XVIII Latin American Congress

Abstract

Introduction Carlos A. Velasco-Benítez Department of Pediatrics, University of Valle, Cali, Colombia. The author reports no conflicts of interest. In the 35-year history of the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN), this is the second supplement of the Journal of Pediatric Gastroenterology and Nutrition that we have edited. Within the framework of the XVIII Latin American Congress and the IX Iberoamerican Congress for our specialty, we used this opportunity to find articles written by the present presidents of the American society and the European society, as well as those responsible for this great event that was held November 19–21, 2011, in Punta Cana, Dominican Republic, and some other members of LASGPHAN. With this, the authors of the articles of charge allow their experiences are familiar to Latino and Iberian American peers and globally, leading again to the interaction between different societies that we are part of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition. Management of Chronic Hepatitis B and C Virus Infection in Children: A 2011 Update Kathleen B. Schwarz Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD. The author reports no conflicts of interest. Both hepatitis B virus (HBV) and hepatitis C virus (HCV) are global health problems. Much has been written about these 2 infections in adults. Knowledge about epidemiology, pathogenesis, monitoring, natural history, and antiviral therapy of these infections in infants, children, and adolescents has emerged much more slowly than it has in adults. Nonetheless, in the last decade, much has been learned about the pediatric issues; this review updates these areas of knowledge for these 2 major pathogens. HBV The number of children with HBV infection is not known. However, it is reasonable to assume that a significant proportion of the 370 million individuals in the world with this infection are in the pediatric age group because maternal–fetal transmission remains the major mode of acquisition in much of the world. The infection is most common in Asia and Africa, but as many as 1 million adults in North America have the infection, which is considered an area of low endemicity. In Latin America, there are marked regional differences in prevalence rates. In the late 1990s, seropositive rates (positive for immumoglobulin [Ig] M or IgG anti-core antibody) were highest in the Dominican Republic (∼20%) and the Amazon basin and lowest in Chile (0.6%) (1). Prevalence rates increase in late adolescence, suggesting that sexual transmission is the major mode of transmission. HBV is a vaccine-preventable disease. Administration of active and passive vaccine within 12 hours of birth of an infant born to a mother known to have the infection is 95% protective if followed up with completion of the active vaccination series in the first 6 months of life. In infants born from high-risk mothers (those with HBV DNA >2 million cpm and/or those who had an infant previous who contracted the infection despite vaccination), however, as many as 30% of infants who are appropriately vaccinated still contract the infection. For this reason, there is active investigation about the utility of administering antiviral therapy during the third trimester of pregnancy to these high-risk mothers (2). There are several stages of HBV infection in children: immune active, immune tolerant, or inactive carriers. The immune active phase is characterized by elevated liver enzymes, detectable HBV DNA, and, usually, positive tests for HBeAg, although there are a few children with HBeAg-negative hepatitis. Individuals with immune active disease are always HBsAg positive. The immune-tolerant phase is characterized by a high viral load, normal liver enzymes, and positive tests for HBsAg and HBeAg. For inactive carriers, the only sign of infection is HBsAg positivity. They have seroconverted to HBeAb, have normal liver enzymes, and HBV DNA below the lower limit of detection. According to published articles on the long-term follow-up, the passage from tolerance to active and finally inactive phase would occur in >11% of infected children every year who are between ages 2 and 9 to 10 years (3,4). In these reports, >85% of children seroconverted before age 18 years from HBeAg positive/Anti–HBe negative to HBeAg negative/Anti–HBe positive (inactive phase), most of them with nondetectable HBV DNA in serum. Such passage from tolerance-active-inactive phases occurred similarly in treated or untreated children (5). A group of pediatric hepatologists experienced in monitoring and treating children with HBV infection recently published guidelines on monitoring (6). The frequency of performing liver enzymes, hepatitis B serology, HBV DNA, α-fetoprotein, and liver ultrasound to screen for cancer was outlined in some detail. The