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Safety of Adding Oats to a Gluten-Free Diet for Patients With Celiac Disease: Systematic Review and Meta-analysis of Clinical and Observational Studies

      Background & Aims

      Patients with celiac disease should maintain a gluten-free diet (GFD), excluding wheat, rye, and barley. Oats might increase the nutritional value of a GFD, but their inclusion is controversial. We performed a systematic review and meta-analysis to evaluate the safety of oats as part of a GFD in patients with celiac disease.

      Methods

      We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases for clinical trials and observational studies of the effects of including oats in GFD of patients with celiac disease. The studies reported patients’ symptoms, results from serology tests, and findings from histologic analyses. We used the GRADE approach to assess the quality of evidence.

      Results

      We identified 433 studies; 28 were eligible for analysis. Of these, 6 were randomized and 2 were not randomized controlled trials comprising a total of 661 patients—the remaining studies were observational. All randomized controlled trials used pure/uncontaminated oats. Oat consumption for 12 months did not affect symptoms (standardized mean difference: reduction in symptom scores in patients who did and did not consume oats, −0.22; 95% CI, −0.56 to 0.13; P = .22), histologic scores (relative risk for histologic findings in patients who consumed oats, 0.24; 95% CI, 0.01–4.8; P = .35), intraepithelial lymphocyte counts (standardized mean difference, 0.21; 95% CI, reduction of 1.44 to increase in 1.86), or results from serologic tests. Subgroup analyses of adults vs children did not reveal differences. The overall quality of evidence was low.

      Conclusions

      In a systematic review and meta-analysis, we found no evidence that addition of oats to a GFD affects symptoms, histology, immunity, or serologic features of patients with celiac disease. However, there were few studies for many endpoints, as well as limited geographic distribution and low quality of evidence. Rigorous double-blind, placebo-controlled, randomized controlled trials, using commonly available oats sourced from different regions, are needed.

      Keywords

      Abbreviations used in this paper:

      AGA (serum gliadin antibodies), CD (celiac disease), CI (confidence interval), DH (dermatitis herpetiformis), EmA (serum IgA-class anti-endomysium antibodies), GFD (gluten-free diet), IEL (intraepithelial lymphocyte), Ig (immunoglobulin), RCT (randomized controlled trial), RR (relative risk), tTGA (serum IgA-class tissue transglutaminase antibodies)

       Background and Context

      The addition of oats to a gluten-free diet might increase its nutritional value, however concerns regarding the safety of consuming oats by patients with celiac disease have been raised.

       New Findings

      In our study, we found no evidence that addition of oats to a gluten-free diet affects symptoms or the activity of celiac disease.

       Limitations

      There were few studies in some of the analyses, the quality of the studies was low and most of them were conducted in Europe, making extrapolations to North American populations using locally-sourced oats difficult.

       Impact

      Until new evidence arises, the addition of “pure” oats to a gluten-free diet is acceptable for patients with celiac disease. However, the introduction of oats to a gluten-free diet should be monitored to confirm no adverse effects occur.
      Celiac disease (CD) is an autoimmune disorder, triggered by gluten and related prolamins in genetically susceptible individuals.
      • Setty M.
      • Hormaza L.
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      Celiac disease: risk assessment, diagnosis, and monitoring.
      CD primarily affects the proximal small intestine, where it progressively leads to villous atrophy. The cornerstone of treatment for CD is a gluten-free diet (GFD), which excludes wheat, barley, and rye.
      • Lebwohl B.
      • Ludvigsson J.F.
      • Green P.H.
      Celiac disease and non-celiac gluten sensitivity.
      This diet enables patients with CD to control their symptoms and avoid intestinal and extraintestinal complications, including osteoporosis, with associated increased risk of bone fractures, and development of certain types of cancer.
      • Comino I.
      • Moreno M.L.
      • Souza C.
      Role of oats in celiac disease.
      Patients with CD react adversely if they consume gluten, which is the storage group of proteins in certain cereal grains. The protein fractions considered to be the constituents of most concern in patients with CD include the alcohol-soluble fractions (prolamins) of wheat (gliadins), rye (secalins), and barley (hordeins).
      • Rashid M.
      • Butzner D.
      • Burrows V.
      • et al.
      Consumption of pure oats by individuals with celiac disease: a position statement by the Canadian Celiac Association.
      The prolamine fraction in oats (avenins) is structurally different from other prolamin fractions, and represents only a small proportion of total oats protein.
      • Fric P.
      • Gabrovska D.
      • Nevoral J.
      • et al.
      Celiac disease, gluten-free diet, and oats.
      Van de Kamer et al
      • Van de Kamer J.H.
      • Weijers H.A.
      • Dicke W.K.
      Coeliac disease. IV. An investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease.
      were the first to suggest that oats may be harmful for patients with CD. Some later studies, however, pointed to a lack of oat toxicity.
      • Baker P.G.
      • Read A.E.
      Oats and barley toxicity in coeliac patients.
      Although oats are included in the list of gluten-free ingredients specified in some countries’ regulations, such as Canada,

      Celiac disease and gluten-free claims on uncontaminated oats. Food directorate health products and food branch. Health Canada. Updated May 29, 2015. Available at: http://www.hc-sc.gc.ca/fn-an/consult/2014-cel-oats-contam-avoine-coel/document-consultation-eng.php. Accessed April 20, 2017.

      the safety for patients with CD remains controversial. Although GFD containing oats has been reported to improve CD symptoms in some studies,
      • Haboubi N.Y.
      Taylor S, Jones S. Coeliac disease and oats: a systematic review.
      others have detected intraepithelial lymphocytosis,
      • Arentz-Hansen H.
      • Fleckenstein B.
      • Molberg O.
      • et al.
      The molecular basis for oat intolerance in patients with celiac disease.
      and the development of avenin-reactive mucosal T cells in a small proportion of patients.
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      The general consensus is that pure oats are safe for most patients with CD; however, contamination with other cereal sources needs to be avoided.
      • Rashid M.
      • Butzner D.
      • Burrows V.
      • et al.
      Consumption of pure oats by individuals with celiac disease: a position statement by the Canadian Celiac Association.
      Although adherence to GFD is the only available treatment for CD, it does not always ensure adequate nutrition. Oats may increase nutritional value,
      • Comino I.
      • Moreno M.L.
      • Souza C.
      Role of oats in celiac disease.
      • Haboubi N.Y.
      Taylor S, Jones S. Coeliac disease and oats: a systematic review.
      and improve palatability, texture, and fiber content of the GFD.
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Tapsas D.
      • Fälth-Magnusson K.
      • Högberg L.
      • et al.
      Swedish children with celiac disease comply well with a gluten-free diet, and most include oats without reporting any adverse effects: a long-term follow-up study.
      Indeed, oats contain a higher percentage of protein of superior amino acid balance, vitamins, and minerals as compared with other cereals.
      • Lockhart H.
      • Hunt D.
      Nutrition of oats.
      • Peterson D.M.
      • Brinegar A.C.
      Oats storage proteins.
      On the other hand, up to 70% of those with CD experience either voluntary or inadvertently ingest gluten
      • Hall N.
      • Rubin G.P.
      • Charnock A.
      Intentional and inadvertent non-adherence in adult coeliac disease. A cross-sectional survey.
      indicating the diet is difficult.
      • Pietzak M.M.
      Follow-up of patients with celiac disease: achieving compliance with treatment.
      Thus, oats also could improve GFD compliance and quality of life, although contamination with prolamins from toxic cereal grains is a concern.
      • Comino I.
      • Moreno M.L.
      • Souza C.
      Role of oats in celiac disease.
      • Fric P.
      • Gabrovska D.
      • Nevoral J.
      • et al.
      Celiac disease, gluten-free diet, and oats.
      • Haboubi N.Y.
      Taylor S, Jones S. Coeliac disease and oats: a systematic review.
      Traditional commercial oats are often contaminated with other gluten-containing grains; however, oats grown and processed without contamination, or even cleaned of contaminating grains, so-called pure oats, are available.
      • Van de Kamer J.H.
      • Weijers H.A.
      • Dicke W.K.
      Coeliac disease. IV. An investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease.

      NASSCD Oats statement. April 2016. Available at: http://www.nasscd.org/files/Oats-Statement-NASSCD-April-2016(1).pdf. Accessed June 18, 2017.

      Previous systematic reviews
      • Baker P.G.
      • Read A.E.
      Oats and barley toxicity in coeliac patients.
      • de Souza M.C.
      • Deschênes M.E.
      • Laurencelle S.
      • et al.
      Pure oats as part of the gluten-free diet in celiac disease: the need to revisit the.
      • Ciacci C.
      • Ciclitira P.
      • Hadjivassiliou M.
      • et al.
      The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis.
      • Thies F.
      • Masson L.F.
      • Boffetta P.
      • et al.
      Oats and bowel disease: a systematic literature review.
      • La Vielle S.
      • Pulido O.M.
      • Abbott M.
      • et al.
      Celiac disease and gluten-free oats: a Canadian position based on a literature review.
      attempted to address these outstanding controversies; however, none of them were able to perform a quantitative analysis. Therefore, we performed a systematic review of the literature and a meta-analysis on the symptomatic, serological, and histological response to dietary oats in patients with CD and dermatitis herpetiformis (DH).

