What＇s new in inflammatory bowel disease in 2008？

Ulcerative colitis and Crohn＇s disease represent the two major forms of inflammatory bowel disease. In this highlight topic series of articles we cover the latest developments in genetics and epidemiology, intestinal physiology, mucosal immunology, mechanisms of epithelial cell injury and restitution, current medical therapy, modern surgical management, important extra- intestinal complications such as primary sclerosing cholangitis, cholangiocellular carcinoma and autoimmune hepatitis as well as endoscopic and molecular screening, detection and prevention of small bowel and colorectal cancer.     

Treatment of inflammatory bowel disease： A review of medical therapy

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor （TNF） alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine （6-MP） and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn＇s disease, and infliximab is also approved for the treatment of UC.     

IBD5 polymorphisms in inflammatory bowel disease： Association with response to infliximab

AIM: Inflammatory bowel diseases (IBD) are multifactorial pathologies of unknown etiology. One susceptibility locus, IBD5, has been mapped to chromosome 5q31. We analyzed our Spanish cohorts of Crohn's disease (CD) and ulcerative colitis (DC) patients to determine whether this locus is associated with IBD, and to ascertain the main clinical phenotype influenced by this risk factor. The kind of interaction, either genetic heterogeneity or epistasis, between this IBD5 susceptibility region and the NOD2/CARD15 gene mutations was studied as well. Finally, we assessed whether this locus can predict response to infliximab therapy. METHODS: A case control study was performed with 274 CD and 211 UC patients recruited from a single center and 511 healthy ethnically matched controls. Two polymorphisms were genotyped in the IBD5 locus and three in the CARD15/NOD2 gene. RESULTS: Our results evidence association only with CD especially with the fistulizing phenotype and in the absence of NOD2/CARD15 variants (mutant allele frequency in patients vs controls: OR = 2.03, 95% CI = 1.35-3.06, P<0.01). The frequency of the IBD5 homozygous mutant genotype significantly increased in CD patients lacking response to infliximab (RR = 3.88, 95% CI = 1.18-12.0, P<0.05). UC patients overall do not show association with 5q31 polymorphisms, although a similar trend to the one observed in CD is found within the worse prognosis group. CONCLUSION: The IBD5 variants may enhance an individual carrier's risk for CD, mainly in the absence of the NOD2/CARD15 mutations and in fistulizing patients. The data presented suggest the potential role of the 5q31 polymorphisms as markers of response to infliximab.     

Striking elevation in incidence and prevalence of inflammatory bowel disease in a province of western Hungary between 1977-2001

AIM:An investigation into inflammatory bowel disease andcolorectal cancer in Veszprem Province was conducted from1977 to 2001,METHODS:Both hospital and outpatient records werecollected and reviewed comprehensively.The majority ofpatients were followed up regularly.RESULTS:The population of the province was decreasedfrom 386 000 to 376 000 during the period.Five hundredsixty new cases of ulcerative colitis (UC),212 of Crohn'sdisease (CD),and 40 of indeterminate colitis (IC) werediagnosed.The incidence rates increased from 1.66 to 11.01cases per 100 000 persons for UC,from 0.41 to 4.68 for CDand from 0.26 to 0.74 for IC.The prevalence rate at the endof 2001 was 142.6 for UC and 52.9 cases per 100 000 personsfor CD.The peak onset age in UC patients was between 30and 40 years,in CD between 20 and 30 years.A familyhistory of IBD was present in 3.4% in UC and 9.9% in CDpatients.Smoking increased the risk for CD (OR=1.94) whileit decreased the risk for UC (OR=0.25).Twelve colorectalcarcinomas were observed in this cohort,the cumulativecolorectal cancer risk after 10 years in UC was 2%,after20 years 8.8%,after 30 years 13.3%.CONCLUSION:The incidence and prevalence rates of IBDhave increased steadily in Veszprem Province,now equivalentto that in Western European countries.Rapid increase inincidence rates supports a probable role for environmentalfactors.The rate of colorectal cancers in IBD is similar tothat observed in Western countries.     

