Yield of Gluten Challenge in Patients on Self-Prescribed Gluten-Free Diets.

BACKGROUND: Patients on a gluten-free diet (GFD) whose celiac disease (CD) status is unknown may undergo gluten challenge (GC) to clarify their diagnosis. Though this is an established diagnostic practice, the proportion of patients undergoing GC who are diagnosed with CD is unknown. AIMS: We aimed to analyze which factors were predictive of having CD in a cohort of patients who underwent GC followed by upper endoscopy with duodenal biopsy. METHODS: We identified adult patients at a CD referral center who had been on a GFD and then underwent GC to determine a diagnosis of CD during the years spanning 2006 to 2020. We compared those patients found to have CD (defined as villus atrophy/Marsh 3) on duodenal biopsy with those who did not, using the chi square and Fischer exact tests. RESULTS: We identified 206 patients who underwent GC. Of these 206, 30 (14%) were diagnosed with CD based on post-GC duodenal biopsy. 176 of the 206 (85%) patients reported various gastrointestinal symptoms, including bloating (39%), though these were more common in those without CD (any GI symptoms: 89% vs 67%, p 0.004; bloating: 43% vs 20%, p 0.019). Serology values, when normalized, including pre- and post-challenge TTG IgA (37% vs 1.7%, p 0.001; 23% versus 2.3%, p 0.001), DGP IgG and IgA (57% vs 2.8%, p 0.001; 37% vs 6.2%, p 0.001) were higher in the group of patients with CD. CONCLUSION: Among patients undergoing GC for diagnostic purposes, only 14% had evidence of villus atrophy corresponding with CD on duodenal biopsy. The presence of any elevated pre-challenge serology was associated with CD. Bloating in combination with low serologies may help risk stratify patients as being less likely to have CD upon GC.

Predictors of Subsequent Celiac Disease Seropositivity in Patients Diagnosed with Duodenal Villus Atrophy on Upper Endoscopy.

BACKGROUND: The diagnosis of celiac disease (CD) is based on positive IgA autoantibodies to tissue transglutaminase (TTG IgA) and confirmatory histopathology demonstrating duodenal villus atrophy (VA). Diagnostic challenges can occur when VA is found on duodenal biopsies in patients without prior CD serologies. AIMS: To characterize the predictors of CD seropositivity in patients with VA on biopsy without prior CD serologies. METHODS: We performed a retrospective cohort study of patients found to have duodenal VA on histopathology from 2010 to 2020 who did not have prior CD serologies measured and who had them checked after their biopsy. Patients with known or suspected CD prior to their duodenal biopsy were excluded. RESULTS: Of 162 patients with VA and no prior CD serologies, 50 (31%) subsequently had an elevated TTG IgA consistent with CD. Patients with an elevated TTG IgA were more likely to be non-Hispanic (76% vs. 42%; p < 0.001), white (74% vs. 62%; p = 0.025), and younger (ages 18-39, 26% vs. 12%; p = 0.002) compared to those with a negative TTG IgA. By contrast, these patients were less likely to present in middle adulthood (ages 40-59, 6% vs. 29%; p =  0.002). The most common identified etiologies of seronegative VA were Crohn's disease (13%), seronegative CD (8.9%), H. pylori infection (6.3%), tropical sprue (5.4%), and olmesartan-related enteropathy (3.6%). CONCLUSION: Age and ethnicity may be helpful when stratifying the likelihood of CD in the absence of supporting serologies. A majority of patients (69%) diagnosed with VA without prior CD serologies have negative serologies, consistent with seronegative CD or the spectrum of non-celiac enteropathies for which further evaluation is needed.

A pan-cancer analysis implicates human NKIRAS1 as a tumor-suppressor gene.