      Methods

      We included studies evaluating the effect of oats in patients with CD or DH on a GFD. For CD diagnosis, we used any accepted criteria (duodenal biopsy and/or compatible serology and HLA DQ2/8 positivity, where reported). For DH, we considered any criteria reported, such as immunoglobulin (Ig)A deposits in skin biopsies. Any intervention involving any amount and type of oats (pure, nonpure, kilned, unkilned) along with GFD was considered, and the control group had to receive GFD alone or placebo (negative control) or gluten challenge (positive control). Any other type of comparison and noncontrolled studies (before and after comparison) were included in the review but not considered for quantitative synthesis. We considered the following outcomes: improvement in gastrointestinal symptoms (significant decrease in gastrointestinal symptom rating scale score, visual analogue scale, or other questionnaire), improvement or stable CD autoimmunity (no increase in the levels of CD-specific serology), improvement or stable duodenal histology (defined by Marsh classification, villous/crypt ratio, and/or intraepithelial lymphocyte [IEL] counts), and symptomatic, serological, and mucosal response to oats during long-term follow-up (>1 year).

       Types of Studies

      For the systematic review, we included observational studies (cohort or case-control studies) or clinical trials (randomized controlled trials [RCTs]) up to January 2017. Case reports or case series were excluded. Only results from RCTs were pooled in meta-analysis. We considered crossover trials only if the results were available before crossover, so that the study could be evaluated as a parallel group. We considered publications regardless of language and publication status. We included published abstracts only if we could obtain further details from the investigators. We excluded duplicate studies, or those in which the diagnosis of CD was not confirmed by either serology or biopsy. The search strategy is outlined in Supplementary Table 1.

       Selection of Studies

      To ensure that we captured all eligible studies, 2 authors (MIP-S and NC-C) screened the titles and abstracts and selected the studies. Obvious duplicate studies were removed at this stage. The same reviewers performed the full-text screening independently, using the full text of articles and translation of foreign language articles, where required. Data were entered into an Excel sheet and results were compared. We calculated the agreement at each step (1: title and abstract screening, 2: full-text screening and 3: data extraction) by using Kappa statistics (GraphPad software, San Diego, CA). Raw agreement was reported in percentage and Kappa as fair agreement (k = 0.4–0.59), good agreement (0.6–0.74), or excellent agreement (≥0.75). In cases of disagreement, a third author (P.M.) with experience in the topic was consulted for the final decision. All these steps were properly documented in a table of excluded studies. The 2 reviewers (M.I.P.-S. and N.C.-C.) independently extracted the data and a form was developed to collect information regarding study design, population, intervention, control intervention, and outcomes. The form included information on authors, setting (primary, secondary, or tertiary care), funding source (industry sponsored, grant sponsored, investigator funded), CD activity (information on specific serology and/or biopsy), source (pure/uncontaminated/ contaminated), and quantities of oats consumed, number of patients, and adverse events. Patient demographics, treatment, outcomes, and adverse events were recorded as a mean and SD for continuous data, or proportions with the outcome of interest for dichotomous data. Randomization, concealment, blinding of participants and outcome assessors, incomplete outcome data, and evidence of selective reporting were collected to assess risk of bias. The first author entered the information in RevMan software (RevMan 5.3; Cochrane Collaboration, London, UK) for further analysis and the second author checked for consistency of data.

       Assessment of Risk of Bias for Included Studies

      We used the GRADE system
      to assess the quality of the body of evidence according to study design, consistency, directness, imprecision, and reporting bias.

       Measures of Treatment Effect

      Total number of participants who did or did not develop the outcome in each arm at each time point, and the amount of oats consumed, were collected and reported as the number over the total sample population (n/N). Comparison of dichotomous data was reported as a relative risk (RR), with an associated 95% CI. For quantitative analysis, we performed a meta-analysis using RevMan V5.3. Data were pooled using a random effects model. Statistically significant heterogeneity was assessed through the I2 statistic test and the χ2 test. A value of 0% indicates no observed heterogeneity and larger values denote heterogeneity. Significant heterogeneity was considered present when either the I2 value was >30%, or the P value for the χ2 test was less than .10.
      To address the most important possible sources of heterogeneity, we performed subgroup analysis considering the effect of oats consumption on CD activity according to age (children vs adults).

      Results

      The literature search identified 433 citations, and 2 additional citations were identified by a recursive bibliography search. A total of 395 citations remained after removing duplicates. From these, 342 were excluded at the title and abstract screening stage, and 53 were eligible for full-text screening (Figure 1). A very good inter-reviewer agreement was found at the title and abstract screening stage (k = 0.85) and in the full-text screening step (k = 0.96). After full-text review, 25 articles were excluded. The reasons for exclusion are detailed in Supplementary Table 2. Twenty-eight studies met the inclusion and exclusion criteria for qualitative synthesis and data were extracted from them. The studies included in the systematic review are summarized in Table 1 and Supplementary Table 2. Excluded studies are shown in Supplementary Table 3. A graphical representation of the summary of risk of bias and the risk of bias for individual studies is shown in Figure 2.
      Figure thumbnail gr1
      Figure 1Flowchart of study selection (PRISMA).
      Table 1Characteristics of Included Studies
      Author (ref)Country of origin/study designPopulationInterventionOutcomes assessed
      Baker 1976
      • Baker P.G.
      • Read A.E.
      Oats and barley toxicity in coeliac patients.
      UK

      Single center

      Single cohort

      Before and after comparison
      12 biopsy-proven CD patients; 1 child and 11 adults for ≥6 months on GFDGFD + 60 g of noncontaminated oats/d for 28 d.

      British Drug Houses Avenin, prepared from oat flakes
      • Fric P.
      • Gabrovska D.
      • Nevoral J.
      • et al.
      Celiac disease, gluten-free diet, and oats.
      Improvement in GI symptoms

      Mean reduction in xylose excretion
      Cooper 2012
      • Cooper S.E.
      • Kennedy N.P.
      • Mohamed B.M.
      • et al.
      Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.
      Ireland/UK Single center.

      Single cohort/ Before and after comparison
      46 biopsy-proven CD adult patients. 37 for ≥10 y on GFD, and 9 newly diagnosedGFD+ 50 g/d of pure oats for a period of 1 y;

      Oats sourced from Peter Kölln and confirmed to be free from other grains
      Improvement in GI symptoms

      Immune activation (tTGA)

      Improvement in CD activity (Marsh, IELs)

      IHC staining anti-Ki-67, CD
      • Comino I.
      • Moreno M.L.
      • Souza C.
      Role of oats in celiac disease.
      , CD8, and SM α-actin deposits
      Gatti 2013
      • Gatti S.
      • Caporelli N.
      • Galeazzi T.
      • et al.
      Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italian study.
      Italy

      Multicenter

      DBPC-RCT
      307 biopsy-proven CD children ≥2 y on GFD2 arms: GFD+ purified oats; GFD+ placebo;

      6 mo
      Improvement in GI symptoms (GSRS)

      Immune activation (tTGA)

      Intestinal permeability (LAMA)
      Guttormsen 2008
      • Guttormsen V.
      • Løvik A.
      • Bye A.
      • et al.
      No induction of anti-avenin IgA by oats in adult, diet-treated coeliac disease.
      Norway.

      Single center.

      Cross-sectional
      136 biopsy-proven CD (adult; 82 consuming oats) ≥ 2 y of GFD and 139 controls from communityGFD+ 24 g/d ecologically grown GF oats vs GFD vs controls

      Oats consumed for at least 3 mo
      IgA anti-gliadin

      IgA anti-avenin

      tTGA
      Hardman C.1987
      • Hardman C.M.
      • Garioch J.J.
      • Leonard J.N.
      • et al.
      Absence of toxicity of oats in patients with dermatitis herpetiformis.
      UK

      Single center

      Single cohort/ Before and after comparison
      10 adults biopsy-proven CD and DH, on GFD for a mean of 10 yGFD + mean 62.5 g/d pure oats confirmed GF; for 3 mo

      Oats sourced from Peter

      Kölln and confirmed to be free from other grains
      Changes in dermal IgA deposits

      Changes in AGA, ARA, EmA

      Changes in CD activity (V/C), enterocyte height and IELs
      Hoffenberg 2000
      • Hoffenberg E.J.
      • Haas J.
      • Drescher A.
      • et al.
      A trial of oats in children with newly diagnosed celiac disease.
      US

      Single center

      Single cohort/ Before and after comparison
      10 children biopsy-proven newly diagnosed CD following a GFDGFD + mean 21g/d of pure oatmeal confirmed GF; 6 mo of treatment

      Oatmeal by ConAgra (Omaha, NB)

      Gliadin contamination measured by RIDASCREEN ELISA (R-Biopharm GmbH, Darmstadt, Germany)
      Improvement in GI symptoms (diary-Likert scale)

      Changes in tTGA and histology (Marsh)

      Changes in α-tocopherol to total lipids ratio, iron, zinc, hemoglobin and erythrocyte folate
      Högberg 2004
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      Sweden

      Single center

      RCT
      116 children biopsy-proven CD newly diagnosedGFD+ median 20 g (20–50 g) of non-contaminated oats (pure Semper AB, Sweden) for 1 yChanges in AGA, tTGA

      Changes in mucosal morphology (Marsh)
      Holm K 2006
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      Finland. Single center.

