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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e318272adf4
Special Feature

World Perspective on Celiac Disease

Catassi, Carlo*; Anderson, Robert P.; Hill, Ivor D.§; Koletzko, Sibylle||; Lionetti, Elena; Mouane, Nezha#; Schumann, Michael**; Yachha, Surender K.††

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*Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy

ImmusanT Inc, Cambridge MA

§Wake Forest University School of Medicine, Winston-Salem, NC

||Dr von Haunersches Kinderspital, Kinderklinik und Kinderpoliklinik der Ludwig Maximilian Universität München, München, Germany

University Department of Pediatrics, Catania, Italy

#Pediatric Department of Gastroenterology Nutrition, Hospital Ibn Sina, University Mohammed V, Rabat, Morocco

**Klinik für Gastroenterologie, Rheumatologie und Infektiologie, Campus Benjamin Franklin, Charité—Universitätsmedizin, Berlin, Germany

††Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Address correspondence and reprint requests to Prof Carlo Catassi, Department of Pediatrics, Università Politecnica delle Marche, 60123 Ancona, Italy (e-mail: catassi@tin.it).

Received 30 August, 2012

Accepted 30 August, 2012

C.C. has served as scientific consultant for Menarini Diagnostics and Dr Schär. The other authors report no conflicts of interest.

Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in genetically susceptible individuals. The gliadin and glutenin fractions of wheat gluten and similar alcohol-soluble proteins in other grains (rye and barley) are the primary environmental factors responsible for the development of the intestinal damage. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes: most of the patients with CD are HLA-DQ2–positive, and the remaining patients are mostly HLA-DQ8–positive. The typical intestinal damage is characterized by loss of absorptive villi and hyperplasia of the crypts, and it completely resolves upon elimination of gluten-containing grains from the patient's diet (1,2). Improvement of symptoms following the gluten-free diet (GFD) is not pathognomonic of CD. Nonceliac gluten sensitivity is a recently described clinical entity that will not be covered in this article, particularly because of uncertainty on its clinical presentation and frequency in the pediatric age group (3).

In the past, CD was considered a rare disorder, mostly affecting individuals of European origin, and usually characterized by onset during the first years of life. At that time, diagnosis was entirely based on the detection of typical gastrointestinal symptoms and confirmation by the small intestinal biopsy. The availability of highly sensitive and specific serological tools, first the anti-gliadin and later the anti-endomysium and the anti-transglutaminase (tTG) antibodies, clearly showed that (1) the prevalence of CD is much higher than previously thought because of the high percentage of clinically atypical or even silent forms of CD; (2) CD shows a worldwide distribution and is common in many developing areas, given the widespread distribution of gluten consumption and genetic HLA-related predisposition. Recent understanding of the pathophysiology of this autoimmune disorder paved the way to new therapeutic and preventive strategies, which are presently under scrutiny.

The course of the recent progress in CD basic and clinical research is huge. Its pace has accelerated in the last 15 years, even when compared with other research on gastrointestinal disease, for example, inflammatory bowel disorders. The global nature of CD research is reflected in the wide geographic distribution of CD research productions. Noteworthy, the Journal of Pediatric Gastroenterology and Nutrition was the number 1 highest-publishing CD research journal during the time period of 1995–2009 by a number of PubMed publications (4). In this article, we review the recent advances on CD epidemiology, diagnosis, and treatment, with a special emphasis on the different geographical scenarios.

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Two important issues have absorbed European clinicians and researchers on CD during the last decade:

1. The increasing incidence of CD with major differences between countries and possible environmental risk factors with the opportunity for intervention

