Two-sample Mendelian randomization analysis of causal relationship between eczema and autoimmune diseases

Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.

Study on TCM syndrome-typing of chronic ulcerative colitis

AIMS To study the relationship between the modern clinical and pathohistological classification and TCM Syndrome-Typing of chronic ulcerative colitis (CUC). METHODS Totally 452 patients with CUC were clas- sified according to the standards of TCM Syndrome- Typing set up in the Conference of the Combination of the Chinese-Western Medicine on Digestive Diseases in Linfen. The relevant changes between both classifica- tions were analyzed and compared through the colonofiberscopic and pathohistological examination. RESULTS The type of retention of damp-heat in inte- rior is more commonly seen in the patients with initial onset of disease (P<0.01). There is no significant difference among other TCM Syndrome-Typing groups in patients with chronic persistent and recurrent disease (P>0.05). The congestion,edema,reduction of goblet cells and the infiltration of neutrophils are patho- logically common to all TCM Syndrome-Typing groups. Mucosal ulcer is dominant in damp-heat syndrome while crypt ulcer is dominant in the types of spleen-stomach asthenia and spleen-kidney Yang deficiency (P< 0.01). CONCLUSIONS There appears a certain relation- ship between the TCM syndrome typing and pathohis- tological changes of the colonal mucosa of CUC.

Nutritional status and nutritional therapy in inflammatory bowel diseases

Underweight and specific nutrient deficiencies are frequent in adult patients with inflammatory bowel disease(IBD).In addition,a significant number of children with IBD,especially Crohn's disease(CD) have impaired linear growth.Nutrition has an important role in the management of IBD.In adults with CD,enteral nutrition(EN) is effective in inducing clinical remission of IBD,although it is less efficient than corticosteroids.Exclusive EN is an established primary therapy for pediatric CD.Limited data suggests that EN is as efficient as corticosteroids for induction of remission.Additional advantages of nutritional therapy are control of inflammation,mucosal healing,positive benefits to growth and overall nutritional status with minimal adverse effects.The available evidence suggests that supplementary EN may be effective also for maintenance of remission in CD.More studies are needed to confirm these findings.However,EN supplementation could be considered as an alternative or as an adjunct to maintenance drug therapy in CD.EN does not have a primary therapeutic role in ulcerative colitis.Specific compositions of enteral dietselemental diets or diets containing specific components-were not shown to have any advantage over standard polymeric diets and their place in the treatment of CD or UC need further evaluation.Recent theories suggest that diet may be implicated in the etiology of IBD,however there are no proven dietary approaches to reduce the risk of developing IBD.

Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

The etiopathology of inflammatory bowel disease （IBD） remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflam- mation. IBD including Crohn＇s disease （CD） and ulcerative colitis （UC） is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Thl- mediated inflammatory disorder while UC is regarded as a Th2-1ike disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Thl or Th2 cells, and several cytokines [e.g. interleukin （IL）-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Thl/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.

Immunopathogenesis of inflammatory bowel disease

Crohn＇s disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn＇s disease and T-helpero2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.

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

AIM: To evaluate the safety and efficacy of a long- term 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 infl iximab 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 infl iximab 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.

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.

Inflammatory bowel disease:Genetic and epidemiologic considerations

Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn’s disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.

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.

Extraintestinal manifestations of inflammatory bowel disease:Do they influence treatment and outcome?

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases that often involve organs other than those of the gastrointestinal tract. Immune-related extraintestinal manifestations (EIMs) are usually related to disease activity, but sometimes may take an independent course. Globally, about one third of patients develop these systemic manifestations. Phenotypic classification shows that certain subsets of patients are more susceptible to developing EIMs, which frequently occur simultaneously in the same patient overlapping joints, skin, mouth, and eyes. The clinical spectrum of these manifestations varies from mild transitory to very severe lesions, sometimes more incapacitating than the intestinal disease itself. The great majority of these EIMs accompany the activity of intestinal disease and patients run a higher risk of a severe clinical course. For most of the inflammatory EIMs, the primary therapeutic target remains the bowel. Early aggressive therapy can minimize severe complications and maintenance treatment has the potential to prevent some devastating consequences.

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.

Intestinal inflammation and colorectal cancer:A doubleedged sword?

Chronic inflammation is thought to be the leading cause of many human cancers including colorectal cancer(CRC).Accordingly,epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease,the two major forms of inflammatory bowel disease,have an increased risk of developing CRC.In recent years,the role of immune cells and their products have been shown to be pivotal in initiation and progression of colitis-associated CRC.On the other hand,activation of the immune system has been shown to cause dysplastic cell elimination and cancer suppression in other settings.Clinical and experimental data herein reviewed,while confirming chronic inflammation as a risk factor for colon carcinogenesis,do not completely rule out the possibility that under certain conditions the chronic activation of the mucosal immune system might protect from colonic dysplasia.

Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease

Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.Prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems.With regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's disease.The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy.With regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's disease.Underdosing of thiopurines is a form of undertreatment.Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse.Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine.Finally,thiopurine methyltransferase(TPMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.

Haemostatic system in inflammatory bowel diseases:New players in gut inflammation

Inflammation and coagulation constantly influence each other and are constantly in balance.Emerging evidence supports this statement in acute inflammatory diseases,such as sepsis,but it also seems to be very important in chronic inflammatory settings,such as inflammatory bowel disease(IBD).Patients with Crohn's disease and ulcerative colitis have an increased risk of thromboembolic events,and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels,where most severe inflammatory abnormalities occur.The aims of this review are to update and classify the type of coagulation system abnormalities in IBD,and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level.Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.

Effect of smoking on inflammatory bowel disease: Is it disease or organ specific?

Smoking is an important environmental factor in inflammatory bowel disease （IBD） with differing effects in ulcerative colitis （UC） and Crohn＇s disease （CD）. Never smoking and formerly smoking increase the risk of UC, whereas smoking exacerbates the course of CD. The potential mechanisms involved in this dual relationship are yet unknown. A reasonable assumption is that smoking has different effects on the small and large intestine. This assumption is based on animal and human studies that show that the effects of smoking/nicotine on CD and UC depend on the site of inflammation and not on the type of disease.

Use of mycophenolate mofetil in inflammatory bowel disease

AIM:To assess the efficacy and safety of mycophenolate mofetil(MMF)prospectively in inflammatory bowel disease(IBD)patients intolerant or refractory to conventional medical therapy.METHODS:Crohn's disease(CD)or ulcerative colitis/ IBD unclassified(UC/IBDU)patients intolerant or refractory to conventional medical therapy received MMF(500-2000 mg bid).Clinical response was assessed by the Harvey Bradshaw index(HBI)or colitis activity index(CAI)after 2,6 and 12 mo of therapy,as were steroid usage and adverse effects.RESULTS:Fourteen patients(9 CD/5 UC/IBDU;8M/6F;mean age 50.4 years,range 28-67 years)were treated and prospectively assessed for their response to oral MMF.Of the 11 patients who were not in remission on commencing MMF,7/11(63.6%)achieved remission by 8 wk.All 3 patients in remission on commencing MMF maintained their remission.Ten patients were still on MMF at 6 mo with 9/14(64.3%)in remission,while of 12 patients followed for 12 mo,8 were in remission without dose escalation(66.7%).Three patients were withdrawn from the MMF due to drug intolerance.There were no serious adverse events attributed due to the medication.CONCLUSION:MMF demonstrated efficacy in the management of difficult IBD.MMF appeared safe,well tolerated and efficacious for both short and long-term therapy,without the need for dose escalation.Further evaluation of MMF comparing it to conventional immunosuppressants is required.

Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

Inflammatory bowel disease (IBD) includes two entities, Crohn’s disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient’s quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependant disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn’s disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunossupressants is now advocated by some authors. The rational includes: (1) failure to modify IBD natural history of present therapeutic approach, (2) demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn’s disease and ulcerative colitis, and (3) demonstration that early immunossupression has a very positive impact on pediatric, recently diagnosed Crohn’s disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab (SONIC Study), and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn’s disease patients (AZTEC study).

Regulatory T cells in inflammatory bowel diseases and colorectal cancer

Regulatory T cells(T regs) are key elements in immunological self-tolerance.The number of T regs may alter in both peripheral blood and in colonic mucosa during pathological circumstances.The local cellular,microbiological and cytokine milieu affect immunophenotype and function of T regs.Forkhead box P3+ T regs function shows altered properties in inflammatory bowel diseases(IBDs).This alteration of T regs function can furthermore be observed between Crohn's disease and ulcerative colitis,which may have both clinical and therapeutical consequences.Chronic mucosal inflammation may also influence T regs function,which together with the intestinal bacterial flora seem to have a supporting role in colitis-associated colorectal carcinogenesis.T regs have a crucial role in the immunoevasion of cancer cells in sporadic colorectal cancer.Furthermore,their number and phenotype correlate closely with the clinical outcome of the disease,even if their contribution to carcinogenesis has previously been controversial.Despite knowledge of the clinical relationship between IBD and colitis-associated colon cancer,and the growing number of immunological aspects encompassing sporadic colorectal carcinogenesis,the molecular and cellular links amongst T regs,regulation of the inflammation,and cancer development are still not well understood.In this paper,we aimed to review the current data surrounding the role of T regs in the pathogenesis of IBD,colitis-associated colon cancer and sporadic colorectal cancer.