      RCT
      31 children biopsy-proven CD; 23 in remission and 9 newly diagnosedGFD+ challenge with 45 g/d of pure oats (ELISA confirmed) vs challenge with 20 g of gluten

      24 mo
      Improvement in GI symptoms

      Changes in mucosal morphology (Marsh, IELs)

      Changes in tTGA, EmA, AGA
      Janatuinen 1995
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      Finland

      Two centers

      RCT
      52 adults biopsy-proven CD in remission FU 6 mo and 40 newly diagnosed CD FU × 12 moGFD+ 50–70 g oats vs GFD no oats for 12 months

      Products (Raisio Factories, Finland) supplemented with oats
      Improvement in GI symptoms (100 mm VAS)

      Changes in histology

      Nutrients: Hb, iron, calcium, folate, albumin
      Janatuinen 2000
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      Finland

      Post hoc analysis from Janatuinen 1995
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      52 adults biopsy-proven CD in remission FU 6 months and 40 newly diagnosed CD FU period of 12 monthsGFD+ 50–70 g oats vs GFD no oats × 12 months.

      Products (Raisio Factories) supplemented with oats
      Changes in AGA IgA, AGA IgG and Anti-reticulin antibodies
      Janatuinen 2002
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      Finland

      Two centers
      63 adult biopsy-proven CD; 35 on GFD+oats and 28 on GFD; FU on cohort from Janatuinen 1995
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      GFD+ mean 34 g/d of oats vs GFD × 5 y

      The purity of the oats monitored only during the 6–12-month intervention
      Changes in nutritional status

      Changes in histopathology

      Changes in EmA, ARA, AGA antibodies.
      Kaukinen 2013
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      Finland. Single center

      Cross-sectional
      106 long-term treated adult CD; independently if they consumed oats or notGFD + oats vs GFD no oats. Mean oat consumption 20 g (range 1–100 g)

      Purity of the oats not confirmed

      Mean oat consumption 5 y
      Improvement in GI symptoms (GSRS)

      Improvement in DH

      Changes in histopathology (Marsh) and densities of IELs CD3+, αβ+ and γσ+

      Changes in tTGA; EmA
      Kemppainen2007
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      Finland. Post hoc analysis from Janatuinen 2002
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      42 adult CD (22 consuming oats and 20 not consuming oats)Refer to Janatuinen 2002
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      Changes in densities of CD3 and IELs
      Kemppainen 2008
      • Thompson T.
      Gluten contamination of commercial oat products in the United States.
      Finland. Post hoc analysis of
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      32 biopsy-proven CD adult patients in remission100 g/d of Kilned vs unkilned oats for a period of 12 moChanges in nutritional status

      Changes in EmA

      Improvement in GI symptoms (VAS)

      Changes in histopathology (Marsh)
      Koskinen O 2009
      • Koskinen O.
      • Villanen M.
      • Korponay-Szabo I.
      • et al.
      Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease.
      Finland. Single center. Post hoc analysis of
      • Sey M.S.
      • Parfitt J.
      • Gregor J.
      Prospective study of clinical and histological safety of pure and uncontaminated Canadian oats in the management of celiac disease.
      23 children biopsy-proven CD; in remission and newly diagnosed.GFD+ challenge with 45 g/d of pure oats (ELISA confirmed) vs challenge with 20 g of gluten. Period of 24 moChanges in histopathology (V/C)

      IgA deposits in duodenum

      Changes in tTGA,
      Lundin 2003
      • Lundin K.E.
      • Nilsen E.M.
      • Scott H.G.
      • et al.
      Oats induced villous atrophy in coeliac disease.
      Norway

      Single center CT open label, Before and after comparison
      19 biopsy-proven adult CD on a GFD for a mean of 7 yGFD + oats. 50 g pure/d × 3 mo

      Oats harvested from fields where no wheat, rye, barley, or oats had been grown during the past 10 years

      120 samples tested GF
      Improvement in GI symptoms (Likert scale)

      Changes in histopathology (Marsh)

      Changes in tTGA, EmA, AGA IgA and AGA IgG

      Changes in D-Xylose

      Changes in IFN-γ
      Peraaho 2004
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      Finland

      Single center

      RCT
      39 biopsy-proven

      CD on GFD without

      oats.
      GFD+50 g of oats-containing GF products vs GFD no oats for 1 yImprovement in GI symptoms (GSRS)

      Changes in histopathology (V/C and IELs)

      Changes in quality of life (PGWB)

      Changes in tTGA, EmA
      Reunala 1998
      • Reunala T.
      • Collin P.
      • Holm K.
      • et al.
      Tolerance to oats in dermatitis herpetiformis.
      Finland

      Single center Non-RCT
      23 biopsy-proven adult CD with DH in remission with a GFDGFD+ 50 g/d of oats vs GFD no oats × 6 mo. The oat cereal (Melia Ltd, Raisio, Finland) confirmed GF (ELISA; Ridascreen Gluten Kit, Biopharm, Germany)Symptoms DH, rash

      Changes in histopathology (V/C and IELs)

      Changes in IgA fluorescence of the skin.

      Changes in EmA, AGA
      Sey 2011
      • Sey M.S.
      • Parfitt J.
      • Gregor J.
      Prospective study of clinical and histological safety of pure and uncontaminated Canadian oats in the management of celiac disease.
      Canada

      Single center. Before and after comparison
      15 biopsy-proven adult CD on GFD for at least 1 y. Negative TTGGFD+350 g/wk of pure uncontaminated oats for a period of 12 wk. Oats were donated by Cream Hill Estates (Quebec, Canada).Improvement in GI symptoms (VAS)

      Changes in histopathology (Marsh)

      Changes in tTGA
      Sjoberg 2014
      • Sjöberg V.
      • Hollén E.
      • Pietz G.
      • et al.
      Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease.
      Sweden Multicenter

      Post hoc analysis of
      • Hoffenberg E.J.
      • Haas J.
      • Drescher A.
      • et al.
      A trial of oats in children with newly diagnosed celiac disease.
      28 biopsy-proven children CDGFD+ 25–50 g of noncontaminated oats vs GFD no oats for 12 monthsChanges in histopathology (Marsh)

      Changes in tTGA, EmA

      Changes in inflammatory markers; IL17A, IFN-γ, CXCL8/IL8, IL10, TGF-β1, TNF-α, and CX3CL1 mRNAs
      Srinivasan 1996
      • Srinivasan U.
      • Leonard N.
      • Jones E.
      • et al.
      Absence of oats toxicity in adult coeliac disease.
      Ireland

      Single center Before and after comparison
      Ten biopsy-proven adult CD patients in clinical and histological remissionGFD+ oats; pure: 50 g oats porridge daily for 12 wk; the oats cereal (Peter Kolln, Germany) tested for gluten contamination using HPLC, ELISA, and PCRImprovement in GI symptoms

      Changes in histopathology (enterocyte height, IELs)

      Changes in tTGA, EmA, AGA IgA
      Srinivasan 2006
      • Srinivasan U.
      • Jones E.
      • Carolan J.
      • et al.
      Immunohistochemical analysis of coeliac mucosa following ingestion of oats.
      Ireland

      Single center

      Post-hoc of
      • Srinivasan U.
      • Leonard N.
      • Jones E.
      • et al.
      Absence of oats toxicity in adult coeliac disease.
      Post hoc of Srinivasan
      • Koerner T.B.
      • Cleroux C.
      • Poirier C.
      • et al.
      Gluten contamination in the Canadian commercial oat supply.
      Post hoc of Srinivasan
      • Koerner T.B.
      • Cleroux C.
      • Poirier C.
      • et al.
      Gluten contamination in the Canadian commercial oat supply.
      Immunohistochemistry and IF antibodies to

      HLA-DR, ICAM-1 (CD54), Ki-67, CD25 and mast cell

      tryptase
      Srinivasan 1999
      • Srinivasan U.
      • Jones E.
      • Weir D.G.
      • et al.
      Lactase enzyme, detected immunohistochemically, is lost in active celiac disease, but unaffected by oats challenge.
      Ireland