The NF-κB family of transcription factors and the Ras family of small GTPases are important mediators of proproliferative signaling that drives tumorigenesis and carcinogenesis. The κB-Ras proteins were previously shown to inhibit both NF-κB and Ras activation through independent mechanisms, implicating them as tumor suppressors with potentially broad relevance to human cancers. In this study, we have used two mouse models to establish the relevance of the κB-Ras proteins for tumorigenesis. Additionally, we have utilized a pan-cancer bioinformatics analysis to explore the role of the κB-Ras proteins in human cancers. Surprisingly, we find that the genes encoding κB-Ras 1 (NKIRAS1) and κB-Ras 2 (NKIRAS2) are rarely down-regulated in tumor samples with oncogenic Ras mutations. Reduced expression of human NKIRAS1 alone is associated with worse prognosis in at least four cancer types and linked to a network of genes implicated in tumorigenesis. Our findings provide direct evidence that loss of NKIRAS1 in human tumors that do not carry oncogenic RAS mutations is associated with worse clinical outcomes.

Serological Investigation of Persistent Villous Atrophy in Celiac Disease.

INTRODUCTION: Persistent villous atrophy (VA) is not uncommon in celiac disease (CeD) while patients take a gluten-free diet (GFD). METHODS: We conducted a retrospective study with 122 serum samples collected from controls and patients with CeD either at the initial diagnosis or at the follow-up during endoscopy. These samples were assigned to 3 groups: nonceliac control, non-VA CeD (Marsh score 0-2), and VA CeD (Marsh score 3a-3c). We established an in-house multiplex assay to identify potential serological biomarkers for VA. We assessed autoantibodies reported to affect the small intestine, including IgA and IgG antibodies against tissue transglutaminase (tTG), interferons, villin, actin, autoimmune enteropathy-related 75 kDa antigen (AIE-75), and tryptophan hydroxylase (TPH)-1, as well as 27 cytokines. The apolipoproteins quantified included apo A1, apo B-100, and apo A4, which were produced predominantly by the intestinal epithelium or expressed specifically in villi. RESULTS: Autoantibody levels were high only for tTG antibodies, which performed well in initial CeD diagnosis, but suboptimally for VA prediction during follow-up, because 14.6% of the follow-up patients with VA had low tTG-IgA. Increasing dilution improved tTG-IgA quantification, particularly when the antibody levels were extremely high but did not significantly improve VA detection. Among those with low tTG-IgA and persistent VA, high proinflammatory cytokines were observed in 2 patients. Median low-density lipoprotein cholesterol levels were significantly lower in the VA CeD group ( P = 0.03). Apolipoprotein levels were similar in patients with and without VA but diverged between those on a GFD or not. DISCUSSION: tTG-IgA as a biomarker is suboptimal for VA prediction while on a GFD. Persistent VA is associated with low low-density lipoprotein cholesterol levels and partially related to persistent high proinflammatory cytokines.

Gluten induces rapid reprogramming of natural memory αß and γδ intraepithelial T cells to induce cytotoxicity in celiac disease.

Celiac disease (CD) is an autoimmune disease in which intestinal inflammation is induced by dietary gluten. The means through which gluten-specific CD4+ T cell activation culminates in intraepithelial T cell (T-IEL)-mediated intestinal damage remain unclear. Here, we performed multiplexed single-cell analysis of intestinal and gluten-induced peripheral blood T cells from patients in different CD states and healthy controls. Untreated, active, and potential CD were associated with an enrichment of activated intestinal T cell populations, including CD4+ follicular T helper (TFH) cells, regulatory T cells (Tregs), and natural CD8+ αß and γδ T-IELs. Natural CD8+ αß and γδ T-IELs expressing activating natural killer cell receptors (NKRs) exhibited a distinct TCR repertoire in CD and persisted in patients on a gluten-free diet without intestinal inflammation. Our data further show that NKR-expressing cytotoxic cells, which appear to mediate intestinal damage in CD, arise from a distinct NKR-expressing memory population of T-IELs. After gluten ingestion, both αß and γδ T cell clones from this memory population of T-IELs circulated systemically along with gluten-specific CD4+ T cells and assumed a cytotoxic and activating NKR-expressing phenotype. Collectively, these findings suggest that cytotoxic T cells in CD are rapidly mobilized in parallel with gluten-specific CD4+ T cells after gluten ingestion.

Novel Drug Therapeutics in Celiac Disease: A Pipeline Review.

