prognostic role for serology has also been hypothesised. AIMS: To evaluate anti-Saccharomyces cerevisiae antibody distribution in an unselected Italian inflammatory bowel disease population. To analyse whether anti-Saccharomyces cerevisiae antibody status (positive/negative) and/or anti-Saccharomyces cerevisiae antibody titres are associated with clinical variables and outcome measures in Crohn's disease patients. PATIENTS AND METHODS: A series of 299 inflammatory bowel disease patients were evaluated; serum samples were taken and a short clinical history was recorded. anti-Saccharomyces cerevisiae antibodies IgG enzyme-linked immunosorbent assay Medilab (Milan, Italy) kit was used in order to determine anti-Saccharomyces cerevisiae antibody status. RESULTS: Sensitivity, specificity and likelihood ratio for positive test in the differential diagnosis of inflammatory bowel disease was 59%, 89%, 8.1, respectively. Clinical variables significantly associated with anti-Saccharomyces cerevisiae antibody status in logistic regression were found to be ileal location (p=0.01) and earlier age at diagnosis (p<0.01). Among ileal Crohn's disease patients, there was a trend in concordance between anti-Saccharomyces cerevisiae antibody titres and higher number of surgical procedures which was not statistically significant applying more complex statistics. CONCLUSIONS: In an Italian inflammatory bowel disease population, anti-Saccharomyces cerevisiae antibodies status showed characteristics similar to those previously reported. Anti-Saccharomyces cerevisiae antibody positivity is associated with ileal involvement and with earlier onset of Crohn's disease.

The role of endoscopy in inflammatory bowel disease.

Endoscopy is an essential tool for diagnosis, management and prognostic evaluation of inflammatory bowel disease. However dyscomfort, potential risks and costs associated to endoscopic examinations should contribute to the narrowing of indications to those cases in which the result of endoscopy is essential to determine a variation in the management strategy. Ileocolonoscopy performed by an expert endoscopist allows accurate diagnosis of Crohn's disease or ulcerative colitis in up to almost 90% of cases. Colonoscopy has a prognostic role during a severe flare of disease (the occurrence of severe endoscopic lesions have a negative prognostic value with significantly higher risk not to respond to medical treatment) both in ulcerative colitis and in Crohn's disease; moreover in Crohn's disease the evaluation of recurrent lesions at anastomosis after curative surgery has a strong prognostic role (endoscopic recurrence closely correlates with clinical/surgical recurrence) and preliminary data suggest that mucosal healing assessed with endoscopy after biologic treatments could be associated with a better prognosis. Finally colonoscopy is essential for cancer surveillance during the long-term follow-up. Furthermore there are new endoscopic techniques under evaluation in inflammatory bowel disease, like wireless capsule endoscopy or double balloon enteroscopy for the imaging of small bowel, or endoscopic ultrasound for evaluation of strictures or of perianal disease. Finally some operative techniques like balloon dilation could possibly be employed more frequently in the future in the management of Crohn's disease. Future perspectives in endoscopy for IBD are chromoendoscopy and newer endoscopic imaging techniques, possibly leading to an "in-vivo histology".

Infliximab in the treatment of severe ulcerative colitis: a follow-up study.

Conventional treatment options for patients with severe steroid-refractory ulcerative colitis (UC) include intravenous cyclosporine, which is frequently burdened by toxicity, or colectomy. Preliminary data suggest a benefit of anti-tumor necrosis factor alpha (Infliximab) therapy in patients with steroid refractory UC. Thirteen patients with severe UC, refractory to therapy with methyl-prednisolone, 60 mg IV daily were treated with a single intravenous infusion of Infliximab 5 mg/kg. Ten out of 13 patients (77%) had a clinical response to therapy defined by a CAI < or = 10 on two consecutive days. Two patients (15%) underwent total colectomy because of clinical worsening; one patient refused surgery and was lost to follow-up. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 25.6 months (range 17-24); in this period of time 8 out of 10 patients (80%) maintained clinical remission and were able to discontinue corticosteroids therapy. Infliximab appears to be an effective agent for inducing long standing remission in refractory patients with severe UC.