      Single center Non RCT

      Post hoc of
      • Koerner T.B.
      • Cleroux C.
      • Poirier C.
      • et al.
      Gluten contamination in the Canadian commercial oat supply.
      26 adult patients (11 nonceliac disease controls, 9 active CD, 6 CD in remission); 10 of CD were from previous study
      • Koerner T.B.
      • Cleroux C.
      • Poirier C.
      • et al.
      Gluten contamination in the Canadian commercial oat supply.
      after oat challenge
      GFD+oats vs GFD no oatsImmunohistochemistry and IF antibodies to human lactase (M-LAC) activity

      Changes in tTGA, EmA, AGA IgA
      Storsrud 2003
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      Sweden

      Single center Before and after comparison
      20 adult biopsy-proven CD patients on GFD for more than 1 yGFD+ mean 90 g of rolled oats (Kungsornen, Jarna, Sweden) which was free from wheat, rye, and barley (ELISA); Study period of 24 moChanges in histopathology (Villous architecture, IELs)

      Changes in BMI and nutritional status

      Changes in EmA
      Storsrud 2003
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      Sweden. Single center. Post hoc analysis of
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      Post hoc analysis of
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      Post hoc analysis of
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      Changes in GI symptoms (questionnaire unclear)

      Intakes of energy and nutrients in the diet (Food Composition Tables, Energy and Nutrients; Sweden)
      Tapsas 2014
      • Tapsas D.
      • Fälth-Magnusson K.
      • Högberg L.
      • et al.
      Swedish children with celiac disease comply well with a gluten-free diet, and most include oats without reporting any adverse effects: a long-term follow-up study.
      Sweden Multicenter

      Cross-sectional study
      316 children and adolescents biopsy-proven CD on GFDGFD exposed to oats (89.2% of population) vs GFD not exposed to oats (10.8% of population)Assessment of GFD compliance

      Prevalence of oats consumption in CD population
      Tuire 2012
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      Finland

      Single center Cross-sectional study
      177 adult CD patients adhering to long-term strict GFDGFD with and without oatsIdentify factors (including oats consumption) contributing to increased IELs with normal villous architecture
      NOTE. Studies in alphabetical order.
      ARA, acetylene reduction assay; BMI, body mass index; DBPC, double blind placebo-controlled trial; ELISA, enzyme-linked immunosorbent assay; FU, follow-up; GI, gastrointestinal; GSRS, gastrointestinal symptoms rating scale; HPLC, high-performance liquid chromatography; IFN, interferon; IHC, Immunohistochemistry; IL, interleukin; LAMA, Lactulose-Manitol; PCR, polymerase chain reaction; PGWB, psychological general well-being; TGF, transforming growth factor; VAS, visual analogue scale; V/C, villous crypt ratio.
      Figure thumbnail gr2
      Figure 2(A) Risk of bias graph: summary of risk of bias presented as percentages across all included studies. (B) Risk of bias for individual studies according to Cochrane tool for assessment of risk of bias.

       Characteristics of Included Studies

      Of the 28 studies, 12 were clinical trials; 6 were RCTs (3 in children
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Gatti S.
      • Caporelli N.
      • Galeazzi T.
      • et al.
      Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italian study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      ; 3 in adults
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      ), 2 non-RCTs,
      • Reunala T.
      • Collin P.
      • Holm K.
      • et al.
      Tolerance to oats in dermatitis herpetiformis.
      • Srinivasan U.
      • Jones E.
      • Weir D.G.
      • et al.
      Lactase enzyme, detected immunohistochemically, is lost in active celiac disease, but unaffected by oats challenge.
      and 4 post hoc analyses from RCTs.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      • Koskinen O.
      • Villanen M.
      • Korponay-Szabo I.
      • et al.
      Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease.
      • Sjöberg V.
      • Hollén E.
      • Pietz G.
      • et al.
      Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease.
      There were also 10 before and after comparison studies
      • Fric P.
      • Gabrovska D.
      • Nevoral J.
      • et al.
      Celiac disease, gluten-free diet, and oats.
      • Hardman C.M.
      • Garioch J.J.
      • Leonard J.N.
      • et al.
      Absence of toxicity of oats in patients with dermatitis herpetiformis.
      • Cooper S.E.
      • Kennedy N.P.
      • Mohamed B.M.
      • et al.
      Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.
      • Srinivasan U.
      • Leonard N.
      • Jones E.
      • et al.
      Absence of oats toxicity in adult coeliac disease.
      • Srinivasan U.
      • Jones E.
      • Carolan J.
      • et al.
      Immunohistochemical analysis of coeliac mucosa following ingestion of oats.
      • Hoffenberg E.J.
      • Haas J.
      • Drescher A.
      • et al.
      A trial of oats in children with newly diagnosed celiac disease.
      • Lundin K.E.
      • Nilsen E.M.
      • Scott H.G.
      • et al.
      Oats induced villous atrophy in coeliac disease.
      • Sey M.S.
      • Parfitt J.
      • Gregor J.
      Prospective study of clinical and histological safety of pure and uncontaminated Canadian oats in the management of celiac disease.
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      and 6 observational studies. Of the observational studies, 2 involved long-term follow-up of patients exposed or nonexposed to oats who had participated in previous RCTs
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      and 4 had a cross-sectional design.
      • Tapsas D.
      • Fälth-Magnusson K.
      • Högberg L.
      • et al.
      Swedish children with celiac disease comply well with a gluten-free diet, and most include oats without reporting any adverse effects: a long-term follow-up study.
      • Guttormsen V.
      • Løvik A.
      • Bye A.
      • et al.
      No induction of anti-avenin IgA by oats in adult, diet-treated coeliac disease.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      Further details on geographical distribution and sample size are described in Table 1 and Supplementary Table 2.
      No study compared the effect of regular versus pure/uncontaminated oats on the outcomes assessed. Five of the 28 studies failed to report whether oats were from a contaminated or uncontaminated source
      • Srinivasan U.
      • Jones E.
      • Weir D.G.
      • et al.
      Lactase enzyme, detected immunohistochemically, is lost in active celiac disease, but unaffected by oats challenge.
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      ; however, only 1 of them
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      showed increased IELs in a proportion of patients after oats consumption. The effect of oats over 1 year was assessed by 14 studies.
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      • Koskinen O.
      • Villanen M.
      • Korponay-Szabo I.
      • et al.
      Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease.
      • Sjöberg V.
      • Hollén E.
      • Pietz G.
      • et al.
      Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease.
      • Cooper S.E.
      • Kennedy N.P.
      • Mohamed B.M.
      • et al.
      Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      Six studies
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      evaluated the impact of oats on symptoms, 12 on serological and histological responses.

       The Effect of Oats on Gastrointestinal Symptoms

      Twelve articles evaluated the effect of GFD plus oats on gastrointestinal symptoms. Three RCTs
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Gatti S.
      • Caporelli N.
      • Galeazzi T.
      • et al.
      Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italian study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      involving 168 patients, reported symptomatic responses to GFD plus oats, compared with GFD alone. Two studies
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Gatti S.
      • Caporelli N.
      • Galeazzi T.
      • et al.
      Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italian study.
      used gastrointestinal symptom rating scale scores, and the other
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      a visual analogue scale. In a double-blind placebo-controlled trial, Gatti et al
      • Gatti S.
      • Caporelli N.
      • Galeazzi T.
      • et al.
      Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italian study.
      found a significant decrease in gastrointestinal symptoms in both groups after 6 months; however, the results were published while the study was still blinded. Therefore, we excluded this study from the meta-analysis. The meta-analysis was based on only 2 studies in adult patients with CD who reported no symptomatic differences after 12 months of GFD with or without oats
      • Tapsas D.
      • Fälth-Magnusson K.
      • Högberg L.
      • et al.
      Swedish children with celiac disease comply well with a gluten-free diet, and most include oats without reporting any adverse effects: a long-term follow-up study.
      • La Vielle S.
      • Pulido O.M.
      • Abbott M.
      • et al.
      Celiac disease and gluten-free oats: a Canadian position based on a literature review.
      (standardized mean difference, −0.22; 95% CI −0.56 to 0.13; P = .22) (Figure 3A).
      Figure thumbnail gr3
      Figure 3(A) Forest plot of comparison of RCTs: symptomatic response (gastrointestinal symptoms) in patients with CD on GFD with oats vs GFD without oats, continuous outcome. (B) Forest plot of comparison of RCTS: histological response: GFD with oats vs GFD without oats, continuous outcome. (C) Forest plot of comparison of RCTs: IEL counts in CD patients on GFD, with and without oats (continuous outcome); (2) IEL counts on GFD with and without oats (dichotomous outcomes). (D) Forest plot of comparison of CD-specific serology: tTG after challenge with oats vs challenge with gluten.
      Two RCTs compared GFD with oats with other positive control (ie, GFD or another type of oat). The first study
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      assessed the symptomatic response to a challenge with gluten-free oats versus a “gluten challenge” that allowed the consumption of wheat, rye, and barley in children with CD on a strict GFD. In the oat-challenged group, 4 of 10 patients had symptoms that resolved while continuing the consumption of oats and none of whom showed signs of CD activity. In the gluten-challenged group, 4 of 10 patients developed abdominal symptoms coincident with small bowel histological deterioration. All of the patients included became asymptomatic during an oat-containing GFD.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      In the second study, Kemppainen et al
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      randomized patients to GFD plus kilned or GFD plus unkilned oats, and found no difference in symptoms between the groups (RR, 1.88; 95% CI, 0.57–6.19; P = .30).
      Of the remaining 7 studies, 6 were small, and before and after comparison trials, 5 in adults,
      • Fric P.
      • Gabrovska D.
      • Nevoral J.
      • et al.
      Celiac disease, gluten-free diet, and oats.
      • Srinivasan U.
      • Leonard N.
      • Jones E.
      • et al.
      Absence of oats toxicity in adult coeliac disease.
      • Lundin K.E.
      • Nilsen E.M.
      • Scott H.G.
      • et al.
      Oats induced villous atrophy in coeliac disease.
      • Sey M.S.
      • Parfitt J.
      • Gregor J.
      Prospective study of clinical and histological safety of pure and uncontaminated Canadian oats in the management of celiac disease.
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      and 1 in children,
      • Hoffenberg E.J.
      • Haas J.
      • Drescher A.
      • et al.
      A trial of oats in children with newly diagnosed celiac disease.
      and 1 had a cross-sectional design.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      None of them demonstrated CD activity after oat consumption. Further study characteristics are summarized in Table 1 and Supplementary Table 2.
      Overall, the quality of evidence for the effect of oats on gastrointestinal symptoms was very low. There were 2 RCTs, involving 131 patients, that were at high risk of performance and detection bias and 1 study was at high risk of attrition bias. We detected serious risk of indirectness, as the effect estimates were in both directions and had large CIs. Therefore, we have very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of effect. Summary of findings are shown in Table 2.
      Table 2Summary of Findings for the Following Outcomes: Gastrointestinal Symptoms, Histological Response, and CD-Specific Serology
      Gastrointestinal symptoms
      Patient or population: celiac disease