same group also published detailed guidelines on whom to treat and what agents to consider (7). These recommendations are summarized briefly. It is clear that asymptomatic carriers require no antiviral treatment; however, because children may move from one stage to another, periodic monitoring is still indicated for this group. Generally speaking, immune-tolerant children do not respond to single-agent therapy, and treatment outside clinical trials is not indicated; however, D’Antigua et al (8) did publish a small pilot study demonstrating that 8 weeks of treatment with lamivudine to decrease the viral load followed by interferon and lamivudine for 40 weeks was effective in achieving HBeAg seroconversion and loss of HBV DNA in approximately 25%. There is agreement that children with immune active disease should be considered for treatment. α-Interferon and lamivudine were the first drugs to be approved by the Food and Drug Administration for treatment of children with HBV infection. α-Interferon is given 3 times per week for 24 weeks and is generally the treatment of choice (7). Although pegylated interferon is efficacious in adults with HBV infection, it is not approved for subjects younger than 18 years. α-Interferon is approved for children ages 1 year and older. It should not be given to children younger than 12 months because of the risk of spastic diplegia in up to 20% (9). Lamivudine is well tolerated but is associated with unacceptably high drug-resistance rates: 23% after 1 year of therapy in children and 70% after 3 years of therapy in adults. Adefovir dipivoxil is approved in children ages 12 years and older but was not effective in younger subjects. Entecavir is presently approved for children ages 16 years and older and is a greatly effective nucleoside analogue, which inhibits the reverse transcriptase of HBV. In adults, drug-resistance rates remain extremely low after 5 years of therapy. A small phase I pilot study and a large multicenter trial of entecavir in children ages 2 to 18 years are under way. Tenofovir and telbivudine are approved in children ages 16 years or older (7). A potential problem with all of the nucleoside/nucleotide analogues is hepatic flare when the drugs are discontinued because none of the agents developed thus far are able to clear the closed circular cytoplasmic DNA template of the virus. HCV The number of children in the world with chronic HCV is not known, but it has been estimated that in North America, there are approximately 20,000 to 40,000 (10). There are approximately 170 million subjects in the world infected with HCV. Because maternal–fetal transmission is the only source of new infections that cannot be prevented, it is anticipated that an increasing number of the world's individuals with this infection will be children who acquired it from their mothers. The worldwide prevalence of HCV is approximately 3.1%, but Latin America actually has one of the lowest prevalence rates globally, approximately 1.23% (11). In contrast to HBV, HCV is not a vaccine-preventable disease. Transmission via injection drug use and shared needles is thought to be the most common mode of transmission in adults, whereas in children, transmission is generally via the maternal fetal route, about 4% to 5% of infected mothers transmit the infection to their offspring. Analogous to the situation with HBV, mothers with high titers of HCV (>2 million cpm) have the highest risk of transmission. Cesarean section does not prevent transmission. There is some suggestion that the use of fetal monitoring increases transmission to the offspring (12), so this practice should be avoided. HCV in children is generally asymptomatic, although there are a number of children with HCV who have developed end-stage liver disease during childhood and who have undergone liver transplantation (13). There are a few cases of hepatocellular carcinoma developing during childhood in children with the infection (14). According to the American Academy of Pediatrics, the most cost-effective way of testing infants born to mothers with HCV infection is to wait until the child is 18 months old and then do an enzyme-linked immunosorbent assay test for anti-HCV antibody. The reason for this recommendation is that maternal antibody may last for months. If the anti-HCV test is positive at 18 months, then there is clear evidence that the antibody is that of the infant and not of the mother. If the antibody at 18 months is positive, there should be verification of active infection by HCV RNA quantitative testing, and the genotype should be determined. Children with chronic HCV frequently have normal liver enzymes or enzymes just above the upper limit of normal. Generally, liver biopsies show mild inflammation and periportal fibrosis, but advanced disease can be seen (15). One of the major management decisions is whether