2. How to diagnose CD with a high degree of certainty but the with least burden to the patient

The availability of highly sensitive and specific antibody tests allowed screening persons at increased risk and from the general population in different European countries, disclosing that ∼1% of the population is affected by CD (5,6). Clinically overt CD represents only the tip of the iceberg and most celiac cases in Europe have not been discovered so far; however, there was another interesting finding connected to studies on celiac epidemiology: apparently prevalence rates differ significantly between European countries, although the applied diagnostic tools had been identical (6). In Finland, the prevalence of CD was as high as 2.4%, whereas in Italy 0.7% and in Germany as few as 0.3% of the population of comparable age had CD. One of the highest prevalence of CD (∼3%) in Europe was reported in Swedish children born during the so-called epidemic of CD in the early 1990s (7). This prevalence is almost 6 times higher than the 0.53% reported in unselected Swedish adults screened in 1994 (8). What are the causes for the huge differences in prevalence between countries and for the increasing incidence found during the last decades in the same populations? Genetic differences between European populations appear to be an unlikely cause for the extent of the difference because HLA types at risk for CD are similarly distributed in the different countries. Likewise, genetic factors do not explain the rising incidence during the last decades, which goes in parallel with the epidemiology of other autoimmune or immune-mediated diseases, such as type 1 diabetes mellitus (T1D) (9). Therefore, environmental or lifestyle factors may be responsible for the differences between European countries and changes over time.

The Swedish epidemic of CD allowed investigating the role of early feeding habits such as the continuation of breast-feeding at the time of gluten introduction, the age at first feeding of gluten, and the amount of gluten given at the time of weaning. Several cohort studies confirmed the relevance of early feeding practices on the manifestation of CD in children at risk for CD (10). It has been estimated that 50% of celiac cases could be prevented when gluten is introduced in small amounts while the mother is still breast-feeding. Too early (within the first 3 months of life) or too late (after 6–7 months of life) introduction of gluten seems to increase the risk. This knowledge gained from retrospective or prospective observational cohort studies formed the basis of a large randomized controlled trial funded by the European Union within the 6th framework program (www.preventceliacdisease.com). Around 1000 infants with at least 1 first-degree family member with CD and positive HLA type DQ2 and/or DQ8 are randomized to receive either 100-mg gluten or placebo during the 5th and 6th month of life. Thereafter, all of the children gradually increase their gluten intake. The study will not be unblinded until 2013 when the youngest child will turn 3 years. Another prospective study is presently ongoing in Italy to investigate the relation between the age at gluten introduction and risk of CD development in infants at family risk of CD (11). The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort, including >6000 children in Europe and United States, is one of the studies aimed to identify potential risk or protective factors for the development of CD and T1D (12).

Since the previous guidelines for the diagnosis of CD of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition had been published in 1990 (13), the understanding of disease pathology has substantially increased. So far the histological examination of biopsies had the highest effect on final diagnosis, but the unambiguousness of duodenal biopsies had been questioned because lesions may be patchy or sometimes only occur in the duodenal bulb and histological findings are not always CD-specific. In addition, interpretation depends not only on orientation of the tissue but is also prone to high interobserver variability. New diagnostic guidelines had been developed and were presented to the scientific community at the annual European Society of Pediatric Gastroenterology, Hepatology and Nutrition meeting in Istanbul in 2010 and published recently (14). A systematic review on the performance of CD-specific serological tests showed that endoscopy may be omitted in a subgroup of children with symptoms of malabsorption with high titers for tissue transglutaminase IgA antibodies (>10 times cutoff values) (15). No such data are available for asymptomatic or oligosymptomatic children with high risk for CD (first-degree relative with CD or history of other CD-associated disorders). A large multicenter trial, the ProCeDE study (Prospective Celiac Disease Diagnostic Evaluation), is under way to provide prospective data to assure that the suggested diagnostic procedure is valid also in clinical practice with specificity >99%.

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The natural history of CD shows a wide variation among patients. When CD is diagnosed in adulthood, it is often impossible to establish whether the patient has a long-standing or newly developed disease. There is usually a sequential development of appearance of CD antibodies, intestinal enteropathy, onset of symptoms, and (sometimes) complications; however, the duration of each step ranges from a few weeks to decades. It was previously thought that loss of gluten tolerance leading to immunological and mucosal changes typical of CD usually developed early in life, soon after exposure to the environmental trigger (ie, at weaning), while the onset of clinical manifestations of the disease occurred much later. This concept has recently been challenged by long-term studies showing that seroconversion to CD autoimmunity may occur at any time (16). This observation suggests that genetic susceptibility and ingestion of gluten-containing grains are necessary but not sufficient conditions to lose tolerance to gluten and develop CD. Identifying both the mechanism responsible for gluten tolerance and how this tolerance is lost in subjects genetically susceptible to CD can pose the basis for breakthrough discoveries for preventing other autoimmune diseases.