      Intervention: GFD with oats

      Comparison: GFD without oats
      OutcomesAnticipated absolute effects (95% CI)Relative effect (95% CI)№ of participants (studies)Quality of the evidence (GRADE)Comments
      Risk with GFD without oatsRisk with GFD with oats
      Overall symptoms improvement- Continuous outcome---131 (2 RCTs)⊕◯◯◯

      VERY LOW a,d,e,f
      Outcome was assessed by GSRS scores and VAS.
      Symptoms improvement- Kilned vs unkilned oats200 per 1000376 per 1000

      (114 to 1000)
      RR 1.88

      (0.57 to 6.19)
      31 (1 RCT)⊕◯◯◯

      VERY LOW a,b,c
      *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

      CI: Confidence interval; RR: Risk ratio; SMD: Standardised mean difference
      GRADE Working Group grades of evidence

      High quality: We are very confident that the true effect lies close to that of the estimate of the effect

      Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

      Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

      Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
      aStudy was not blinded for participants, personnel or outcome assessors. High risk of performance and detection bias.

      bSmall study, few patients and large CI.

      cNo explanation was provided.

      dOne study was at high risk of attrition bias.

      eBoth studies differ in population, and outcome measurement, however results were similar after subgroup analysis.

      fEffect estimate in both directions and large CI.
      Histological response
      Patient or population: celiac disease – adult and children

      Intervention: GFD with oats

      Comparison: 1-GFD without oats 2- gluten challenge
      OutcomesAnticipated absolute effects (95% CI)Relative effect (95% CI)№ of participants (studies)Quality of the evidence (GRADE)Comments
      Risk with GFD without oatsRisk with GFD with oats
      Histological response- ContinuousThe mean histological response- Continuous was 0The mean histological response- Continuous in the intervention group was 0 (0.01 lower to 0.01 higher)-92 (1 RCT)⊕⊕◯◯

      LOW a,b
      Subgroup analyses in children and adult similar results
      Histological response- dichotomous40 per 100010 per 1000

      (0 to 192)
      RR 0.24

      (0.01 to 4.81)
      92 (1 RCT)⊕⊕◯◯

      LOW b,c
      Subgroup analyses in children and adult similar results
      Histological response- kilned vs unkilned oats200 per 1000126 per 1000

      (24 to 648)
      RR 0.63

      (0.12 to 3.24)
      31 (1 RCT)⊕⊕◯◯

      LOW a,b
      Histological response- challenge with oats vs challenge with gluten1000 per 100040 per 1000

      (0 to 660)
      RR 0.04

      (0.00 to 0.66)
      21 (1 RCT)⊕⊕◯◯

      LOW a,b
      *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

      CI: Confidence interval; MD: Mean difference; RR: Risk ratio
      GRADE Working Group grades of evidence

      High quality: We are very confident that the true effect lies close to that of the estimate of the effect

      Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

      Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

      Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
      aThe study was not blinded for participants and personnel; high risk of performance bias.

      bLarge CI.

      cThe study was identified at high risk of attrition bias.
      CD specific serology
      Patient or population: celiac disease children and adults

      Intervention: GFD with oats

      Comparison: GFD 1- without oats 2- gluten challenge
      OutcomesAnticipated absolute effects (95% CI)Relative effect (95% CI)№ of participants (studies)Quality of the evidence (GRADE)Comments
      Risk with GFD without oatsRisk with GFD with oats
      Anti tissue transglutaminase antibodies76 per 1000130 per 1000

      (47 to 357)
      RR 1.71

      (0.62 to 4.71)
      131 (2 RCTs)⊕◯◯◯

      VERY LOW
      Outcome assessors not blinded in 1 study.
      ,
      High rate of drop outs in both studies.
      ,
      One small study with large CI.
      Anti tissue transglutaminase antibodies- Oats challenge vs gluten challenge1000 per 100040 per 1000

      (0 to 570)
      RR 0.04

      (0.00 to 0.57)
      23 (1 RCT)⊕⊕⊕◯

      MODERATE
      One small study with large CI.
      ,
      Participants and personnel not blinded, but outcome assessor blinded.
      EmA182 per 1000264 per 1000

      (140 to 498)
      RR 1.45

      (0.77 to 2.74)
      131 (2 RCTs)⊕◯◯◯

      VERY LOW
      Outcome assessors not blinded in 1 study.
      ,
      High rate of drop outs in both studies.
      ,
      One small study with large CI.
      EmA- Oats challenge vs gluten challenge1000 per 1000110 per 1000

      (20 to 510)
      RR 0.11

      (0.02 to 0.51)
      23 (1 RCT)⊕⊕⊕◯

      MODERATE
      One small study with large CI.
      *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
      GRADE Working Group grades of evidence

      High quality: We are very confident that the true effect lies close to that of the estimate of the effect

      Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

      Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

      Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
      dNo explanation was provided.
      a Outcome assessors not blinded in 1 study.
      b High rate of drop outs in both studies.
      c One small study with large CI.
      e Participants and personnel not blinded, but outcome assessor blinded.