to treat, and if so, with what. A large uncontrolled European trial of pegylated interferon and ribavirin showed that about half of the children with genotype 1 (the interferon-resistant genotype) will develop a sustained viral response to that combination therapy, whereas response rates in children with non-1 genotypes were much higher, on the order of 80% (16). A large multicenter prospective controlled North American trial of pegylated interferon plus or minus ribavirin in children provided conclusive evidence that it is necessary to add ribavirin to pegylated interferon to increase both the end-of-treatment response and the sustained viral response (17). Pegylated interferon plus ribavirin has been approved for children ages 3 years and older. Although treatment guidelines have not been elaborated, there is much agreement among pediatric hepatologists that early aggressive treatment at age 3 years or older is generally well tolerated. If the child living with the stigma of chronic HCV and the fear of developing cirrhosis and cancer as an adult can be converted into a normal child by antiviral therapy, then the effort seems well justified. REFERENCES 1. Parana R, Almeida D. HBV Epidemiology in Latin America. J Clin Virol 2005;34(suppl 1):S130–S133. 2. Degli Esposti S, Shah D. Hepatitis B in pregnancy: challenges and treatment. Gastroenterol Clin North Am 2011;40:355–372. 3. Bortolotti F, Guido M, Bartolacci S, et al. Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study. Hepatology 2006;43:556–562. 4. Marx G, Martin SR, Chicoine JF. Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins. Infect Dis 2002;186:295–301. 5. McMahon BJ, Bulkow LR, Singleton RJ, et al. Elimination of hepatocellular carcinoma and acute hepatitis B in children 25 years after a hepatitis B newborn and catch-up immunization program. Hepatology 2011;54:801–807. 6. Haber BA, Block JM, Jonas MM, et al. Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B. Pediatrics 2009;124:e1007–e1013. 7. Jonas M, Block JM, Haber BA, et al. Treatment of children with chronic hepatitis b virus infection in the United States: patient selection and therapeutic options. Hepatology 2010;52:2192–2205. 8. D’Antiga L, Aw M, Atkins M, et al. Combined lamivudine/interferon-alpha treatment in “immunotolerant” children perinatally infected with hepatitis B: a pilot study. J Pediatr 2006;148:228–233. 9. Michaud AP, Bauman NM, Burke DK, et al. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope 2004;114:1231–1236. 10. Jhaveri R, Grant W, Kauf TL, et al. The burden of hepatitis C virus infection in children; estimated direct medical costs over a 10-year period. J Pediatr 2006;148:353–358. 11. Mendez-Sanchez N, Gutierrez-Grobe Y, Kobashi-Margain RA Epidemiology of HCV infection in Latin America. Ann Hepatol 2010;9(suppl 1):S27–S29. 12. Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinataltransmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880–1889. 13. Barshes NR, Udell IW, Lee TC, et al. The natural history of hepatitis C virus in pediatric liver transplant recipients. Liver Transpl 2006;12:1119–1123. 14. González-Peralta RP, Langham MR Jr, Andres JM, et al. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2009;48:630–635. 15. Goodman ZD, Makhlouf HR, Liu L, et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C trial. Hepatology 2008;47:836–843. 16. Wirth S, Ribes-Koninckx C, Calzado MA, et al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52:501–507. 17. Schwarz KB, Gonzalez-Peralta RP, Murray KF, et al. The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology 2011;140:450.e1-8.e1. What's New in Celiac Disease? Valentina Discepolo, Riccardo Troncone European Laboratory for the Investigation of Food Induced Diseases (ELFID), Department of Pediatrics, University Federico II, Naples, Italy. The authors report no conflicts of interest. Celiac disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of wheat gliadin and related prolamines, affecting human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8–positive individuals. It is characterized by its presence in the serum of anti-tissue transglutaminase 2 (TG2) antibodies and gluten-dependent clinical manifestations. The most common clinical presentation of CD is enteropathy caused by an inflammatory response activated by gluten in the gut that leads to villous atrophy and crypt hyperplasia. The prevalence of CD is high in Western countries, especially in Europe, despite large discrepancies in adult age across different countries (1). Considering positive anti-TG2 and anti-endomysium antibodies (EMA), the overall prevalence of the disease was estimated to be approximately 1% of the general population. In adult subjects ages 30 to 64 years, CD showed a prevalence of 2.4% in Finland, 0.3% in Germany, and 0.7% in Italy (2). The prevalence of antibody-positive individuals