Are there any differences in phenotype or disease course between familial and sporadic cases of inflammatory bowel disease? Results of a population-based follow-up study

BACKGROUND: The influence of familial IBD on phenotype and course of disease in patients with CD and UC has not been studied in population-based cohorts. AIM: To compare phenotype and course of disease between IBD patients with a first-degree relative with IBD and sporadic cases in a population-based cohort followed prospectively for 5 yr. METHODS: Family history of IBD was registered at diagnosis and after 1 and 5 yr. Phenotype and course of disease were compared between sporadic and familial cases. RESULTS: Data for 200 patients with CD and 454 with UC were sufficient for analysis. A first-degree relative with IBD was registered in 14.5% of CD patients and 10.1% of UC patients. The concordance for type of disease was 82% and 70% for CD and UC, respectively. No differences between familial and sporadic cases as regards localization and behavior of disease in CD patients or disease extent in UC patients were observed. In CD patients with colonic involvement, those in the familial group were significantly younger at diagnosis than the sporadic cases. No difference in disease severity in CD patients was observed between the familial and sporadic groups. In UC patients relapse was more frequent in familial cases, but no difference was observed in the need for surgery or medical treatment. CONCLUSIONS: A family history of IBD does not seem to influence phenotype or to be an important prognostic factor for disease course in IBD patients.     

Maintenance of remission with infliximab in inflammatory bowel disease： Efficacy and safety long-term follow-up

AIM To evaluate the safety and efficacy of a longterm therapy with infliximab in Crohn's disease (CD) and ulcerative colitis (UC) patients retrospectively.METHODS The medical charts of 50 patients (40 CD and 10 UC), who received after a loading dose of 3 infliximab infusions scheduled re-treatments every 8 wk as a maintenance protocol, were reviewed.RESULTS Median (range) duration of treatment was 27 (4-64) mo in CD patients and 24.5 (6-46) mo in UC patients. Overall, 32 (80%) CD and 9 (90%) UC patients showed a sustained clinical response or remission throughout the maintenance period. Three CD patients shortened the interval between infusions. Eight (20%) CD patients and 1 UC patient underwent surgery for flare up of disease. Nine out of 29 CD and 4 out of 9 UC patients, who discontinued infliximab scheduled treatment, are still relapse-free after a median of 16 (5-30) and 6.5 (4-16) mo following the last infusion,respectively. Ten CD patients (25%) and 1 UC patient required concomitant steroid therapy during maintenance period, compared to 30 (75%) and 9 (90%) patients at enrolment. Of the 50 patients, 16 (32%) experienced at least 1 adverse event and 3 patients (6%) were diagnosed with cancer during maintenance treatment.CONCLUSION Scheduled infliximab strategy is effective in maintaining long-term clinical remission both in CD and UC and determines a marked steroid sparing effect.Long-lasting remission was observed following infliximab withdrawal.     

Crohn’s disease incidence evolution in North-western Greece is not associated with alteration of NOD2/CARD15 variants

AIM To assess the trends in the incidence of inflammatory bowel disease (IBD) over 23 years in the same area and to identify genetic factors related to incidence evolution.METHODS Patients with IBD arising from Northwestern Greece were systematically recorded through the 1983-2005 period. Trends in disease incidence and genetic patterns related to CARD15 variants were documented and correlated.RESULTS A total of 447 patients with IBD were recorded (23.5% Crohn's disease, 72.7% Ulcerative colitis and 3.8% indeterminate colitis). Mean annual incidence rates of CD and UC were 0.9/100000 (95% CI 0.1-1.7) and 2.7/100000 (95% CI 1.7-4.1) inhabitants,respectively. There was a statistically significant increase of CD incidence (P ＜ 0.01) during the study period, in contrast to the UC incidence. There were no statistical differences in CARD15 variants over the study period.CONCLUSION The incidence of CD in North-western Greece has risen disproportionately to that of UC in the 21st century. This is not related to alterations of genetic background though.     

Microproteinuria in patients with inflammatory bowel disease： Is it associated with the disease activity or the treatment with 5-aminosalicylic acid？