       The Effect of Oats on Duodenal Histology

       Villous atrophy

      Seventeen studies evaluated the histological response to oats in patients with CD. Of these, 5 were RCTs, 2 of which were conducted in children
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      and 3 in adult patients.
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      Three of 5 RCTs compared GFD with and without oats,
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      1 compared a challenge with oats vs a gluten challenge in patients on a GFD,
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      and 1 investigated GFD with kilned and unkilned oats.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      Two of the studies reported histological lesion graded according to Marsh classification,
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      2 as villous/crypt ratios
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      and 1 as histopathological grade index.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      Two of 5 studies
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      reported histological response as a continuous measurement in adult patients with CD treated with GFD plus 50 g of oats per day vs GFD without oats, for 12 months. One of these studies
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      reported no difference in villous structure between the groups (mean for intervention versus control 2.5 and 2.4, respectively; P = NS), although an SD was not provided. The authors were contacted; however, the information was not provided, therefore this study was not included in the meta-analysis. Data were therefore available from 1 article,
      • La Vielle S.
      • Pulido O.M.
      • Abbott M.
      • et al.
      Celiac disease and gluten-free oats: a Canadian position based on a literature review.
      which reported no change in histological index in patients with CD treated with GFD with/without oats after 12 months (mean difference, −0.0; 95% CI, −0.01 to 0.01; P = .92; Figure 3B).
      Three of the 5 RCTs
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      reported on the proportion of patients with either histological improvement or no deterioration as a dichotomous outcome. Högberg et al
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      compared the histological response during GFD with/without pure oats for 12 months in 116 children with CD. A similar proportion of patients in both groups had histological remission (Marsh) (RR, 0.24; 95% CI, 0.01–4.81; P = .35). Kemppainen et al
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      compared the histological response to GFD plus kilned vs unkilned oats after 12 months, and found no differences in the proportion of patients with histological remission, according to Marsh criteria, after treatment (RR, 0.63; 95% CI, 0.12–3.24; P = .58). Holm et al
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      compared the effect of a challenge with gluten-free oats vs a gluten challenge on histological remission. The response was significantly different, as all patients challenged with oats, but none of the patients challenged with gluten, maintained histological remission after the study period (RR, 0.04; 95% CI, 0–0.66; P = .02).
      Of the 12 remaining studies, 7 were before and after comparison trials, 6 in adults
      • Hardman C.M.
      • Garioch J.J.
      • Leonard J.N.
      • et al.
      Absence of toxicity of oats in patients with dermatitis herpetiformis.
      • Cooper S.E.
      • Kennedy N.P.
      • Mohamed B.M.
      • et al.
      Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.
      • Srinivasan U.
      • Leonard N.
      • Jones E.
      • et al.
      Absence of oats toxicity in adult coeliac disease.
      • Srinivasan U.
      • Jones E.
      • Carolan J.
      • et al.
      Immunohistochemical analysis of coeliac mucosa following ingestion of oats.
      • Lundin K.E.
      • Nilsen E.M.
      • Scott H.G.
      • et al.
      Oats induced villous atrophy in coeliac disease.
      • Sey M.S.
      • Parfitt J.
      • Gregor J.
      Prospective study of clinical and histological safety of pure and uncontaminated Canadian oats in the management of celiac disease.
      and 1 in children.
      • Hoffenberg E.J.
      • Haas J.
      • Drescher A.
      • et al.
      A trial of oats in children with newly diagnosed celiac disease.
      One was a non-RCT,
      • Reunala T.
      • Collin P.
      • Holm K.
      • et al.
      Tolerance to oats in dermatitis herpetiformis.
      2 were cross-sectional studies,
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      and 2 were post hoc analyses of RCTs.
      • Koskinen O.
      • Villanen M.
      • Korponay-Szabo I.
      • et al.
      Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease.
      • Sjöberg V.
      • Hollén E.
      • Pietz G.
      • et al.
      Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease.
      None of them showed CD activation after oats. The characteristics of these studies are summarized in Table 1 and Supplementary Table 2.
      The quality of evidence for the effect of oats on histology was low, and was downgraded because the only study included was not blinded, and had high dropout rates, and was therefore at high risk of attrition bias (Table 2). There was also some imprecision detected, as the study was small and had large CIs.

       Intraepithelial lymphocyte counts

      Thirteen studies evaluated changes in IELs in response to oat consumption. Of them, 3 RCTs (2 in adults
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      ; 1 in children
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      ) assessed changes in IELs after moderate consumption of oats for 1 year. A meta-analysis was performed on these studies. There were no differences in IEL counts in patients with CD on a GFD consuming, compared with those not consuming, oats (overall standardized mean difference, 0.1; 95% CI, −0.15 to 0.35; Figure 3C). One RCT
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      assessed histological response to oat challenge compared with challenge with wheat, rye, and barley (“gluten challenge”) in children with CD. After 2 years, IEL density decreased in the oat-challenged group, but increased in the gluten-challenged group.
      In the 10 remaining studies, there were 3 post hoc analyses from RCTs
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      • Koskinen O.
      • Villanen M.
      • Korponay-Szabo I.
      • et al.
      Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease.
      • Sjöberg V.
      • Hollén E.
      • Pietz G.
      • et al.
      Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease.
      ; 4 before and after comparisons (3 in adults
      • Hardman C.M.
      • Garioch J.J.
      • Leonard J.N.
      • et al.
      Absence of toxicity of oats in patients with dermatitis herpetiformis.
      • Srinivasan U.
      • Leonard N.
      • Jones E.
      • et al.
      Absence of oats toxicity in adult coeliac disease.
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      ; 1 in children
      • Hoffenberg E.J.
      • Haas J.
      • Drescher A.
      • et al.
      A trial of oats in children with newly diagnosed celiac disease.
      ), 1 non-RCT study,
      • Reunala T.
      • Collin P.
      • Holm K.
      • et al.
      Tolerance to oats in dermatitis herpetiformis.
      1 cross-sectional,
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      and 1 cohort study
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      evaluating the effect of GFD plus oats in patients with CD. The amount of oats and the length of the study period differed between studies. Their characteristics are summarized in Table 1 and Supplementary Table 2.
      The quality of evidence on the effect of oats on IEL counts was rated as low due to high risk of attrition bias in one study, and imprecision and indirectness in both studies. Therefore, we are moderately confident in the effect estimate and the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

       The Effect of Oats on CD Serology

      Four RCTs assessed the effect of oats on serum IgA-class tissue transglutaminase antibodies (tTGA) (3 in children
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Gatti S.
      • Caporelli N.
      • Galeazzi T.
      • et al.
      Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italian study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      ; 1 in adults
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      ). Two studies, one performed in adults in remission
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      and the other in newly diagnosed children,
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      compared GFD with pure oats and GFD without oats, for 12 months. There was no significant difference in tTGA between the groups (RR, 1.71; 95% CI, 0.62–4.71; P = .89). One double-blind placebo-controlled study comparing GFD with and without oats reported that tTGA was measured, but no actual values were shown.
      • Gatti S.
      • Caporelli N.
      • Galeazzi T.
      • et al.
      Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italian study.
      Four RCTs assessed the effect of oats on serum IgA-class anti-endomysium antibodies (EmA) (2 in children
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      ; 2 in adults
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      ). Two
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      of the 4 studies compared the effect of a GFD with and without oats. There was no significant difference in EmA between the groups (RR, 1.45; 95% CI, 0.77–2.74; P = .25; Figure 3D).
      One RCT
      • Thies F.
      • Masson L.F.
      • Boffetta P.
      • et al.
      Oats and bowel disease: a systematic literature review.
      compared the effect of challenge with oats with a gluten challenge. The results were in favor of oats, as tTGA and EmA were normal in all patients after oat challenge and elevated in all patients after gluten challenge (RR, 0.04; 95% CI, 0–0.57; P = .02), (RR, 0.11; 95% CI 0.02–0.51; P = .005).
      Three RCTs assessed the effect of oats on serum gliadin antibodies (AGA) IgA (2 in children
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      ; 1 in adults
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      ). Two studies
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      compared the effect of a GFD with and without oats for 12 months. Högberg et al
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      evaluated the effect of GFD with a median of 25 g pure oats compared with a GFD without oats in 116 children. After 3 months of diet, AGA were below the cutoff for most children in both groups. Janatuinen et al
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      evaluated the effect of GFD with and without oats in 52 adult patients with CD in remission and in 40 newly diagnosed patients with CD at 12 months. AGA IgA and IgG did not change significantly at any point during the study in the oats group compared with the control group. Holm et al
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      performed a study in 36 children with either previously diagnosed, or newly detected, CD who were challenged with oats or with gluten. Two patients had borderline-positive values after 2 years of oat-containing GFD.
      Two studies evaluated the effect of GFD with and without oats on anti-avenin antibodies. Emanuél et al
      • Emanuél V.
      • Vokhmianina N.V.
      • Gavriliuk I.P.
      [Value of serological diagnosis of celiac disease for the determination of intolerance to prolamines of certain varieties of oats in patients with celiac disease].
      assessed 32 children with biopsy-proven CD and 10 nonceliac controls. Both groups were treated with 2 types of oats: ancient grains or imported oats. Patients with CD showed a different immune reaction to avenin proteins compared with controls. Guttormsen et al
      • Guttormsen V.
      • Løvik A.
      • Bye A.
      • et al.
      No induction of anti-avenin IgA by oats in adult, diet-treated coeliac disease.
      investigated 136 adult patients with CD on a GFD, 82 of whom had been consuming oats for 6 months or more. All patients had increased levels of IgA against wheat, oats, and anti-tissue transglutaminase antibody compared with healthy controls, but no significant differences were found in IgA against oats between oat- and non–oat-consuming patients.
      There were no studies evaluating the effect of GFD with oats on deaminated gliadin peptides antibodies. Further study details are shown in Table 1 and Supplementary Table 2. The quality of evidence for the effect of oats on serological response was low, and was downgraded because the outcome assessors were not blinded in 1 study, but also had high dropout rates, and therefore was at high risk of attrition bias. There was also some imprecision detected, as the study was small and had large CIs. Summary of findings for each individual outcome are shown in Table 2.