Celiac disease (CeD) is a chronic, autoimmune systemic disorder triggered by the ingestion of gluten, a protein found in foods such as wheat, rye, and barley. The only effective treatment for CeD is complete removal of gluten from the diet. A strict gluten-free diet (GFD) results in symptomatic, serologic, and histologic remission in most patients. However, GFD may fail to induce clinical or histologic improvement and some patients may alternatively have difficulty strictly adhering to the GFD for other reasons. Despite this, there are currently no FDA-approved drugs for the treatment of CeD. The complex pathogenic process of CeD is becoming increasingly studied and better understood, enabling the identification of various targets for future therapies. Mechanisms under evaluation include probiotics, digestion of peptides, gluten sensitization, tight junction modulation, deamidation, and immune targets. Multiple investigational drugs are in the pipeline, and several drug candidates have entered late-phase clinical trials. Indeed, current and future studies are needed to target specific etiological mechanisms and provide an alternative to GFD alone. This review provides a broad overview of the various investigative treatment approaches for CeD, summarizing the latest progress in the pipeline.

Clinical Factors Associated With Positive Stool PCR for Gastrointestinal Pathogens in Celiac and Inflammatory Bowel Disease.

GOALS: We aimed to identify the clinical factors of celiac disease (CeD) and inflammatory bowel disease (IBD) associated with positive stool gastrointestinal (GI) polymerase chain reaction (PCR) test. BACKGROUND: Understanding the pattern of enteric infections in CeD and IBD may allow further insight into microbiome-mediated pathogeneses. STUDY: This was a retrospective study of adult patients (age 18 y or above) with CeD and IBD at a large quaternary care institution. We identified patients with CeD or IBD who underwent stool GIPCR evaluation as outpatients (office visit or at endoscopy) between March 2015 and March 2019. Patients with a negative GIPCR test within the study time frame were randomly chosen as controls (1 : 1). The independent relationship between clinical characteristics and positive GIPCR was evaluated using multivariable logistic regression. RESULTS: A total of 266 patients met criteria for the study, including 92 (35%) with CeD and 174 (65%) with IBD. On multivariable analysis of factors associated with positive GIPCR test, CeD patients were more likely to have diarrheal presentation of illness [odds ratio (OR): 2.61, 95% confidence interval (CI) 1.05-6.72], experience extraintestinal manifestations (OR: 2.49, 95% CI: 1.01-6.31), and practice a gluten-free diet for at least 5 years (OR: 4.00, 95% CI: 1.36-11.67), relative to those with a negative GIPCR test. IBD patients with positive GIPCR were more likely to be on corticosteroids (OR: 2.23, 95% CI: 1.02-5.4.84), experience extraintestinal manifestations (OR: 2.60, 95% CI: 1.22-5.53), and use proton-pump inhibitors (OR: 4.07, 95% CI: 1.69-9.77). CONCLUSIONS: Intestinal infections in CeD and IBD are associated with important disease-specific characteristics.

The Distribution of Gastrointestinal Pathogens on Stool PCR Prior to the Development of IBD.

GOALS: We investigated the distribution of pathogens on stool gastrointestinal (GI) polymerase chain reaction (PCR) testing in those who subsequently developed inflammatory bowel disease (IBD). BACKGROUND: Infectious gastroenteritis has been associated with later development of IBD. STUDY: This retrospective study includes patients of all ages hospitalized for diarrhea with positive GIPCR panel and subsequently a new diagnosis of IBD [confirmed by chart review and International Classification of Disease, Clinical Modification code for Crohn's disease (CD) or ulcerative colitis (UC)], between March 2015 to September 2019 at our quaternary care institution. Patients with IBD diagnosis before GIPCR were excluded. Descriptive statistics characterized the distribution of microbial pathogens in relation to later IBD diagnosis. RESULTS: Fifty-four participants were eligible (UC 44%; CD 56%). Median age at time of IBD diagnosis was 35 years [interquartile range (IQR) 18 to 65]. Median time between GIPCR and IBD diagnosis was 3 months (IQR 2 to 9) for all patients. When stratified by organism class, median time to diagnosis was 6 months (IQR 2 to 10) for patients with bacteria, 3 months (IQR 1 to 8) for patients with viruses, and 1 month (IQR 0.75 to 1) for patients with parasites (log-rank P=0.001). Sixty-nine unique pathogens (83% bacteria) were identified on all tests. Escherichia coli was the most common species (71%), of which enteropathogenic E. coli was predominant (38%). CONCLUSIONS: The E. coli species, specifically enteropathogenic E. coli, may be implicated in the development of IBD. This is one of the first studies to evaluate the results of stool GIPCR in the link between the microbiome and IBD pathogenesis.