The progression of gluten sensitization is not necessarily a 1-way process. Maintenance of a normal villous architecture has been described in a few adults spontaneously abandoning treatment of childhood-diagnosed CD (17); however, fluctuation from serum CD autoimmunity positivity to normal values is not rare in at-risk subjects, for example, children with T1D (18). Potential CD, characterized by a serum celiac-type antibody response associated with a normal or minimally abnormal intestinal mucosa at the biopsy, is more common than previously appreciated in children with a family history of CD and positivity of serologic CD markers. During a 2-year follow-up serum, CD markers disappeared in most young children with potential CD despite a regular diet. These “fluctuating” or “latent” cases require periodical reassessment because a proportion of them develop overt intestinal damage over time (11).

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Recognition of CD in North America (NA) has increased markedly in the last decade. Physicians are now more aware of the condition and appreciate that it occurs in approximately 1% of the population (19). The increased awareness is partly because of a national CD education campaign conducted by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Foundation based on evidenced-based guidelines for diagnosis and treatment of CD in children developed by NASPGHAN (20).

Children with CD in NA are usually identified on the basis of symptoms. These are variable and include both gastrointestinal and nongastrointestinal manifestations. Young children present predominantly with typical gastrointestinal symptoms, whereas less typical and nongastrointestinal symptoms occur more often in older children and adolescents. Asymptomatic children at increased risk for CD because of an associated condition may be identified by means of serological screening tests.

In NA it is recommended the tTG be used to test for CD. Because tTG may be less reliable in young children, it should be combined with either anti-gliadin or antideamidated gliadin peptides when testing those younger than 2 years (20). It is recommended that all of the children with typical gastrointestinal symptoms be tested for CD. Those with nontypical or nongastrointestinal manifestations should be tested if no other cause for the symptoms is found. The need to test asymptomatic children at increased risk for CD is under debate. NASPGHAN recommends testing all such cases even though no good studies have demonstrated benefits of treating asymptomatic cases. In contrast, the American Gastroenterology Association recommends only testing those at increased risk if they have a symptom associated with CD (21).

In NA it is recommended that CD be confirmed by means of an intestinal biopsy before starting treatment (20,21). Biopsies should be taken from both the duodenal bulb and more distally to increase diagnostic accuracy (22). Characteristic histological changes, symptom resolution on a GFD, and subsequent negative serological tests over time confirm the diagnosis beyond doubt (20). Nonbiopsy diagnosis of CD remains a goal and may be possible in certain cases (14); however, most physicians in NA are unwilling to diagnose CD with serological tests alone because there is no laboratory standardization of commercial tests for CD in NA and marked variability in test results between laboratories has been documented (21–23).

Recommended treatment for CD in NA is lifelong adherence to a diet that excludes all wheat, barley, and rye referred to as a GFD (20). Oats appear safe but are not generally recommended because of frequent contamination with wheat. Because the diet is burdensome, a number of novel therapies are under investigation as possible alternatives (24). To date, none has yet proven to be as effective and safe as the GFD.

In NA children at risk for CD still face a number of challenges. Despite progress made in raising awareness of the condition, there are still many who remain undiagnosed or experience prolonged diagnostic delays because of failure to use appropriate serological tests. Further education in this regard is needed. The necessity of screening asymptomatic children who belong to at-risk groups for CD also needs clarification. This speaks directly to the principle of “first, do no harm.” Finally, an emerging problem is the growing number of children who are being placed on a GFD without any testing or before the diagnosis of CD being confirmed. A GFD has become the latest fad in NA fanned by celebrities, sports stars, and others who claim health benefits from the diet. Although some may have the entity of nonceliac gluten sensitivity, (25) others may simply benefit from a more healthful diet and not need a GFD. The GFD has both social and economic consequences. The diet is not only burdensome with potential quality-of-life implications, but also more expensive and therefore should not be imposed lightly.

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In north African countries, many screening studies, using appropriate serological test methods, have supported the high prevalence of CD. For instance, the prevalence of subclinical CD in children was 0.53% in Egypt (n = 1500 children) (26), 0.6 % in Tunisia (n = 6286 schoolchildren), (27) and 1% in Libya (2920 children) (28). It is worth mentioning that one of the few mass screening studies conducted in Africa, including 989 schoolchildren, highlighted that the highest CD prevalence in the world, 5.6%, occurs in the African population of Sahrawis. The high intake of gluten-containing food, the high level of consanguinity, and the high frequency of HLA-2 and -DQ8 haplotypes in this population, genetically close and isolated, could explain this huge prevalence (29).

