Smoking in inflammatory bowel diseases： Good,bad or ugly？

Smoking is an important environmental factor in inflammatory bowel disease （IBD）, having different effects in ulcerative colitis （UC） and Crohn＇s disease （CD）. A recent meta-analysis partially confirmed previous findings that smoking was found to be protective against ulcerative colitis and, after onset of the disease, might improve its course, decreasing the need for colectomy. However, smoking increases the risk of developing Crohn＇s disease and worsens its course, increasing the need for steroids, immunosuppressants and re-operations. Smoking cessation aggravates ulcerative colitis and improves Crohn＇s disease. Data are however, largely conflictive as well as the potential mechanisms involved in this dual relationship are still unknown. In this review article, the authors review the role of smoking in inflammatory bowel diseases.     

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.     

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn＇s disease

AIM： To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine （AZA）, AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn＇s disease （CD）. METHODS： Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed （M/F： 155/185, duration： 9.4 ± 7.5 years） with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. RESULTS： A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 ± 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/ biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location （P = 0.001）, presence of perianal disease （P 〈 0.001）, prior steroid use （P = 0.006）, early AZA （P = 0.005） or AZA/biological therapy （P = 0.002）, or smoking （P = 0.032） were independent predictors of disease behavior change. CONCLUSION： Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.     

How expensive is inflammatory bowel disease？ A critical analysis

Economic analysis of chronic diseases is required for proper allocation of resources and understanding costeffectiveness studies of new therapies. Studies on health care cost of ulcerative colitis （UC） and Crohn＇s disease （CD） are reviewed here. These studies were carried out in various countries with disparate health care systems. In the United States, data were often modeled or retrieved from large insurance schemes. Surgery and in-patient hospitalization accounted for over half the outlay on UC and CD. Fistulous disease in CD and parenteral nutrition were very costly. In Canada, overall charges were lower than in the United States, but there too, surgical costs were relatively high. In European studies, economic data were abstracted directly from patients＇ files. One pan-European study examined the outlay on UC and CD in a community-based prospective inception cohort followed for 10 years. Overall costs in Europe were lower than in the United States. Surgery, hospitalization, year of follow-up, disease phenotype in CD and ASCA-positivity impacted significantly on costs. In all studies, the cost data were right skewed, aminosalicylates were expensive drugs, and biological agents the most expensive; moreover indirect costs were not calculated. Infliximab raised costs considerably in CD, but there were no long-term followup studies, so that the cost-benefit of biological agents remains unknown. In conclusion, costs of managing UC and CD vary by country, surgery, genotype and several other factors. The most important question for further research is whether the biological therapies are cost-effective in the long-term.     

Nutritional therapy for active Crohn’s disease

Nutritional therapy for active Crohn’s disease （CD） is an underutilised form of treatment in adult patients, though its use is common in the paediatric population. There is evidence that nutritional therapy can effectively induce remission of CD in adult patients. Enteral nutrition therapy is safe and generally well tolerated. Meta-analysis data suggest that corticosteroids are superior to nutritional treatment for induction of remission in active CD. However, the potential side effects of such pharmacotherapy must be taken into consideration. This review examines the evidence for the efficacy of elemental and polymeric diets, and the use of total parenteral nutrition in active CD.     

Do clinical factors help to predict disease course in inflammatory bowel disease?

While therapeutic strategies able to change the natural history of the disease are developing,it is of major importance to have available predictive factors for aggressive disease to try and target these therapeutic strategies.Clinical predictors have probably been the most broadly studied.In both Crohn's disease(CD) and ulcerative colitis(UC),age at diagnosis,disease location and smoking habit are currently the strongest predictors of disease course.A younger age at onset is associated with more aggressive...     

Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies

Spondyloarthropathies （SPA） are commonly observed extra-intestinal manifestations of both Crohn＇s disease （CD） and ulcerative colitis （UC）, the two major forms of inflammatory bowel diseases （[BD）. However, the immunological link between these two clinical entities is still poorly understood. Several lines of evidence indicate that SpA may originate from the relocation to the joints of the immune process primarily induced in the gut. The transfer of the intestinal inflammatory process into the joints implicates that immune cells activated in the gut-draining lymph nodes can localize, at a certain point of the intestinal disease, either into the gut or into the joints. This is indicated by the overlapping expression of adhesion molecules observed on the surface of intestinal and synovial endothelial cells during inflammation. Moreover bacterial antigens and HLA-B27 expression may be implicated in the reactivation of T cells at the articular level. Finally, accumulating evidence indicates that a T helper 17 cell-mediated immune response may contribute to IBD and IBD-related SpA with a crucial role played by tumor necrosis factor-α in CD and to a lesser extent in UC.     

Why is damage limited to the mucosa in ulcerative colitis but transmural in Crohn’s disease?