AIM: To investigate whether microproteinuria in patients with inflammatory bowel disease (IBD) is associated with the disease activity or the treatment with 5-aminosalicylic acid (5-ASA). METHODS: We prospectively studied microproteinuria in 86 consecutive patients with IBD, 61 with ulcerative colitis (UC) and 25 with Crohn's disease (CD), before as well as 2 and 6 months after their inclusion in the study. Forty-six patients received 5-ASA for a period of 28.8 months (range 1-168 mo). Microalbuminuria (mALB) and urine levels of the renal tubular proteins beta2-microglobulin (beta2mGLB) and beta-N-acetyl-D-glucosamidase (beta-NAG) as well as the creatinine clearance were determined in a 12-h overnight urine collection. Tumor necrosis factor-alpha (TNF-alpha) serum levels were also measured. RESULTS: A total of 277 measurements (194 in UC patients and 83 in CD patients) were performed. The prevalence of abnormal microproteinuria in UC and CD patients was 12.9% and 6.0% for mALB, 22.7% and 27.7% for beta2mGLB, and 11.3% and 8.4% for beta-NAG, respectively. mALB was not associated with IBD activity. Beta2mGLB and beta-NAG urine levels were correlated to UC activity (UCAI: P<0.01; UCEI: P<0.005). mALB in UC patients and beta-NAG urine levels in CD patients were related to TNF-alpha serum levels. An association was noticed between microproteinuria and smoking habit. Treatment with 5-ASA was not correlated to the severity of microproteinuria or to the changes of creatinine clearance. CONCLUSION: Microproteinuria is mainly associated with UC and its activity but not affected by 5-ASA.     

Peripheral arthritis in patients with long-term inflammatory bowel disease. Results from 20 years of follow-up in the IBSEN study

Objectives: Peripheral arthritis and related musculoskeletal manifestations, often classified as peripheral spondyloarthritis, are frequently seen in patients with inflammatory bowel disease (IBD). Few long-term studies have reported on the prevalence of these conditions. The aim of this study was to determine the prevalence of IBD-related peripheral arthritis and peripheral spondyloarthritis in IBD patients during 20 years of disease course, and to assess whether these conditions were associated with the intestinal IBD severity and activity.

Materials and methods: In an inception cohort (the IBSEN study), IBD patients were followed prospectively for 20 years. At the 5 year follow-up the patients underwent a rheumatological examination and at the 20 year follow-up they completed a questionnaire with identical questions. When peripheral arthritis was characteristic and not explained by other specific diagnoses, it was defined as IBD-related peripheral arthritis. The Assessment of Spondyloarthritis International Society criteria were used to define peripheral spondyloarthritis, including patients with peripheral arthritis, enthesitis and/or dactylitis.

Results: After 20 years of follow-up, 441 patients were included (296 ulcerative colitis and 145 Crohn’s disease). The prevalence of IBD-related peripheral arthritis was 17.2% and peripheral spondyloarthritis 27.9% during the disease course. IBD severity and activity were not different between those with a history of IBD-related peripheral arthritis or peripheral spondyloarthritis and those without. A higher proportion of women had IBD-related peripheral arthritis and peripheral spondyloarthritis.

Conclusion: During 20 years of disease course, more than every sixth patient had suffered from IBD-related peripheral arthritis and every fourth from peripheral spondyloarthritis.     

Recent advances in basic and clinical aspects of inflammatory bowel disease： Which steps in the mucosal inflammation should we block for the treatment of inflammatory bowel disease？

There are four steps in the interaction between intestinal microbes and mucosal inflammation in genetically predisposed individuals from the viewpoints of basic and clinical aspects of inflammatory bowel disease （IBD）. The first step is an interaction between intestinal microbes or their components and intestinal epithelial cells via receptors, the second step an interaction between macrophages and dendritic cells and mucosal lymphocytes, the third step an interaction between lymphocytes and vascular endothelial cells, and the fourth step an interaction between lymphocytes and granulocytes producing proinflammatory cytokines or free radicals and mucosal damage and repair. Recent therapeutic approaches for IBD aim to block these four steps in the intestinal inflammation of patients with IBD.     

Association of extraintestinal manifestations and anaemia with disease outcomes in patients with inflammatory bowel disease

Objective: The association between extraintestinal manifestations (EIMs) and disease activity suggest a common pathogenetic link with inflammatory bowel disease (IBD). We report on the association of EIMs and anaemia with long-term disease outcomes, including treatment steps, hospitalization, and surgery in the prospective population-based IBD inception cohort from Veszprem province.

Methods: Data of 678 incident IBD patients (Crohn’s disease/ulcerative colitis(CD/UC): 331/347) diagnosed from 1st January 2000 to 31st December 2012 were analyzed (CD: m/f: 176/155, median age at diagnosis: 28, IQR: 21–40 years, disease duration: 6, IQR: 2–9 years; UC: m/f: 200/147, median age at diagnosis: 36, IQR: 26–50 years, duration: 7, IQR: 4–10 years).