is estimated to be approximately 0.8% in the United States, with >90% of these individuals showing the histological lesions typical of CD (3). Significant recent progress has been made in different areas of research in CD. Here we briefly review the most recent findings in genetics as well as the most promising therapeutic and preventive strategies being developed to find an alternative to the gluten-free diet (GFD). WHAT'S NEW IN GENETICS? Susceptibility to CD is significantly influenced by genetic factors, as suggested by the high familial aggregation and by the fact that approximately 75% of monozygotic twins are concordant for the disease (4). The concordance rate among HLA-identical siblings is approximately 30%, indicating that a significant part of the genetic susceptibility maps to the HLA region on chromosome 6. In fact, specific HLA-DQA1 and HLA-DQB1 risk alleles are necessary, but not sufficient, for disease development. Approximately 95% of celiac patients express HLA-DQ2, compared with 30% of the general population, and the remaining 5% carries HLA-DQ8 (5). Individuals homozygous for DQ2 or heterozygous for DQA1*05(α-chain)-DQB1*02(β-chain)/DQA1*0201-DQB1*02 were found to have a 5-fold increased risk of developing CD. This phenomenon seems to be attributable to the presence of a second DQB1*02 allele next to 1 DQA1*05-DQB1*02 haplotype, independently of the second DQA1 allele (4–6). The risk for the sibling of a patient with CD to develop CD was estimated to be 10%, ranging from 0.1% to >25% when the HLA-DQ haplotypes of the patient, the parents, and the sibling are considered. According to this approach, 3 risk groups were identified: very low risk (<1%), high risk (between 1% and 10%), and very high risk (>25%) to develop CD (6). The well-established role of HLA-DQ heterodimers is to present gluten peptides to CD4+ T cells, activating a proinflammatory immune response in the gut. HLA alleles are responsible for 40% of the global genetic risk for CD, whereas the remaining 60% of the genetic susceptibility is the result of an unknown number of non-HLA genes, each of which is expected to contribute some effect. The first genome-wide association study, performed in 2007, identified the interleukin (IL)-2/IL-21 risk locus (4q27) related to CD (7). Subsequent studies implicated 12 further risk regions, most of which contain candidate genes that have a functional role in the immune system. Many of the identified celiac loci overlap with ones related to other immune-related diseases (8–10). The autoimmune diseases, which show the strongest overlap with CD in terms of genetic susceptibility, are type 1 diabetes mellitus and autoimmune thyroiditis, as confirmed by epidemiological observations. The strongest associations outside the HLA and the 4q27 region were found in the RGS1 gene, in the 3p21 region, encoding multiple chemokine receptors, in the 2q11–12 region that encodes for IL-18 receptor subunits, and in the LPP gene, whose role in CD pathogenesis remains to be determined (7). A second genome-wide association study was performed in 2010. Thirteen novel risk regions with genome-wide significant evidence of association were found, including regions containing genes that have obvious immunological functions (eg, CCR4, CD80, ICOSLG, TNFRSF14, and ZMIZ1) (11). An additional 13 regions met “suggestive” criteria for association, containing multiple genes involved in the immune response, including CD247, FASLG/TNFSF18/TNFSF4, IRF4, TLR7/TLR8, TNFRSF9, and YDJC. The authors found that approximately 71% of expression quantitative trait loci single nucleotide polymorphisms showed a negative effect on gene expression, suggesting that most of the single nucleotide polymorphisms related to CD evoke a downregulation of gene expression. The authors refined their findings, identifying 4 different groups of genes corresponding to immunological pathways: T-cell development in the thymus, innate immune detection of viral RNA, T- and B-cell co-stimulation (or co-inhibition), and cytokines, and chemokines and their receptors (11). These data together suggest that immunological alterations, more than intestinal barrier dysfunction or digestive enzymes function impairment, are involved in the pathogenesis of CD (5,12). The improved knowledge about non-HLA genes has allowed a more precise quantification of the risk of developing the disease. Considering non-HLA genes, a new model has been developed to improve the identification of high-risk individuals and to move toward an early diagnosis and better prognosis estimation in high-risk families and population-based screening. Romanos et al (13) showed that individuals carrying >13 non-HLA risk alleles had a higher risk of developing CD compared with those carrying from 0 to 5 risk alleles. Combining HLA and non-HLA risk genotypes in a unique model, the sensitivity