^a Calculated using sensitivity/1 – specifi city and assuming specifi city = 99% when reported as 100%.

^b Calculated using 1 – sensitivity/specifi city and assuming sensitivity = 99% when reported as 100%.

^c >1 tTG assays utilized.

Therapy

The mainstay of therapy for celiac disease is a lifelong gluten-free diet. Because biopsy findings suggesting celiac disease may also be compatible with other conditions, some clinicians advocate a follow-up biopsy to confirm remission after implementation of a gluten-free diet. However, most are satisfied with a symptomatic response. In addition to a gluten-free diet, supplemental vitamins such as iron, folic acid, or vitamin K should be given where deficiencies are documented. Calcium and vitamin D may be deficient, and consideration may be given to measuring bone mineral density, particularly in women. Although it is suggested that the institution of a gluten-free diet protects against increasing bone loss, some patients may be candidates for hormone replacement or bisphosphonate therapy [62].

Poor dietary compliance is the most common reason for failure of a gluten-free diet. However, the complications of intestinal lymphoma and adenocarcinoma must be considered. Patients with persistent symptoms in whom other diagnoses are excluded are described as having refractory sprue [63]. There are considerable uncontrolled data to support the use of corticosteroids for this indication. Anecdotal evidence suggests that azathioprine [64] and cyclosporine [65] may also be effective in patients who do not respond to corticosteroids. In one known case of steroid-refractory celiac disease, infliximab followed by azathioprine was successfully used to induce and maintain remission [66]. In a subset of patients with refractory celiac disease, there is an increase in aberrant intraepithelial lymphocytes. Denoted refractory celiac disease type II, these patients have a significantly increased lifetime risk for enteropathy associated T cell lymphoma. Due to its resistance to conventional treatment regimens the prognosis is poor, with a five-year survival of less than 50% [67]. Emerging research into novel treatment strategies have been disappointing. In an open label phase II pilot study, Al-Toma et al. [68] evaluated the use of cladribine, a cyto-toxic purine nucleoside, to treat type II refractory celiac disease. Of the 17 patients enrolled in the study, six demonstrated a clinical improvement (weight, diarrhea, hypoalbuminemia), 10 developed a histological improvement, and six had a decrease in aberrant T cells. Although one patient developed complete clinical and histological recovery, seven patients still developed fatal enteropathy associated T cell lymphoma and one died secondary to complications of emaciation. The authors concluded that cladribine may induce clinical and histological improvement in a minority of patients but does not prevent T cell lymphoma and may in fact precipitate it.

Currently, the greatest controversy pertaining to therapy is the safety of including modest amounts of oats in the diet. Historically, wheat and rye were the first grains with demonstrated toxicity in celiac patients, followed subsequently by reports of toxicity with oats and barley. Similar injurious effects were not found with corn, rice and potatoes [69]. Biologic plausibility exists for the safety of oats, which stems from three primary difference between the gluten found in oat (avenin) and wheat (gliadin), barley (hordein) and rye (secalin) [70]. First, oat avenin is unique because it does not share substantial sequence homology with wheat gliadin, barley hordein, or rye secalin. Second, barley hor-deins and rye secalins are antigenically related to wheat gliadin, whereas oat avenin is not. Third, oat avenin accounts for a smaller fraction of total protein as compared to wheat gliadin, barley hordein, or rye secalin. Thus, even if oat avenin were toxic in celiac disease, it would take a larger quantity to bring about the same effect as for wheat, barley, or rye. In vitro studies, however, have produced mixed results, with some studies demonstrating an immune response to avenin whereas others do not [71–73].

Despite this, clinical evidence is now accumulating to demonstrate a lack of toxicity of oats in newly diagnosed patients with celiac disease and in celiac disease patients in remission. In the largest study to date, Janathuinen et al. randomized 52 celiac patients on stable gluten free diets and 40 newly diagnosed celiac patients to a conventional gluten free diet (GFD) versus a GFD that included oats [74]. Patients in the established celiac disease group were followed for six months, while the newly diagnosed celiac group were followed for one year in terms of symptoms, BMI, laboratory parameters (hemoglobin, iron studies, albumin) and duodenal histology. Mean oat consumption was approximately 50 g per day. Upon completion of the study, there was no significant difference in symptoms, BMI, laboratory parameters, or histology. All previously established celiac patients remained in remission and all newly diagnosed celiac patients were in remission at one year except for one in the control group. Six patients in the oats group withdrew from the study citing pruritis, abdominal complaints, or unspecified reason for withdrawing, although this was similar to the control group.

To provide long-term evidence for the safety of oats, a five-year follow-up study of the same patients was conducted [75]. Of the original 81 patients (39 oats, 42 controls) who had completed the initial study, 63 were recruited into the follow-up study (4 and 14 drop-outs in oat and control arm, respectively). Among the remaining 35 patients in the ase oat group, 12 patients had stopped consuming oats, citing the following reasons: uncertainty regarding the long-term safety of oats (nine patients), flatulence (one patient) and rash (two patients). The remaining 23 patients in the oat group and 28 in the control group were subsequently enrolled in the study. During the five-year interval, mean oat consumption was 34 g/day, with approximately two-thirds of patients consuming oats at least once a week. Similar to the original study, there was no significant difference in duodenal histology scores between those who consumed oats versus a conventional gluten-free diet. Although this study provides the first evidence of long-term safety of oats, it can be criticized for its high attrition rate. This is concerning as it may represent a substantial portion of symptomatic patients who were not accounted for.