       The Effect of Oats on Dermatitis Herpetiformis

      Three non-RCT studies in adult patients assessed the effect of oats on DH, all with different study design. Reunala et al
      • Reunala T.
      • Collin P.
      • Holm K.
      • et al.
      Tolerance to oats in dermatitis herpetiformis.
      enrolled 22 patients with CD with DH in remission on a GFD. Eleven patients were treated with GFD plus 50 g pure oats, and 11 without oats, for 6 months. There was no difference in terms of the recurrence of skin lesions in patients with DH on GFD with and without oats after the study period. Kaukinen et al
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      found 13 patients with DH in a cross-sectional study; 9 were on a GFD with oats (mean 60 g per day; purity of oats not confirmed) and 4 on GFD without oats. There was no difference in the recurrence of skin lesions in patients with DH on GFD with and without oats. Finally, Hardman et al
      • Hardman C.M.
      • Garioch J.J.
      • Leonard J.N.
      • et al.
      Absence of toxicity of oats in patients with dermatitis herpetiformis.
      performed a before and after comparison trial in which 10 patients with DH were treated with GFD plus pure oats (mean 62 g per day) for 12 weeks. None of the patients reported pruritus, rash, or recurrence of DH during this period. Further details are shown in Table 1 and Supplementary Table 2.

       Long-term Effect of Oats

      No study compared the effect of regular vs pure/uncontaminated oats on any of the outcomes assessed. Five of the 28 studies did not report whether oats were from a contaminated or uncontaminated source
      • Srinivasan U.
      • Jones E.
      • Weir D.G.
      • et al.
      Lactase enzyme, detected immunohistochemically, is lost in active celiac disease, but unaffected by oats challenge.
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      ; however, only 1 of them
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      showed increased IELs in a proportion of patients after oats consumption. The long-term effect of oats over 1 year was assessed by 14 studies.
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Högberg L.
      • Laurin P.
      • Fälth-Magnusson K.
      • et al.
      Oats to children with newly diagnosed coeliac disease: a randomised double blind study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Unkilned and large amounts of oats in the coeliac disease diet: a randomized, controlled study.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      • Koskinen O.
      • Villanen M.
      • Korponay-Szabo I.
      • et al.
      Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease.
      • Sjöberg V.
      • Hollén E.
      • Pietz G.
      • et al.
      Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease.
      • Hardman C.M.
      • Garioch J.J.
      • Leonard J.N.
      • et al.
      Absence of toxicity of oats in patients with dermatitis herpetiformis.
      • Cooper S.E.
      • Kennedy N.P.
      • Mohamed B.M.
      • et al.
      Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      • Kemppainen T.
      • Janatuinen E.
      • Holm K.
      • et al.
      No observed local immunological response at cell level after five years of oats in adult coeliac disease.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      Six studies
      • Peräaho M.
      • Kaukinen K.
      • Mustalahti N.
      • et al.
      Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      • Janatuinen E.K.
      • Pikkarainen P.H.
      • Kemppainen T.A.
      • et al.
      A comparison of diets with and without oats in adults with celiac disease.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Pikkarainen P.H.
      • et al.
      Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.
      • Størsrud S.
      • Hulthén L.R.
      • Lenner R.A.
      Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences.
      • Kaukinen K.
      • Collin P.
      • Huhtala H.
      • et al.
      Long-term consumption of oats in adult celiac disease patients.
      evaluated the effect of oats on gastrointestinal symptoms and 12 on serological and histological responses. There was no change on any of the previous outcomes after long-term consumption of oats.

      Discussion

      There is still uncertainty regarding the effect of oats in CD despite previous reviews.
      • Baker P.G.
      • Read A.E.
      Oats and barley toxicity in coeliac patients.

      Celiac disease and gluten-free claims on uncontaminated oats. Food directorate health products and food branch. Health Canada. Updated May 29, 2015. Available at: http://www.hc-sc.gc.ca/fn-an/consult/2014-cel-oats-contam-avoine-coel/document-consultation-eng.php. Accessed April 20, 2017.

      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Nutrient intakes during diets including unkilned and large amounts of oats in celiac disease.
      • Thompson T.
      Gluten contamination of commercial oat products in the United States.
      • Hernando A.
      • Mujico J.R.
      • Mena M.C.
      • et al.
      Measurement of wheat gluten and barley hordeins in contaminated oats from Europe, the United States and Canada by Sandwich R5 ELISA.
      • Gelinas P.
      • McKinnon C.M.
      • Mena M.C.
      • et al.
      Gluten contamination of cereal foods in Canada.
      In our updated review of the literature, we found no deterioration in gastrointestinal symptoms in patients with CD consuming oats for 12 months. Although the evidence on oats and lack of symptom induction in adult patients comes from RCTs, the quality was rated as very low. Of 6 small, before and after comparison studies, 2 reported more frequent gastrointestinal symptoms after oats intake.
      • Fric P.
      • Gabrovska D.
      • Nevoral J.
      • et al.
      Celiac disease, gluten-free diet, and oats.
      • Størsrud S.
      • Olsson M.
      • Arvidsson Lenner R.
      • et al.
      Adult coeliac patients do tolerate large amounts of oats.
      These had limitations due to small sample size, lack of control group, and unclear assessment of diet compliance. Furthermore, there was no clear association between the presence of symptoms and CD activity, making it unclear whether symptoms were related to mild CD activation or to the increased fiber contained in oats.
      • Tuire I.
      • Marja-Leena L.
      • Teea S.
      • et al.
      Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease.
      Studies investigating changes in histological parameters have mostly shown no change or slight improvement in Marsh scores, villous/crypt ratios, and IEL counts. Once more, the quality of evidence from RCTs was low, due to attrition bias detected in one of the studies and also imprecision in the results.
      There were no RCTs evaluating the effect of oats in patients with DH; however, the results of the 3 non-RCTs suggest that skin manifestations were not worsened after consumption of oats.
      All serologic markers associated with celiac autoimmunity are gluten-dependent, and a rise in their values suggests exposure to gluten.
      • Rubio Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • et al.
      Diagnosis and management of celiac disease.
      Our review found no difference in the levels of tTG, AGA, or EmA antibodies in patients with CD on GFD with or without oats; however, the values were increased after gluten challenge.
      • Holm K.
      • Mäki M.
      • Vuolteenaho N.
      • et al.
      Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study.
      The results were confirmed by noncontrolled studies in both adults and children. Although the RCTs overall suggest that pure oats do not trigger immune activation, this should be taken with caution, as the overall quality of evidence was low. A position statement by the Canadian Celiac Association
      • Rashid M.
      • Butzner D.
      • Burrows V.
      • et al.
      Consumption of pure oats by individuals with celiac disease: a position statement by the Canadian Celiac Association.
      suggested that screening for tTG or EmA may not identify the rare patient who reacts to oats, as these tests may not be sufficiently sensitive for detecting “mild” dietary transgressions, especially with short-term challenge. Therefore, a positive tTG or EmA result helps to confirm CD activity, but a negative test may not exclude it.
      • Rashid M.
      • Butzner D.
      • Burrows V.
      • et al.
      Consumption of pure oats by individuals with celiac disease: a position statement by the Canadian Celiac Association.
      Only 1 RCT involving 60 patients
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      evaluated the effect of kilning process. Kilning is an industrial heating process performed to preserve the main properties of oats and to lengthen its shelf life.
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Nutrient intakes during diets including unkilned and large amounts of oats in celiac disease.
      Both kilned and unkilned oats were tolerated by patients with CD
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Nutrient intakes during diets including unkilned and large amounts of oats in celiac disease.
      ; however, the results will need to be confirmed in future studies.
      There are numerous aspects to consider when comparing studies evaluating the safety of oats, such as the compliance with GFD, amount and frequency of oats consumption, as well as the cultivars used in the production of pure oats.
      • de Souza M.C.
      • Deschênes M.E.
      • Laurencelle S.
      • et al.
      Pure oats as part of the gluten-free diet in celiac disease: the need to revisit the.
      This information was often omitted. Similar to previous reviews,
      • de Souza M.C.
      • Deschênes M.E.
      • Laurencelle S.
      • et al.
      Pure oats as part of the gluten-free diet in celiac disease: the need to revisit the.
      we found that the available studies differed in study design, number of subjects, time period, and clinical and biological parameters used. Furthermore, there was disparity and lack of information regarding the quantity, source, and the cultivar(s) of oats.
      • de Souza M.C.
      • Deschênes M.E.
      • Laurencelle S.
      • et al.
      Pure oats as part of the gluten-free diet in celiac disease: the need to revisit the.
      Accuracy of assays measuring oat immunotoxicity was out of the scope of this review but is an important area for future research because there is no accepted standard for detection of immunoreactive proteins.
      The purity of oats will depend on the country of origin and local regulations. Although most gluten-free products containing oats have been confirmed safe in countries like Finland and Norway,
      • Guttormsen V.
      • Løvik A.
      • Bye A.
      • et al.
      No induction of anti-avenin IgA by oats in adult, diet-treated coeliac disease.
      regular oats in North America are likely to be contaminated with wheat and barley.
      • Thompson T.
      Gluten contamination of commercial oat products in the United States.
      • Hernando A.
      • Mujico J.R.
      • Mena M.C.
      • et al.
      Measurement of wheat gluten and barley hordeins in contaminated oats from Europe, the United States and Canada by Sandwich R5 ELISA.
      • Gelinas P.
      • McKinnon C.M.
      • Mena M.C.
      • et al.
      Gluten contamination of cereal foods in Canada.
      • Koerner T.B.
      • Cleroux C.
      • Poirier C.
      • et al.
      Gluten contamination in the Canadian commercial oat supply.
      • Koerner T.B.
      • Cleroux C.
      • Poirier C.
      • et al.
      Gluten contamination of naturally gluten-free flours and starches used by Canadians with celiac disease.
      For this reason, oats used in gluten-free foods should be produced/processed under protocols that ensure purity during all phases of production. Ensuring safety will depend on reliable testing measures that consistently guarantee less than 20 ppm of gluten.