Results: EIMs were present in 30% of the CD and 17.3% of the UC patients. In CD, female gender (p?=?0.02) need for steroid (p ?p?=?0.02), while in UC, young age at onset (p?=?0.03), extensive disease (p?=?0.003), female gender (p?=?0.07), need for steroids (p?p?=?0.004) and need for IBD-related hospitalization (p?=?0.01) were associated with the presence of EIMs. Anaemia was present in 56.7% of the CD and 30.2% of the UC patients. In both CD and UC anaemia was associated with age at onset (p_CD?=?0.001, p_UC?=?0.04), disease location/extent (p_CD?=?0.02, p_UC?p_CD,UC?p_CD?p_UC?=?0.002) and hospitalization (p_CD?=?0.004, p_UC?p?=?0.002).

Conclusions: The presence of EIMs was associated with disease phenotype in UC and with treatment strategy in both CD and UC. Additionally, anaemia was associated with hospitalization and surgery in both CD and UC, suggesting that EIMs and anaemia may be helpful in stratifying disease severity in IBD.     

Treatment of extraintestinal manifestations in inflammatory bowel disease

Opinion statement Extraintestinal manifestations (EIM) of inflammatory bowel disease (IBD) occur rather frequently and may be found in up to 30% of patients. However, surprisingly few randomized, controlled studies have been conducted that were specifically aimed at the treatment of EIM of IBD patients. Therefore, most therapies of EIM are empiric or deduced from studies in populations with other type of patients. EIM may be associated with active IBD. Treatment of active IBD is, therefore, the mainstay of treatment of EIM. Lifestyle modification as a means of therapy is a recent subject of study in chronic conditions, such as IBD. Based on epidemiologic and experimental findings, EIM of various tracts can be modified by optimizing alimentary intake, refraining from sedentary lifestyle, and adapting smoking habits. Not many new drugs for treatment of EIM have been developed during the past few years; the role of infliximab has been extended in particular in Crohn’s disease-related EIM. Careful consideration of prescribed drugs remains necessary due to potential interaction with the course of IBD.     

炎症性肠病的肠外表现与治疗

炎症性肠病(IBD)病变主要累及肠道,但亦常合并各种肠外表现。许多肠外表现可作为IBD的首发症状出现,有些甚至危及生命。目前关于IBD肠外表现的报道较多,但大样本的流行病学调查不多,而其特有的治疗更少。     

Treatment of the extraintestinal manifestations of inflammatory bowel disease

There is a paucity of randomized, controlled therapy studies of the extraintestinal manifestations of inflammatory bowel disease (IBD). Most current therapeutic approaches are empiric or based on approaches to therapy in other settings. In the past year anecdotal evidence has emerged for the use of therapies that neutralize tumor necrosis factor-α in both ankylosing spondylitis and the dermatologic extraintestinal manifestations. Topical tacrolimus has also emerged as a potentially useful therapy for dermatologic manifestations. Finally, patients with IBD occasionally become transplant recipients. One study reported worsening IBD after orthotopic liver transplantation for primary sclerosing cholangitis, and another reported the benefit of renal transplantation in amyloidosis-induced renal failure.     

Patient awareness of extraintestinal manifestations of inflammatory bowel disease

IntroductionPatient awareness of extraintestinal manifestations of inflammatory bowel diseases is important in improving patient understanding of their disease and health outcomes. We aim to characterize patient awareness of extraintestinal complications related to their disease.MethodsA cross-sectional survey was administered from July 2011 to May 2012. All adult (> 18 years) IBD patients attending gastroenterology clinics at a major tertiary teaching hospital (Mount Sinai Hospital, Toronto, ON, Canada) with a confirmed diagnosis of inflammatory bowel disease were invited to participate.ResultsA total of 299 patients participated: 177 Crohn's disease, 104 ulcerative colitis, and 18 IBD-unclassified. The vast majority of respondents obtained their information from their gastroenterologist (92%) and from the internet (78%). Most patients felt their inflammatory bowel disease knowledge was “very good” (34%) or “enough to get by” (54%). Most patients were aware of risk of colon cancer (75%), arthritis (77%), dermatological manifestations (49%), ocular inflammation (47%), and osteoporosis (53%). However, few patients were aware of venous thromboembolism (18%), nephrolithiasis (12%), or primary sclerosing cholangitis (20%). The majority of respondents were unsure of the signs and symptoms of venous thromboembolism, that the risk was increased during flares and hospitalizations, and that they require prophylaxis during an inflammatory bowel disease-related hosp italization.ConclusionAlthough the majority of respondents demonstrated awareness of most extraintestinal manifestations, few realized that venous thromboembolism was a life-threatening systemic complication of inflammatory bowel disease. Greater knowledge of venous thromboembolism would enable patients to more promptly seek potentially life-saving intervention.     