in identifying high-risk patients increased by 6.2% compared with using only HLA risk alleles. Approximately 50% of the genetic heritability of CD has yet to be explained. A possible role of epistatic interactions between risk genes has been hypothesized, amplifying otherwise common variants or, conversely, greatly penetrant but rare mutations, which still need to be identified, and this may explain the missing heritability (14). Abadie et al (14) proposed a model of CD pathogenesis that integrates genetic and immunological factors. According to this model, intestinal T-cell immune responses need to reach a threshold to be able to induce tissue damage. This threshold depends on several elements: the dosage effect of the HLA genes, the posttranslational modifications that increase the binding affinity of the antigen to the HLA molecule, and the recruitment of TCR repertoires able to recognize the antigens. Furthermore, the authors analyzed the 64 actually known candidate genes and found that 40 of these 64 genes can be considered to be part of a functional network. Moreover, some of these genes are associated with the IL-15 and the interferon (IFN)-α pathways, both known to play a crucial role in CD pathogenesis. In accordance with these observations, the authors suggest that patients with CD may be divided into 3 main subgroups, depending on the combination of genetic susceptibility markers, which can determine their functional phenotype: IL-15 high expressers, IFN-α high expressers, and IL-15/IFN-α high expressers. Ultimately, they imagine a heterogeneous disease in which environmental factors and genetic susceptibility genes can interplay determining whether a subject could develop CD once gluten consumption starts, or if other factors are required to develop the disease. Further studies are needed to assess this intriguing hypothesis. WHAT'S NEW IN DIAGNOSIS? Presently, the diagnosis of CD is made on the basis of 2 mandatory criteria: the finding of intestinal villous atrophy with crypt hyperplasia and abnormal surface epithelium while the patient is on a gluten-containing diet (GCD), and a full clinical remission after removal of gluten from the diet (15). The finding of circulating IgA anti-TG2 antibodies and EMA at the time of diagnosis and their disappearance while receiving a GFD adds weight to the diagnosis (16). The European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) has set up a working group to define new diagnostic guidelines for CD. These recommendations provide for the first time the possibility of avoiding the need for an intestinal biopsy to confirm the diagnosis of CD in a specific subset of patients (17). Laboratory Tests The most specific laboratory tests used in the diagnostic evaluation of CD are anti-TG2 antibodies or EMA in the blood. Also, tests measuring antideamidated gliadin peptides could be reasonably specific; these antibodies appear particularly useful in children younger than 2 years or in uncertain cases. Interpreting antibody test results should also take into account the total IgA level in the serum, the age of the patient, the gluten dietary intake, and any use of immunosuppressive drugs. Short-term gluten exposure or long-term GFD may result in unreliable negative results. In IgA-competent subjects, the results of CD-specific IgA class antibodies should be primarily taken into account, whereas in individuals showing low-serum IgA levels (total IgA <0.2 g/L), conclusions should be drawn considering CD-specific IgG class antibodies. To reveal the presence of HLA-DQ2 and HLA-DQ8 molecules, HLA testing can be a useful tool to exclude CD if both markers are absent. This test should also be used in individuals with an uncertain diagnosis of CD to add strength to the diagnosis. HLA testing also may be performed in asymptomatic at-risk subjects to select those who are in need of further investigation. Histological Evaluation The gut architectural features found in patients with CD may vary among several levels of degradation and are not specific for CD because they can be found in other enteropathies. The intestinal lesions may have a patchy distribution and, in a small group of patients, only appear in the duodenal bulb. On this basis, according to the new ESPGHAN diagnostic criteria, multiple biopsies (at least 5) should be taken, preferably during upper endoscopy, and analyzed reporting details regarding the orientation of the specimen and the features of the villi. The degree of villous atrophy and crypt elongation should be analyzed in particular, including the villous–crypt ratio, counting of intraepithelial lymphocytes, and a grading according to Marsh-Oberhuber (18). Diagnostic Approach The ESPGHAN guidelines provide recommendations about the diagnostic approach to some specific subsets of patients. Testing for CD-specific antibodies can be used