Turning to the burden of typical CD, it varies widely within countries and within populations. For instance, a 4.7% prevalence (7/150 children) was reported in the Egyptian study (25), compared with 22.5% (18/80 children) reported in Sudan (30). The prevalence of CD in high-risk north African population, because of immune disorder diseases, is consistent with literature data. In this case, studies have been performed particularly in T1D. A CD prevalence of 6.4% and 16.4% was reported in Egyptian and Algerian patients with T1D, respectively (26,31).

In summary, mass screening CD studies in north Africa found nearly the same prevalence of subclinical CD than in western European population. The true prevalence of symptomatic CD is more difficult to estimate, because of its clinical variability and the many immune disorder diseases associated to CD. This frequency depends on variable clinical symptoms and degree of severity of the disease, and on the accessibility to screening tests in the clinical practice; however, most studies suggested that CD is rare in sub-Saharan Africa. The few reported studies are sporadic case reports or small sample of patients with digestive and malnutrition symptoms, such as chronic diarrhea, poor appetite, weight loss, pallor, and proximal muscle wasting (32).

The prevalence of CD has not been ascertained in many African countries. Studies among African immigrant communities in developed countries have shown controversial results. Some studies report that CD may be a rare disorder, or underdiagnosed. For example, in United States, only 9 (1.3%) African American patients with CD were identified among a group of 700 biopsy-proven CD patients from 1981 to 2004 (33). No positive test was identified using mass serological screening test among 860 African Brazilian individuals from 10 African countries (34).

CD shows a variable prevalence in Africa, but the poor living condition and the limited availability of diagnostic facilities could result in the lack of awareness and low suspicion of the disease. Therefore, assessing the true prevalence of CD through mass screening test studies in general population of sub-Saharan countries is needed. Moreover, genetic studies to identify risk factors or even specific genetic protective factors should be beneficial for young children in term of prevention.

Overall, improving the management of CD in Africa is still challenging; it needs an appropriate CD IEC (information, education, communication) strategy to increase the clinical awareness of all doctors, and to implement diagnoses guidelines tests, enabling the treatment of all of the celiac patients in at-risk groups. Because of limited economic resources, an easy, efficient, and affordable diagnostic approach and methods should be developed for Africa. Additionally, CD treatment is based on GFD. This diet is mostly based on local food in African countries. Consequently, research is needed for the assessment of the risk of macro- or micronutrients deficiencies, for a nutritional support in patients with CD, and for the transfer of technology and knowledge for the manufacturing of affordable gluten-free product.

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CD is being increasingly recognized in India both in children and in adults. During the last 3 years, research thrust has been mostly focused on prevalence, identification of nondiarrheal variety, family studies, dietary compliance, and recognition of refeeding syndrome.

In a large community-based cross-sectional study in Northern India, an overall prevalence of CD was found to be 1.04%. Prevalence of 0.56% has been found among healthy blood donor from Chandigarh, India (35). In 189 children with T1D, 11% had concomitant CD, 90.5% of whom were asymptomatic and diagnosed only on screening (36). In children suffering from Down syndrome, 6% prevalence of CD was shown, with statistical significance in those with pallor. In 190 children with short stature from north India, 13.7% were found to have CD. Routine upper gastrointestinal endoscopy in patients with chronic liver disease revealed endoscopic changes in 4.4%, which was confirmed as CD by positive serology and abnormal histology. In women with primary infertility and in pregnancies with intrauterine growth restriction, seroprevalence of IgA tTG was 5.6% and 9.3%, respectively. Rates of previous preterm births, low-birth-weight infants, and cesarean section were higher in seropositive women compared with seronegative subjects. Megaloblastic anemia was found in 7% of children with CD screened in a pediatric hematology unit. The prevalence of CD among first-degree family members of children with CD was 4.4%. A total of 96.6% index cases of CD and all IgA-tTGA–positive first-degree relatives were positive for HLA-DQ2. Only 15% of the first-degree relatives were negative for HLA-DQ2/DQ8 (37).