STAT signaling in the intestine.

The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.

Risk of Adverse Outcomes in Hospitalized Patients With Autoimmune Disease and COVID-19: A Matched Cohort Study From New York City.

OBJECTIVE: To examine the effect of autoimmune (AI) disease on the composite outcome of intensive care unit (ICU) admission, intubation, or death from COVID-19 in hospitalized patients. METHODS: Retrospective cohort study of 186 patients hospitalized with COVID-19 between March 1, 2020, and April 15, 2020 at NewYork-Presbyterian Hospital/Columbia University Irving Medical Center. The cohort included 62 patients with AI disease and 124 age- and sex-matched controls. The primary outcome was a composite of ICU admission, intubation, and death, with secondary outcome as time to in-hospital death. Baseline demographics, comorbidities, medications, vital signs, and laboratory values were collected. Conditional logistic regression and Cox proportional hazards regression were used to assess the association between AI disease and clinical outcomes. RESULTS: Patients with AI disease were more likely to have at least one comorbidity (87.1% vs 74.2%, P = 0.04), take chronic immunosuppressive medications (66.1% vs 4.0%, P < 0.01), and have had a solid organ transplant (16.1% vs 1.6%, P < 0.01). There were no significant differences in ICU admission (13.7% vs 19.4%, P = 0.32), intubation (13.7% vs 17.7%, P = 0.47), or death (16.1% vs 14.5%, P = 0.78). On multivariable analysis, patients with AI disease were not at an increased risk for a composite outcome of ICU admission, intubation, or death (ORadj 0.79, 95% CI 0.37-1.67). On Cox regression, AI disease was not associated with in-hospital mortality (HRadj 0.73, 95% CI 0.33-1.63). CONCLUSION: Among patients hospitalized with COVID-19, individuals with AI disease did not have an increased risk of a composite outcome of ICU admission, intubation, or death.

Relationship Between Dietary Fiber Intake and Short-Chain Fatty Acid-Producing Bacteria During Critical Illness: A Prospective Cohort Study.

BACKGROUND: Dietary fiber increases short-chain fatty acid (SCFA)-producing bacteria yet is often withheld in the intensive care unit (ICU). This study evaluated the safety and effect of fiber in ICU patients with gut microbiome sampling. METHODS: This was a retrospective study nested within a prospective cohort. Adults were included if newly admitted to the ICU and could receive oral nutrition, enteral feedings, or no nutrition. Rectal swabs were performed at admission and 72 hours later. The primary exposure was fiber intake over 72 hours, classified in tertiles and adjusted for energy intake. The primary outcome was the relative abundance (RA) of SCFA producers via 16S RNA sequencing and the tolerability of fiber. RESULTS: In 129 patients, median fiber intake was 13.4 g (interquartile range 0-35.4 g) over 72 hours. The high-fiber group had less abdominal distension (11% high fiber vs 28% no fiber, P < .01) and no increase in diarrhea (15% high fiber vs 13% no fiber, P = .94) or other adverse events. The median RA of SCFA producers after 72 hours was 0.40%, 0.50%, and 1.8% for the no-, low-, and high-fiber groups (P = .05 for trend). After correcting for energy intake, the median RA of SCFA producers was 0.41%, 0.32%, and 2.35% in the no-, low-, and high-corrected-fiber categories (P < .01). These associations remained significant after adjusting for clinical factors including antibiotics. CONCLUSIONS: During the 72 hours after ICU admission, fiber was well tolerated, and higher fiber intake was associated with more SCFA-producers.