It has been a big puzzle as why the inflammation of ulcerative colitis (UC) is limited to the mucosa, while in Crohn’s disease (CD) the inflammation is transmural and can be seen in all layers of the gut. Here, I give a tentative explanation extended from the unified hypothesis I proposed on the etiology of inflammatory bowel disease. This hypothesis suggested that both UC and CD are caused by weakening of the gut barrier due to damage of the protective mucus layer and the underlying tissue by the poorly inactivated digestive proteases resulting from a reduction of gut bacteria by dietary chemicals like saccharin and sucralose. However, the large amounts of bacteria in the colon make the recruitment of neutrophils and formation of crypt abscess the main manifestation of UC, while the infiltration of antigens and dietary particles in the small and large intestine mainly cause the recruitment of macrophages and formation of granulomas as the main manifestations in CD. The fast reacting and short life span of neutrophils make the fight and damage limited to the surface of the mucosa. In contrast, the long life span and constant movement of macrophages may bring the harmful agents deep into the tissue. Therefore, the pathogenesis of UC may be more like bacterial pneumonia, while CD may be more like pneumoconiosis or tuberculosis of the lung.     

Old-age inflammatory bowel disease onset：A different problem？

Inflammatory bowel disease (IBD) in patients aged > 60 accounts for 10%-15% of cases of the disease. Diganostic methods are the same as for other age groups. Care has to be taken to distinguish an IBD colitis from other forms of colitis that can mimick clinically, endoscopically and even histologically the IBD entity. The clinical pattern in ulcerative colitis (UC) is proctitis and left-sided UC, while granulomatous colitis with an inflammatory pattern is more common in Crohn’s disease (CD). The treatment o...     

Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn＇s disease

The hypothesis postulating that Mycobacterium avium paratuberculosis （MAP） is the cause of Crohn＇s disease （CD） has been circulating for many years. Advances in molecular techniques, such as polymerase chain reac- tion and culture methods, have enabled researchers to demonstrate that there is an association between MAP and CD. Recently, genome-wide association studies have identified novel susceptibility genes for CD, which are critical for generation of an adaptive immune re- sponse that is protective against intracellular patho- gens, including M. tuberculosis infection. However, the role of MAP as a cause of CD suffered a setback with the report that administration of antimycobacte- rial therapy failed to lead to a sustained response in CD patients. Accordingly, this review sought neither to confirm nor refute this, but instead to survey recent literature on the role of MAP in CD.     

Inflammatory bowel disease： Moving toward a stem cell-based therapy

The incidence and prevalence of Crohn＇s disease （CD） and ulcerative colitis （UC）, the two major forms of inflammatory bowel diseases （IBD）, are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal fi ndings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.     

No association of the cytotoxic T-lymphocyte associated gene CTLA4 ＋49A/G polymorphisms with Crohn＇s disease and ulcerative colitis in Hungarian population samples

AIM： The goal of the current work was to analyse the prevalence of the ＋49A/G variant of the cytotoxic T-lymphocyte antigen 4 gene （CTLA4） in Hungarian patients with Crohn＇s disease （CD） and ulcerative colitis （UC）.
METHODS： A total of 130 unrelated subjects with CD and 150 with UC, and 170 matched controls were genotyped for the single nucleotide polymorphism （SNP）. The genotypes were determined by using PCR/RFLP test.
RESULTS： The G allele frequency and the prevalence of the GG genotype were 38.1% and 12.3% in the CD group, 40.6% and 18.6% in the UC patients, and 37.4% and 15.9% in the control group, respectively.
CONCLUSION： The results of the current study show that carriage of the ＋49G SNP in heterozygous or in homozygous form does not confer risk either for CD or for UC in the Hungarian population.     

Etiopathogenesis of inflammatory bowel diseases

Theories explaining the etiopathogenesis of inflammatory bowel disease (IBD) have been proposed ever since Crohn's disease (CD) and ulcerative colitis (UC) were recognized as the two major forms of the disease. Although the exact cause(s) and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid: IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.     

Evidence for the involvement of infectious agents in the pathogenesis of Crohn＇s disease

Many advances have been made in the understanding of Crohn’s disease （CD） pathogenesis during the last decade. CD is currently seen as a predominantly T-lym-phocyte-driven disease characterized by the presence of a complex cocktail of interacting cytokines, chemokines and other mediators produced by a variety of cell types. Prevailing theories of CD pathogenesis suggest that patients’ T-lymphocytes are inappropriately activated in the setting of an immune imbalance, which is itself caused by an unfortunate confluence of genetic and environmental factors. The T-cell response then leads to the chronic inflammation characteristic for the disease. Various environmental factors may play a role in the development of CD, but microbes are most consistently implied. This theory is based on epidemiological, clinicopathological, genetic and experimental evidence. Despite the abundance of arguments for the implication of bac-teria in the aetiopathogenesis of CD, the precise role of bacteria in this disease still remains elusive. Three not necessarily mutually exclusive theories have been proposed： （1） an unidentified persistent pathogen; （2） an abnormally permeable mucosal barrier leading to exces-sive bacterial translocation; and （3） a breakdown in the balance between putative ＂protective＂ versus ＂harmful＂ intestinal bacteria （＂dysbiosis＂）. At present, one cannot exclude with certainty any of these three proposed hy-potheses; they may all apply to CD to a certain extent.     