In 1 report CD was shown to be associated with splenic calcification without features of CEC syndrome (CD, epilepsy, and cerebral calcification). These calcifications resolved after 6 weeks of GFD. An 8-year-old girl, the youngest patient reported so far, had lupus anticoagulant positivity, an uncommon association. Resolution of idiopathic pulmonary hemosiderosis (Lane-Hamilton syndrome) on GFD was seen in 3 patients followed up to 17 months.

Severely malnourished patients with CD are at risk for developing potentially life-threatening refeeding syndrome, which may mimic celiac crisis, especially in developing countries. In an observation from north India, 5 of 35 patients with CD were severely malnourished (body mass index <14 kg/m2) and were identified as life-threatening refeeding syndrome. All mimicked celiac crisis but worsened with introduction of GFD. They were managed by correction of electrolytes and gradual feeding without the need for steroids (38). In another randomized study, addition of short-course prednisolone therapy of 4 weeks along with GFD was shown to suppress apoptosis rapidly; however, prednisolone addition at the same time was shown to suppress epithelial regeneration. Thus, the authors concluded that steroids should be rapidly withdrawn after a short course of therapy. Soluble interleukin-2 receptor and interleukin-6 levels have a good correlation with CD activity and can thus be used as reliable markers for detecting minimal transgression from GFD. Dietary noncompliance to GFD was observed in 18% cases in north India, more common among adolescents, children living in joint families, and those with more number of siblings. Dietary restrictions have effect on child's social activities, and thus psychosocial parameters (PSC score) are better in the dietary compliant group (39). The Indian Council of Medical Research has adopted CD as a thrust area, with emphasis upon finding out countrywide prevalence and capacity building.

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The GFD is a safe and effective treatment option for CD; however, this diet is often difficult to sustain, owing to small levels of gluten contamination in food products and the social burden imposed by the GFD. In a minority of adult patients with so-called “refractory CD,” the disease does not respond to treatment with a GFD. Therefore, in the last decade, researchers have become increasingly interested in therapeutic alternatives for continuous or intermittent use of a GFD in patients with CD (40).

Newly developed treatment modalities for CD are based on presently available insights into the pathogenesis of the disease. These therapies focus on engineering gluten-free grains, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease in intestinal permeability by blockage of the epithelial zonuline receptor, inhibition of intestinal tTG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation byHLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten (24). The exciting history of a possible “vaccination” against CD will be briefly described herein.

In 1989, Sollid et al (41) definitively implicated HLA-DQ2.5 in CD. Around 20% of whites, western and southern Asians, and >90% of patients with CD possess the 2 genes that encode HLA-DQ2.5; it is one of a polymorphic family of receptors on antigen-presenting cells that orchestrate the specificity of immune responses by presenting short antigen-derived peptides to T cell receptors on CD4 T cells. Thus, the essential role for HLA-DQ2.5 (or DQ8 and DQ2.2, present in patients negative for HLA-DQ2.5) also predicts a central role for gluten-reactive CD4 T cells in the pathogenesis of CD. In 1993, Sollid laboratory confirmed the presence of gluten-specific, intestinal CD4 T cells in HLA-DQ2.5–positive patients, and showed almost all are restricted by HLA-DQ2.5 (42). Defining the gluten peptides recognized by CD4 T cells in CD now seemed practical and supremely important because better food tests, more palatable foods, and even pharmacological agents preventing immune recognition or inducing tolerance to gluten may be possible.

For historical and practical reasons, efforts to identify antigenic peptides mostly focused on the first fully sequenced gluten protein, A-gliadin, even though hundreds of potentially toxic gluten (gliadin and glutenin), hordein, and secalin proteins are expressed by wheat, barley, and rye, respectively. Initially, A-gliadin p31–49 was reported to be an HLA-DQ2.5–restricted T-cell epitope and then shown to cause villous atrophy when instilled into the duodenum of patients (43). These observations could not be replicated, and subsequent studies indicate this peptide has direct injurious effects when incubated with patient biopsies and immortalized cell lines. The controversy surrounding the role of A-gliadin p31–49 highlighted difficulties in interpreting the relevance of T cells cultivated in vitro. A quantitative, short-term, highly sensitive assay requiring minimal manipulation of T cells collected from patients was needed, but seemed impractical if the only source of relevant T cells was intestinal biopsies.