Anesthesia Assistance in Screening Colonoscopy and Adenoma Detection Rate Among Trainees.

BACKGROUND AND AIMS: The use of anesthesia assistance (AA) for screening colonoscopy has been increasing substantially over the past decade, raising concerns about procedure safety and cost without demonstrating a proven improvement in overall quality indicators such as adenoma detection rate (ADR). The effect of AA on ADR has not been extensively studied among trainees learning colonoscopy. We aimed to determine whether type of sedation used during screening colonoscopy affects trainee ADR. METHODS: Using the electronic endoscopy databases of two hospitals in our medical center, we identified colonoscopies performed by 15 trainees from 2014 through 2018, including all screening examinations in which the cecum was reached. Multivariable logistic regression was used to determine factors associated with adenoma detection. RESULTS: We identified 1420 unique patients who underwent screening colonoscopy by a trainee meeting the inclusion criteria. Of these, 459 (32.3%) were performed with AA. Overall trainee ADR was 39.6%, with ADR increasing from 35.0% in year one of training to 42.8% in year three (p = 0.047). ADR for cases with AA was 37.9%, while ADR for conscious sedation cases was 32.0% (p = 0.374). Despite this 5.9% absolute difference, the use of AA was not associated with finding an adenoma on multivariable analysis when controlling for patient age, sex, smoking status, body mass index, trainee year of training, mean withdrawal time, supervising attending ADR, and bowel preparation quality (OR 0.85; 95% CI 0.67-1.09). CONCLUSIONS: Despite providing the ability to more consistently sedate patients, the use of AA did not affect trainee ADR. These results on trainee ADR and sedation type suggest that the overall lack of association between AA use and ADR is applicable to the trainee setting.

The Microbiome in Celiac Disease.

The healthy microbiome is necessary for normal immune development in the gut. Alterations in the microbial makeup after a critical window increase the risk of autoimmunity, including celiac disease. Although this dysbiosis has been described in adult and pediatric patients, factors leading to dysbiosis are still being elucidated. Genetics has some role in determining the microbiome makeup of the host, but other factors have yet to be determined. The microbiome remains an important therapeutic target in many autoimmune conditions, including celiac disease, however studies have yet to determine the ideal replacement therapy to correct the dysbiosis.

Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease.

AIMS: Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associated with high morbidity, requires identification of a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs) for diagnosis. However, data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII are limited. METHODS: We analysed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active CD, 172 CD on gluten-free diet (GFD), 33 RCDI, and three RCDII patients and 14 patients without CD. TCR-GR patterns were divided into clonal, polyclonal and prominent clonal peaks (PCPs) and these patterns were correlated with clinical and pathological features. RESULTS: Clonal TCR-GR products were detected in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with GFD. PCPs were observed in all disease phases (range 12%-33%). There was no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). A higher frequency of surface CD3(-) IELs was noted in cases with clonal TCR-GR, but the PCP pattern did not show associations with any clinical or pathological feature. Persistence of clonal or PCP pattern on repeat biopsy was seen for up to 2 years without evidence of RCDII. CONCLUSIONS: Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD.

Commercially available glutenases: a potential hazard in coeliac disease.

BACKGROUND: The only treatment for celiac disease (CD) is a gluten-free diet (GFD). However, there is interest among patients in a medical therapy to replace or help with a GFD. Therapies include gluten-degrading enzymes (glutenases). There are glutenases available marketed as dietary supplements that have not been demonstrated to digest the toxic epitopes of gluten. METHODS: We investigated the contents, claims, and disclaimers of glutenase products and assessed patient interest using Google AdWords to obtain Google search frequencies. RESULTS: Among 14 glutenase product, all contained proteases, eight contained X-prolyl exopeptidase dipeptidyl peptidase IV, two did not state the protease contents, and eight failed to specify the name or origin of all proteases. Eleven contained carbohydrases and lipases and three probiotics. One declared wheat and milk as allergens, two contained herbal products (type not stated) and one Carica papaya. Thirteen claimed to degrade immunogenic gluten fragments, four claimed to help alleviate gastrointestinal symptoms associated with eating gluten. Disclaimers included not being evaluated by the US Food and Drug Administration and products not intended to diagnose, treat, cure, or prevent any disease. On Google AdWords, the search frequency for the product names and the search terms was 3173 searches per month. CONCLUSIONS: The names of these products make implicit claims that appear to be supported by the claims on the labels and websites for which there is no scientific basis. Google search data suggest great interest and therefore possible use by patients with CD. There needs to be greater oversight of these 'drugs'.