      NASSCD Oats statement. April 2016. Available at: http://www.nasscd.org/files/Oats-Statement-NASSCD-April-2016(1).pdf. Accessed June 18, 2017.

      Recently, oats that have been optically or mechanically cleaned to eliminate other grains have been used to produce gluten-free cereal products for the mass market. These are available and have, in some cases, been determined to be gluten-free (<20 ppm of gluten). None of these oat products have as yet been subjected to clinical studies. All RCTs published to date investigating the safety of pure oats consumption in CD were conducted in Europe, which emphasizes the urgent need for studies in North America and other regions of the world where CD is prevalent. Results from studies in Europe using locally sourced oats cannot be extrapolated to North America.
      The methodology of our systematic review and meta-analysis, including the search and selection of studies, data extraction, and final analysis of results, was rigorous. We attempted to increase the scope of our review and reduce the risk of biases in all steps of this process. We acknowledge that the data are not robust enough to make definitive, evidence-based recommendations on the safety of oats for patients with CD at this point. In this sense, we endorse the recommendations by the North American Society for the Study of Celiac Disease

      NASSCD Oats statement. April 2016. Available at: http://www.nasscd.org/files/Oats-Statement-NASSCD-April-2016(1).pdf. Accessed June 18, 2017.

      to support the use of pure oats in CD, but to monitor levels of tTGA before and after their introduction into the diet. Persistent or recurrent symptoms should prompt an assessment that may include an intestinal biopsy.

      NASSCD Oats statement. April 2016. Available at: http://www.nasscd.org/files/Oats-Statement-NASSCD-April-2016(1).pdf. Accessed June 18, 2017.

      In conclusion, the results of our systematic review evaluating oat safety in adults and children with CD are reassuring, and suggest that noncontaminated oats are tolerated by the great majority of patients. However, our confidence is limited by the low quality and limited geographic distribution of the data. Current evidence suggests that noncontaminated oats can be used in patients with CD but there is still a need for more rigorous data from well-designed RCTs evaluating the effect of pure oats in the short and long term, in both children and adult patients with CD. Ideally, relevant information regarding the source of oats, including cultivars and amount of oats consumed and compliance to GFD should be provided.

      Acknowledgment

      The North American Society for the Study of Celiac Disease council has reviewed this document and endorses its conclusions.

      Supplementary Material

      Supplementary Table 1Search Strategy
      SEARCH OVID-MEDLINE (MESH Terms)
      • 1.
        Celiac Disease
      • 2.
        celiac.mp
      • 3.
        Celiac Disease/ or Glutens/ or coeliac.mp
      • 4.
        gluten.mp. or Glutens
      • 5.
        enteropathy.mp
      • 6.
        4 and 5
      • 7.
        gluten-sensitive.mp
      • 8.
        sprue nontropical.mp
      • 9.
        oats.mp. or Avena sativa
      • 10.
        pure-oats.mp
      • 11.
        9 or 10
      • 12.
        1 or 2 or 3 or 4 or 6 or 7 or 8
      • 13.
        11 and 12
      Supplementary Table 2Summary of All Studies Evaluating the Effect of Oats in CD
      NOTE. Study design: 1 = Randomized controlled trial; 2 = Non-randomized controlled trial, 3 = Before and after comparison; 4 = Cross-sectional; 5 = Post hoc from RCT; 6 = Cohort; 7 = Post hoc cohort.
      Green: no change in outcome after oats consumption, yellow: change of outcome in low proportion of patients; red: significant worsening after oat consumption.
      GF, gluten-free; GI, gastrointestinal symptoms.
      Supplementary Table 3Excluded studies
      Author, yrReason for exclusion
      1. AnonymousNot original study-commentary
      2. Arentz-Hansen H, 2004
      • Arentz-Hansen H.
      • Fleckenstein B.
      • Molberg O.
      • et al.
      The molecular basis for oat intolerance in patients with celiac disease.
      Not clinical trial - study in vitro
      3. Branski D, 1996
      • Branski D.
      • Shine M.
      Oats in celiac disease.
      Not original study
      4. Butzner JD, 2011
      • Butzner J.D.
      Pure oats and the gluten-free diet: are they safe?.
      Not original study
      5. Campbell JA, 1982
      • Campbell J.A.
      Foods for patients with celiac disease.
      Not original study
      6. Chaptal J, 1957
      • Chaptal J.
      • Jean R.
      • Dossa D.
      • et al.
      Celiac disease caused by intolerance to gliadin from wheat, oats & milk products.
      Case series
      7. Dissanayake AS, 1974
      • Dissanayake A.S.
      • Truelove S.C.
      • Whitehead R.
      Lack of harmful effect of oats on small-intestinal mucosa in coeliac disease.
      Case report
      8. Hardy M, 2015
      • Hardy M.Y.
      • Tye-Din J.A.
      • Stewart J.A.
      • et al.
      Ingestion of oats and barley in patients with celiac disease mobilizes cross-reactive T cells activated by avenin peptides and immuno-dominant hordein peptides.
      Not clinical trial - study in vivo
      9. Emmanuel V, 2007
      • Emanuél V.L.
      • Vokhmianina N.V.
      • Gavriliuk I.P.
      Value of serological diagnosis of celiac disease for the determination of intolerance to prolamines of certain varieties of oats in patients with celiac disease.
      Not intended outcome
      10. Hollen E 2003
      • Hollén E.
      • Högberg L.
      • Stenhammar L.
      • et al.
      Antibodies to oat prolamines (avenins) in children with coeliac disease.
      Not clinical study
      11. Hollen E 2006
      • Hollén E.
      • Holmgren Peterson K.
      • Sundqvist T.
      • et al.
      Coeliac children on a gluten-free diet with or without oats display equal anti-avenin antibody titres.
      Post- hoc analysis
      12. Lovik A 2009
      • Lovik A.
      • Gjoen A.U.
      • Morkrid L.
      • et al.
      Oats in a strictly gluten-free diet is associated with decreased gluten intake and increased serum bilirubin.
      Post –hoc analysis
      13. Lovik A 2009
      • Lovik A.
      • Morkrid L.
      • Guttormsen V.
      • et al.
      Oats in a strictly gluten-free diet: Do oats increase serum levels of bilirubin?, Poster Discussion Sessions.
      Abstract from Lovik 2009
      14. Kemppainen 2010
      • Kemppainen T.A.
      • Heikkinen M.T.
      • Ristikankare M.K.
      • et al.
      Nutrient intakes during diets including unkilned and large amounts of oats in celiac disease.
      Post-hoc analysis
      15. Kumar 1995
      • Khumar P.J.
      • Farthing M.G.J.
      Oats and celiac disease.
      Not original study-commentary
      16. Peraaho 2004
      • Peräaho M.
      • Collin P.
      • Kaukinen K.
      • et al.
      Oats can diversify a gluten-free diet in celiac disease and dermatitis herpetiformis.
      Not intended outcome
      17. Sharkey 2012
      • Sharkey L.
      • Corbett G.
      • Currie E.
      • et al.
      Responses to dietary intervention guided by follow-up duodenal biopsy in coeliac disease.
      Not intended intervention
      18. De Souza MC, 2015
      • de Souza M.C.
      • Deschenes M.E.
      • Laurencelle S.
      • et al.
      Pure oats as part of the gluten-free diet in celiac disease: The need to revisit the issue.
      Not original study
      19. Tapsas D, 2014
      • Tapsas D.
      • Fälth-Magnusson K.
      • Högberg L.
      Urinary nitric oxide metabolites in children with celiac disease after long-term consumption of oats-containing gluten-free diet.
      Not intended outcome
      20. Tjellstrom, 2014
      • Tjellström B.
      • Stenhammar L.
      • Sundqvist T.
      • et al.
      The effects of oats on the function of gut microflora in children with coeliac disease.
      Not intended outcome
      21. Troncone R, 1987
      • Troncone R.
      • Auricchio S.
      • De Vincenzi M.
      • et al.
      An analysis of cereals that react with serum antibodies in patients with coeliac disease.
      Not clinical trial
      22. Van de Kamer 1953
      • Van de Kamer J.H.
      • Weijers H.A.
      • Dicke W.K.
      Coeliac disease. IV. An investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease.
      Not intended comparison

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