as a first diagnostic tool to select subjects for whom further investigation is required. In patients showing negative anti-TG2 antibodies and EMA but presenting severe symptoms and a strong clinical suspicion of CD, small intestinal biopsies and HLA testing should be performed in addition. If histology shows enteropathy, but DQ2/DQ8 heterodimers are not present, CD is not likely. In subjects presenting clinical symptoms suggestive of CD and high titers of anti-TG2 antibodies (>10-fold), the likelihood for villous atrophy is high. In these cases, intestinal biopsy could be avoided if EMA and HLA testing are also found to be positive. In asymptomatic individuals at risk for CD, HLA testing is recommended as a first-line test to select patients who need further investigation. If the patient carries the DQ8 and/or DQ2 allele, then CD-specific antibody tests should be performed, and, if positive, the demonstration of an enteropathy (by performing upper endoscopy) should always be part of the diagnostic approach. A GFD should be introduced only after a conclusive diagnosis has been made because patients receiving a GFD when the diagnosis is still undefined may affect both histological and serological results. According to the last ESPGHAN criteria, unclear symptomatic cases unresponsive to the GFD and patients with an uncertain diagnosis may require further investigation, including gluten challenge and intestinal biopsies. WHAT'S NEW IN THERAPY? The overall accepted treatment for CD is presently lifelong avoidance of dietary intake of gluten. The gluten threshold considered to be safe for patients with CD is approximately 10 mg/day. Such a dietary regimen can be demanding and sometimes socially frustrating for patients with CD. Thus, there is the need to develop new dietary and nondietary approaches to treat CD. Different therapeutic strategies have been proposed and several more could be developed in the future, according to the present knowledge of CD pathogenesis. Furthermore, a mouse model is strongly needed to test the different possible treatments and a reliable marker is also required to test their efficacy. Several approaches may be proposed for treatment of CD, from already available generic drugs that could find a new potential use in the treatment of CD to investigational new drugs that have already been advanced and are undergoing clinical trials. Some molecules under investigation to treat other autoimmune diseases could also be relevant to CD therapy (19). Because gluten is one of the most common elements of the human diet, avoiding its intake presents a challenge for many patients with CD, and it would be far easier if patients with CD were able to eat minimal amounts of gluten per day. Accordingly, gluten-detoxifying strategies are in development. Most of the toxic gluten peptides are greatly resistant to proteolysis because gastric and pancreatic endoproteases are unable to cleave after the proline or glutamine residues that are ubiquitous within gluten peptides, and the brush border enzymes cannot cleave long peptides. This scenario leads to the accumulation of long fragments within the gut lumen, which can elicit an HLA-DQ2- or HLA-DQ8-restricted T-cell response in patients with CD. Based on this observation, a potential treatment with exogenous proline- and/or glutamine-specific proteases has been proposed; these enzymes could accelerate gluten detoxification. ALV003 and AN-PEP are 2 glutenases that are being tested in clinical trials, even if the exact amount of gluten that can be detoxified by a given enzyme-based drug dose has yet to be assessed (20,21). Moreover, polymers able to sequester gluten have been tested as a possible alternative strategy to block the toxic effects of gluten in the small bowel. Both in vitro and in vivo (22) experiments showed that one of these polymers, P(HEMA-co-SS), can bind gluten peptides and reduce their toxicity (23). Another possible therapeutic strategy envisaged to treat CD is to reduce intestinal permeability, which has been reported to be increased in patients with CD. Zonulin is a protein claimed to be greatly expressed in the gut of patients with CD, whose serum levels have been shown to correlate with increased gut permeability. AT-1001 (lorazatide) is a zonulin antagonist that is undergoing phase II clinical trials in patients with CD. The intestinal permeability induced by gluten intake also could be reduced by selectively inhibiting RhoA or ROCK (rho kinase), the 2 molecules known to be relevant in regulating tight junction structure (19). TG2 is responsible for the deamidation of gluten peptides, a process needed for their presentation by antigen-presenting cells. It also may have other functions in the pathogenesis of CD, although not all of them have been completely clarified. TG2 antagonists can even play a role in the treatment of