A further obstacle to mapping immunogenic gluten peptides was that HLA-DQ2.5 and -DQ8 preferentially bind peptides rich in glutamate and aspartate, and yet gluten proteins, unusually rich in glutamine, have few acidic amino acids. This paradox was resolved in 1998 by Sollid and Frits Koning laboratories’ finding that gliadin-specific T cells raised from intestinal biopsies preferentially respond to deamidated gliadin and recognize deamidated gluten peptides including glutamine residues converted to glutamate by tissue transglutaminase (TG2), an enzyme richly expressed in inflamed intestinal mucosa and also a target for autoantibodies in CD (44).

Searching for gluten peptide–specific T cells in blood had been discouraged because of reports by the Sollid (45) laboratory and others that T-cell lines and clones raised against gliadin using peripheral blood do not reflect the specificity of intestinal T cells; however, in 2000, Anderson et al (46) reported that 3-day oral wheat bread challenge in HLA-DQ2–positive patients following strict GFD transiently mobilizes T cells specific for deamidated gliadin at frequencies (on day 6) readily detected without in vitro expansion. When screened with overlapping peptides spanning A-gliadin pretreated with transglutaminase, these peripheral blood T cells are focused on the same 2 overlapping HLA-DQ2.5–restricted α-gliadin epitopes (47).

Blood collected after in vivo antigen challenge provides an abundant source of “relevant” gluten-specific T cells and overcomes artifacts introduced by in vitro antigen presentation and long-term culture. After “unbiased” T cell epitope mapping of peptide libraries including 16,838 candidate 12-mers derived from wheat gliadins and glutenins, barley hordeins and rye secalins with blood from >200 HLA-DQ2–positive donors after wheat, barley, or rye challenge, Tye-Din et al (48) reported in 2010 that T cells specific for just 3 immuno-dominant peptides consistently account for most gluten-specific T cells in HLA-DQ2.5–positive patients.

How could this new knowledge be used to benefit patients? The first generation of drugs designed to reduce exposure of the immune system to gluten are increasingly viewed as potential supplements to GFD. With deeper understanding of the specificity of gluten-specific T cells, a peptide-based therapeutic vaccine (Nexvax2) is now under development with the intention of restoring immune tolerance to gluten and allowing an unrestricted diet. Development of Nexvax2 draws upon clinical development of peptide immunotherapy for cat-allergic rhinitis, and proof of concept studies in an HLA-DQ2 T-cell receptor transgenic mouse.

Development of Nexvax2 is aided by some unique features of CD: tissue from the target organ can be safely accessed, relevant T cells can be sourced in blood, and exposure to the causative antigen through gluten challenge or dietary indiscretion appears to be safe and self-limited. Although much will be learnt about pharmacological manipulation of antigen-specific T cells, successful development of Nexvax2 promises to not just benefit HLA-DQ2.5–positive patients with CD, but could also serve as a template for design and development of therapeutic vaccines for other autoimmune diseases.

In summary, pharmacological treatment of CD is presently under scrutiny by basic research and clinical studies. The way to go for these alternative treatments is however still long and full of pitfalls. The GFD is still the only CD treatment option, which, regardless of the social aspect, is extremely effective and lacks any significant side effects (24).

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CD is not only a common clinical problem but it is also attracting worldwide research interest as never before from those working in a multitude of disciplines, including clinical medicine, molecular medicine, pathology, genetics, biochemistry, immunology, epidemiology, pharmacology, and food science.

Further studies are needed to quantify the incidence of CD in apparently “celiac-free” areas, as sub-Saharan Africa and the far east. In many developing countries, the frequency of CD is likely to increase in the near future, given the diffuse tendency to adopt a Western, gluten-rich dietary pattern. Because most cases presently escape diagnosis all over the world, an effort should be made to increase the awareness of CD clinical polymorphism. A cost-effective case-finding policy could significantly reduce the morbidity and mortality associated with untreated disease. The new international guidelines will facilitate the diagnostic process. Although several pharmacological agents for CD are presently under development, the GFD remains the effective and safe treatment option for patients affected with this disorder.

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