Ustekinumab and vedolizumab for extraintestinal manifestations in inflammatory bowel disease - a retrospective study

IntroductionExtraintestinal manifestations (EIM) are associated with diminished quality of life. The efficacy of Ustekinumab and vedolizumab for EIM treatment is not well established. The aim was to compare the effectiveness of ustekinumab and vedolizumab for treatment of EIM in IBD.MethodsWe included IBD patients treated with vedolizumab or ustekinumab in the Gastroenterology department, Sheba Medical Center, for up to 52 weeks between 2015 and 2021. Patients with active EIM before treatment initiation were included.Results111 patients were included. 53 patients (48%) were treated with ustekinumab; 88% (n-99) had CD. The most common EIM was arthralgia (95/111, 84%). Patients treated with ustekinumab were more likely to be anti-TNF experienced (n-51/53 [96%] compared with vedolizumab n = 36/58 [62%], p < 0.001).Clinical response of EIM at week 52 was achieved in 36% of patients treated with ustekinumab (n-18/50) and 34% of patients (n-19/54) treated with vedolizumab, with no statistically significant difference (p = 0.9). No statistical significance was achieved for patients presented with arthralgia. Clinical response of arthralgia at week 52 was seen in 34% (n-19/55) and 36% (n-18/46) of the patients treated with vedolizumab and ustekinumab, respectively, (p = 0.3).ConclusionIn this study, no difference was found between vedolizumab and ustekinumab regarding their effect on EIM in IBD patients for up to 52 weeks.     

Treatment of immune-mediated extraintestinal manifestations of inflammatory bowel disease with infliximab

The introduction of infliximab into clinical practice is one of the most significant advances in the care of patients who have IBD. Infliximab has become an important part of the medical armamentarium to treat extraintestinal manifestations that often are refractory to other medications and are a significant cause of morbidity in these patients. Two other TNF inhibitors recently have demonstrated efficacy in CD: certolizumab pegol and adalimumab. The Food and Drug Administration has approved adalimumab for use in RA. One predicts that these agents also may have activity in the extraintestinal manifestation for IBD. To determine whether future biologics are effective in the EIM of IBD, one may need to look no further than the vast clinical trial experience in primary chronic inflammatory diseases of the joints and skin: RA and psoriasis. For example, the Food and DRug Administration recently has approved an anti-B-cell therapy, rituximab, and a T-cell costimulation modulator, abatacept, for use in RA. It certainly will be of interest to determine whether these biologic agents demonstrate efficacy in the intestinal and EIM of IBD.     

Efficacy of infliximab for extraintestinal manifestations of inflammatory bowel disease

Opinion statement Crohn’s disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD), are associated with extraintestinal manifestations (EIMs) in approximately 40% of patients. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, is effective for induction and maintenance of remission of CD and UC. The role of infliximab for EIMs related to IBD has been less studied, but it is likely as effective. The EIMs may run a course that parallels IBD activity or may present separately. The EIMs that parallel intestinal inflammation (eg, peripheral arthritis, pyoderma gangrenosum, erythema nodosum, and episcleritis) generally respond to infliximab. Therefore, treating patients with IBD who have one of these EIMs will more often than not improve the EIM. The EIMs that run a separate course from IBD are more difficult to treat. Ankylosing spondylitis (AS), uveitis, and primary sclerosing cholangitis (PSC) have variable responses to IBD medications. Infliximab is efficacious for uveitis and is approved by the US Food and Drug Administration for treatment of AS. The efficacy of infliximab for PSC is unknown. The dosing schedule of infliximab for IBD patients with EIMs should be induction doses with 5 mg/kg at 0, 2, and 6 weeks followed by every 8 weeks. Whether long-term infliximab therapy is necessary to maintain remission of EIMs, as in the case of IBD, has not been established.