Osteoporosis in celiac disease and in endocrine and reproductive disorders

As the increase in lifespan brings to light diseases that were previously not clinically detectable, osteoporosis has become an issue of worldwide significance. The disease is marked by a loss of bone mass; the bones become less dense, fragile and more prone to fracturing. Because it is regulated by endocrine and environmental factors, osteoporosis presents a multifactorial etiopathogenesis, with the genetic component accounting for 70% of an individual variation in bone mass density （BMD）, the principal determinant, with age, of fracture risk. Pathological conditions such as celiac disease （CD） exacerbate the process of bone loss, so that the occurrence of osteoporosis in celiac subjects is of particular note： indeed, the screening of osteoporosis patients for this disease is advisable, since it may be the only sign of undiagnosed CD. An increase in interleukin IL-1β, of the IL-1 system, in the relatives of celiac patients confirms the genetic predisposition to osteoporosis and its presence is evidence of an association between the two conditions. The direct effect on the bones of CD is secondary to poor absorption of calcium and vitamin D. In women osteoporosis is indirectly associated with early menopause and amenorrhea, and it may follow prolonged breast-feeding and frequent pregnancies, while in men it is associated with hypogonadism and GH deficit. These endocrine and non-endocrine factors exert their effects on bones by modulating the RANK/RANK-L/OPG system. An appropriate lifestyle from adolescence onwards, together with early diagnosis of and treatment for CD and primaryand secondary endocrine pathologies are important for the prevention of damage to the bones.     

Rifaximin and Crohn’s disease

In a recent article,Longman and Swaminath analyzed our paper on the use of rifaximin in patients with moderately active Crohn’s disease(CD).Here we report some considerations concerning their article.The exploratory post-hoc subgroup analysis showed that early-stage disease and,differently from that written by Longman and Swaminath,also colonic involvement seemed to be associated with a significant higher efficacy of rifaximin-EIR 800 mg twice daily.Early-stage disease is generally considered as the more easily treatable phase of CD,and the better response to rifaximin in Crohn’s colitis is in accordance with the high concentration of bacteria in the colon.In addition,patients with C reactive protein level>5 mg/L achieved remission more significantly than patients with normal values,thus suggesting that the symptoms were probably caused by inflammation instead of by non-inflammatory causes.We also analyze the role of rifaximin against gut bacteria and the clinical situations that could obtain the best results from antibiotics.     

Molecular basis of the potential of mesalazine to prevent colorectal cancer

Patients with ulcerative colitis （UC） and Crohn＇s disease （CD） are at increased risk for developing colorectal cancer （CRC）, and this is believed to be a result of chronic inflammation. Although conclusive evidence is still missing, both epidemiological and experimental observations suggest that certain drugs used to treat inflammation, such as mesalazine, can reduce the incidence of colitis-associated CRC. Therefore, in recent years, several studies have been conducted to dissect the mechanisms by which mesalazine interferes with CRC cell growth and survival. This review summarizes the current information on the molecular mechanisms that underlie the antineoplastic action of mesalazine.     

Crohn＇s disease in Japanese is associated with a SNP-haplotype of N-acetyltransferase 2 gene

AIM: To investigate the frequency and distribution of N-acetyltransferase 2 (NAT2) and uridine 5'-diphosphate (UDP)-glucuronosyltransferase 1A7 (UGT1A7) genes in patients with ulcerative colitis (UC) and Crohn's disease (CO). METHODS: Frequencies and distributions of NAT2 and UGT1A7SNPs as well as their haplotypes were investigated in 95 patients with UC, 60 patients with CD, and 200 gender-matched, unrelated, healthy, control volunteers by PCR-restriction fragment length polymorphism (RFLP), PCR-denaturing high-performance liquid chromatography (DHPLC), and direct DNA sequencing. RESULTS: Multiple logistic regression analysis revealed that the frequency of haplotype, NAT2*7B, significantly increased in CD patients, compared to that in controls (P=0.0130, OR = 2.802,95%CI = 1.243-6.316). However, there was no association between NAT2 haplotypes and UC, or between any UGT1A7 haplotypes and inflammatory bowel disease (IBD). CONCLUSION: It is likely that the NAT2 gene is one of the determinants for CD in Japanese. Alternatively, a new CD determinant may exist in the 8p22 region, where NAT2 is located.     

Recent trends in the surgical management of inflammatory bowel disease

Surgery is required in the vast majority of patients with Crohn＇s disease （CD） and in approximately one-third of patients with ulcerative colitis （UC）. Similar to medical treatments for IBD, significant advances have occurred in surgery. Advances in CD include an emphasis upon conservatism as exemplified by more limited resections, strictureplasties, and laparoscopic resections. The use of probiotics in selected patients has improved the outcome in patients with pouchitis following restorative proctocolectomy for UC. It is anticipated that ongoing discoveries in the molecular basis of IBD will in turn identify those patients who will best respond to surgery.