To assess the safety of high doses of oats, Storsrud et al. challenged 20 celiac patients to a high dose oat diet [76]. During the two-year study period, patients were periodically assessed for symptoms, biochemical nutritional markers, EMA and duodenal histology. Fifteen patients completed the study, consuming on average 93 g of oat/ day. Similar to previous studies, there was no significant change in symptoms, biochemistry, EMA, or duodenal histology after exposure to oats. Three patients withdrew from the study for non-medical reasons and two withdrew due to abdominal distension and flatulence. Follow-up histology for both patients did not reveal any evidence of relapse and their symptoms were attributed to the increase in dietary fiber from the oats.

Despite the encouraging data supporting the safety of oats, significant concern remains due to the possibility of contamination with wheat, rye and barley. From the planting to the harvesting and manufacturing stage, multiple opportunities for contamination exist. In a 2008 study of 134 oat products from Canada, USA and Europe, 109 were found to be contaminated with wheat, barley, or rye [77]. The study utilized the new R5-ELISA assay, which replaced the conventional barley insensitive ω-ELISA. Similarly, another study utilizing the R5-ELISA assay to examine four lots of oats from three brands found that only three lots were gluten free [78]. To address the issue of contamination, government and advisory bodies are beginning to implement purity standards for the production of pure oats. Recently, the Canadian Celiac Association, in conjunction with Health Canada and Agriculture Canada, established strict planting, harvesting, processing and testing criteria to facilitate the production of pure oats. Safety data for pure oats manufactured under these guidelines are lacking and future studies are needed to ensure the safety of these products.

For the time being, the ultimate decision regarding whether to incorporate oats into the gluten free diet will have to be made on a case by case basis. Although numerous studies support the safety of oats, the strength of the evidence is generally limited by the small sample size. In addition, rare case reports have emerged describing cases of oat intolerance. In a 2003 case report, Lundin et al. [79] described a patient who developed diarrhea and villous atrophy during an oat challenge. During her oat challenge, her histology progressed from Marsh 1 to Marsh 3A. Elimination of oats from her diet resulted in resolution of her histology to Marsh 1. During a second oat challenge, her symptoms returned and she subsequently developed Marsh 3b lesions. Since the purity of the oats was confirmed by the barley insensitive w-ELISA assay in this case, it is plausible that her relapse was secondary to barley contamination although this cannot be confirmed. A minority of oat samples were further analyzed by western blot and mass spectrometry. Of six samples subject to additional testing, one was found to be contaminated. Thus, in deciding whether to include oats in the gluten-free diet, one must weigh the nutritional benefit of oats against the risk of contamination and the rare possibility of true oat intolerance.

Prognosis

Celiac disease, if left unrecognized and untreated, has the potential to result in severe complications which are for the most part secondary to malnutrition. When appropriate dietary therapy is instituted, the prognosis for celiac disease is usually good; however, untreated, the morbidity and mortality, and the risk of certain malignancies has been postulated to be increased in a celiac population. Past studies have suggested an increase in age-adjusted mortality attributable to the disease itself [28]. However, these studies may have been biased because of the inclusion of substantial numbers of untreated patients. More recent studies have suggested that at least short-term survival is not different from that of the general population [16]. Despite this finding there is evidence, both from retrospective and cohort studies, which suggests an increased risk of certain malignancies [80]. A recent retrospective Italian study identified seven malignancies in a cohort of 549 celiac patients followed for a mean of seven years [81].

Immunological stimulation and increased permeability are among the characteristics of the gut in celiac disease which lend biological credence to the possibility that celiac patients are at increased risk for malignancies such as lym-phoma and adenocarcinoma of the small bowel. Although the epidemiological studies are heterogeneous in their design and findings, most of the epidemiological evidence to date confirms a general increase in morbidity. The left-hand column of Table 10.2 summarizes some of the data from these studies.

Most of the reports are based on case-control studies. This design is particularly subject to problems with bias and confounding. A selection bias toward the inclusion of particularly ill or refractory patients is one of the most frequently cited criticisms of the studies, which show a mortality rate that is increased as much as 3.4-fold over that of the general population [82–85] and complicating malignancy rates as high as 14% [83]. Measurement bias is another potential problem. Patients presenting with abdominal symptoms secondary to a malignancy may be more likely to undergo investigations like small bowel biopsy, which could lead to a diagnosis of celiac disease. Finally, some of the risk factors for celiac disease such as ethnic/geographic origin or immune markers (e.g. the class II HLA antigens HLA-DR3 and HLA-DQw2) could potentially be independent risk factors for certain diseases.

Table 10.2 A subjective assessment of current evidence attempting to establish a causal or non-causal relationship (see text).

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