The impact of acid suppression medications and non-steroidal anti-inflammatory drugs on clinical and histologic features in celiac disease.

INTRODUCTION: The prevalence of celiac disease (CD) in the US has increased in past decades, as has use of proton pump inhibitors (PPIs), histamine-2-receptor antagonists (H2RAs), aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs). We aimed to measure the association between medication use and distribution of villous flattening (VF) among newly diagnosed CD patients. METHODS: We performed a cross-sectional study of adult patients with newly-diagnosed CD at two institutions. We collected data on regular use of these medications, clinical presentation, CD serologic status, and distribution of VF. We compared current ASA/NSAID users to non-users, and current PPI/H2RA users to non-users, with regard to these clinical characteristics. RESULTS: Of 148 patients with newly-diagnosed CD, current users of ASA/NSAIDs were older than non-users (47 vs 39 years, p=0.003) and users of PPI/H2RAs were older than non-users (48 vs 39 years, p=0.004). PPI/H2RA users comprised 12% of seropositive patients, compared to 55% of seronegative patients (p<0.01). Patient gender and distribution of villous flattening in the bulb and distal duodenum did not differ by PPI/H2RA or ASA/NSAID use. CONCLUSIONS: PPI/H2RA use was associated with seronegative CD. Given the effect of these medications on gastric milieu, the impact of these drugs on presentation and course of CD deserves further investigation.

Microbiome as mediator: Do systemic infections start in the gut?

The intestinal microbiome is emerging as a crucial mediator between external insults and systemic infections. New research suggests that our intestinal microorganisms contribute to critical illness and the development of non-gastrointestinal infectious diseases. Common pathways include a loss of fecal intestinal bacterial diversity and a disproportionate increase in toxogenic bacterial species. Therapeutic interventions targeting the microbiome - primarily probiotics - have yielded limited results to date. However, knowledge in this area is rapidly expanding and microbiome-based therapy such as short-chain fatty acids may eventually become a standard strategy for preventing systemic infections in the context of critical illness.

Clinical manifestations of celiac disease.

Celiac disease (CD) is an immune-based condition affecting multiple organ systems. Clinical manifestations are manifold in form and number due to the multisystem nature of CD. There has been a progressive change in the clinical manifestations over the recent decades with fewer patients, both adults and children, presenting with a diarrheal, classical form. This, in children, is seen in only the youngest, while growth issues, screening at-risk groups and recurrent abdominal pain are the most common modes of presentation among children. Among adults, diarrhea is the most common presentation followed by anemia. Screening at-risk groups, metabolic bone disease and incidental recognition at endoscopy performed for reflux are the other main modes of presentation. The bulk of those with CD remain undiagnosed. The symptoms are often common, and increased medical education should lead to greater awareness in the medical community and an increased rate of diagnosis.

When combination therapy isn't working: emerging therapies for the management of inflammatory bowel disease.

Although antagonists of tumor necrosis factor have resulted in major therapeutic benefits in inflammatory bowel disease, the magnitude and durability of response are variable. Similar to previously available drugs such as 5-aminosalicylates and immunomodulators, the therapeutic effect is not universal leaving many people searching for options. The development of newer agents has benefited from advances in the understanding of the pathophysiology of the disease. Uncontrolled activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules are broadly targeted for therapeutic intervention. There is increasing evidence of an important role of the innate immune system and the intestinal epithelium, and the therapeutic paradigm is also shifting from immunosuppression to the reinforcement of the intestinal barrier, and modification of the disease process. In this review, we explore the limitation of current therapy as well as mechanisms of actions of new drugs and the efficacy and adverse events from data from clinical trials.