Prospective study of the effects of concomitant medications on thiopurine metabolism in inflammatory bowel disease.

BACKGROUND: Thiopurines are increasingly used in the treatment of inflammatory bowel disease (IBD), being the most common immunosuppressive therapy; however, potentially harmful interactions between thiopurines and other drugs (especially 5-aminosalicylic acid, 5-ASA) were described. AIM: To explore potential interactions between thiopurines and concomitant medications. METHODS: A total of 183 consecutive IBD patients were enrolled. Clinical characteristics and concomitant medications were recorded. Thiopurine metabolism was analysed with thiopurine S-methyl transferase (TPMT) genetic variants and enzyme activity assays. Comparisons were carried out with stratification of patients according to clinical characteristics and active treatments. RESULTS: Based on TPMT genetics, 95% IBD patients were wild-type homozygous, the remaining being heterozygous. Median TPMT activity was 24.9 U/Hgb g (IQR 20.7-29.5). No difference in TPMT activity was noted according to 5-ASA exposure. IBD patients on thiopurines had higher TPMT activity levels, but no dose-effect was evident. No difference in TPMT activity was observed in 41 (63%) patients co-treated with 5-ASA. In patients on active thiopurines also, 6-TGN and 6-MMP levels were evaluated and no significant difference was observed based on co-medication. TPMT activity was independently associated only with thiopurines dose (P = 0.016). CONCLUSIONS: Our data suggest the absence of significant interactions between thiopurines and 5-ASA.

The role of endoscopic assessment in ulcerative colitis in the era of infliximab.

Endoscopic evaluation of mucosal appearance is important for the clinical management of ulcerative colitis patients, as it offers valuable prognostic tools and data useful to change the management and treatment strategies. In the field of severe ulcerative colitis, partial endoscopy and bioptic sampling allows to obtain additional and relevant prognostic information: if severe endoscopic lesions are present, response to standard treatment is less likely, and if CMV superinfection is detected, anti-viral treatment should be added to conventional treatments. When clinical remission is obtained with conventional treatments, distal colonoscopy may add valuable data: the occurrence of complete endoscopic healing is a major predictor of long-term remission with no clinical activity. Finally, biologic treatments, and mainly infliximab, were shown to induce remarkable and significant mucosal healing also in ulcerative colitis, and patients with complete endoscopic healing in response to infliximab were shown to be more likely to experience fewer clinical relapses during the follow-up. Therefore endoscopic evaluation has to be considered a major prognostic marker in ulcerative colitis. In this review data from the Literature supporting this role will be reviewed.

Genotype-phenotype relationship in inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic diseases of unknown etiology. Much effort has been made in the last years to clarify the pathogenesis of inflammatory bowel disease (IBD). Data are not conclusive at the moment, but the most important known risk factor for developing IBD is a positive familial history. Genetic analyses have shown a linkage between loci on several chromosomes and IBD (IBD1 gene on chromosome 16 for CD and on chromosome 12 for UC). The association of genotype to specific phenotypes of disease could be hypothesized by the concordance of clinical characteristics in familial IBD, by the association of specific HLA haplotypes to clinically different groups of patients, and by different responses to treatment related to different polymorphisms of other chromosome 6 genes. The clinical heterogeneity of IBD has led to classifications of patients with Crohn's disease based upon clinical features (e.g. Rome and Vienna classifications) that allow the identification of subgroups of patients with similar clinical behavior. The possible drawbacks of these classifications are the lack of validation of intra-interobserver concordance, the absence of prospective evaluations, and stratification into too many subgroups. Furthermore, in our experience, clinical presentation (surgical or medical) seems to have a good correlation with prognosis, is easy identifiable, and can be applied at the time of diagnosis. In UC, extension of disease and clinical behavior correlate with prognosis. For these reasons, studies correlating genotype to phenotype should be performed to improve our knowledge of the diseases and possibly to stratify patients into different subgroups for more personalized treatments, in clinical trials and for research purposes.