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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:753–758

ncidence of Autoimmune Diseases in Celiac Disease: Protective Effect ofhe Gluten-Free Diet

ACQUES COSNES,* CHRISTOPHE CELLIER,‡ SHEILA VIOLA,§ JEAN–FREDERIC COLOMBEL,� LAURENT MICHAUD,¶

ACQUES SARLES,# JEAN–PIERRE HUGOT,** JEAN–LOUIS GINIES,‡‡ ALAIN DABADIE,§§ OLIVIER MOUTERDE,� �

ATTHIEU ALLEZ,¶¶ ISABELLE NION–LARMURIER* AND THE GROUPE D’ETUDE ET DE RECHERCHE SUR LA MALADIEOELIAQUE

Hôpital St-Antoine and Université Pierre & Marie Curie, Paris, France; ‡Hôpital Europén Georges Pompidou, Paris, France; §Hôpital Trousseau, Paris, France;Hôpital Claude Huriez, Lille, France; ¶Hôpital Jeanne de Flandre, Lille, France; #Hôpital d’Enfants de la Timone, Marseille, France; **Hôpital Robert Debré, Paris,rance; ‡‡Centre Hospitalier Universitaire, Angers, France; §§Hôpital Sud, Rennes, France; � �Centre Hospitalier Universitaire, Rouen, France; and the ¶¶Hôpital St-

ouis, Paris, France

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ackground & Aims: Celiac disease may be associatedith autoimmune diseases. The aims of the present studyere to determine in celiac patients which factors modulate

he risk of autoimmune disease and to evaluate the effect ofhe gluten-free diet. Methods: The occurrence of autoim-

une disease and compliance to gluten-free diet werepecified retrospectively in 924 celiac patients recruitedrom 27 French pediatric and adult gastroenterologyenters. Results: One or several autoimmune diseases hadeveloped in 178 patients. The cumulative risk of autoim-une disease was 8.1% � 1% at age 15, and 15.7% � 1.5% at

ge 30. Factors associated with an increased risk were fam-ly history of autoimmunity (hazard ratio, 2.36; 95% confi-ence interval, 1.71–3.31) and diagnosis of celiac diseaseefore 36 years of age (hazard ratio, 2.65; 95% confidence

nterval, 1.79 –3.85). After diagnosis of celiac disease, 55 of88 patients developed an autoimmune disease. The cumu-ative risk of subsequent autoimmune disease was lower inatients compliant to a gluten-free diet versus noncompli-nt patients (at 10 years, 6% � 2% vs 15.6% � 5.9%, respec-ively; P � .02). The incidence of autoimmune diseases was.4 per 1000 patient-years during adherence to a gluten-freeiet versus 11.3 per 1000 patient-years during nonadherence

o the diet (P � .002). Results were similar in both theediatric and the adult populations. Conclusions: Celiacatients most at risk for autoimmune disease are thoseiagnosed early in life and having a family history of auto-

mmunity. The gluten-free diet has a protective effect.

eliac disease (CD) is a common autoimmune disorderinduced by the intake of gluten proteins present in wheat,

arley, and rye, and characterized by the presence of antitrans-lutaminase autoantibodies and intestinal villous damage. Inatients with autoimmune disease such as type 1 diabetesellitus or thyroiditis, screening may lead to a diagnosis of

atent CD in 5% to 10% of patients.1–3 Conversely, the preva-ence of autoimmune diseases is increased in patients with CDhen compared with a control population.4

Prolonged exposure to gluten in CD may promote the de-elopment of other autoimmune diseases. Indeed, in a pediatricopulation of 909 celiac patients, Ventura et al5 showed thathe prevalence of autoimmune disorders was related to the

uration of exposure to gluten. Actually, the older the patient

t diagnosis, the higher the prevalence of autoimmune disease,ith a prevalence reaching 34% in celiac patients diagnosedetween the ages of 20 and 25 years. However, it should beoted in this study that most patients were symptomatic chil-ren with a duration of exposure to the risk of autoimmuneisease similar to the duration of exposure to gluten. The effectf gluten-free diet was not evaluated. Two studies of celiacdults from Italy6 and Finland7 did not confirm that the dura-ion of gluten exposure was important in the development ofutoimmune diseases. In the latter study, 31% of autoimmuneiseases were detected subsequent to the diagnosis of CD de-pite an overall excellent compliance to the gluten-free diet.7

Autoimmune diseases develop at different ages, for example,ype 1 diabetes mellitus usually develops during childhood ordolescence,8 whereas autoimmune thyroiditis often is diag-osed during the fifth decade of life.9 Adherence to a gluten-freeiet also varies with age, with a high level of poor compliance indolescence.10,11 Thus, it is crucial to analyze the incidence ofutoimmune diseases, and not only the prevalence, in relationoth to age and compliance to a gluten-free diet.

The present study had 2 objectives: first, to determine ineliac patients the factors associated with an increased risk ofutoimmune disease during life, and, second, to evaluate if theluten-free diet protects against the subsequent development ofutoimmune disease.

Patients and MethodsPatientsPatients were recruited over a 5-year period (2003–2007)

rom 27 French centers of Gastroenterology and Pediatric Gas-roenterology. Physicians in these centers were asked to includell patients with a diagnosis of CD that they saw consecutivelys inpatients or outpatients during the period of recruitment. Aiagnosis of CD required a duodenal biopsy showing increased

ntraepithelial lymphocyte count, crypt hypertrophy, and vil-ous atrophy.12 Recruitment was ended when the predefinedumber of patients included in the study was reached.

Abbreviation used in this paper: CD, celiac disease; GFD, gluten-freeiet.

© 2008 by the AGA Institute1542-3565/08/$34.00

doi:10.1016/j.cgh.2007.12.022

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754 COSNES ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 7

A total of 924 patients were included in the study, 378 fromediatric centers and 546 from adult gastroenterology centers,

ncluding 124 patients who had been diagnosed with CD dur-ng childhood. The diagnosis of CD was made more than 6

onths before the inclusion visit in 788 patients (85%). These88 patients were included in the study of the effect of gluten-ree diet.

Autoimmune DiseasesThe presence of autoimmune disease in patients and in

heir first- and second-degree relatives was evaluated by use of atructured questionnaire and a review of patient charts. Theuestionnaire was completed by the physician during the in-lusion visit in the presence of the patient. The presence of onef the autoimmune disorders belonging to a prefixed list wasearched for in all subjects. The date of the diagnosis of auto-mmune disease was recorded using medical charts. Only clin-cally patent autoimmune disorders were taken into account,nd at the time of clinical evaluation there was no particularearch for biological abnormalities.

Gluten-Free DietThe adherence to a gluten-free diet was evaluated ret-

ospectively by the physician in charge of the patient. In addi-ion, the patient (or his/her parents) was interviewed during thenclusion visit to ascertain compliance and the absence of un-ntentional gluten ingestions. There was no systematic clinical,mmunologic, or histologic monitoring of the compliance tohe diet, and the physician used his own criteria to assessompliance. Finally, the time that elapsed between the diagno-is of CD and inclusion in the study was divided into periodsith good compliance to the diet, periods under gluten-free dietut with poor compliance, and periods under normal diet.hese 2 latter periods were pooled in further analyses.

Statistical AnalysisThe all-life cumulative risk of autoimmune disease was

ssessed using the Kaplan–Meier method with the date of births the starting point. Variables suspected to be associated withutoimmune disease (diagnosis of CD in childhood [�16 y], orate adulthood [older than the median age at diagnosis indults], sex, main symptoms revealing CD [digestive, nutri-ional, hematologic], interval between first symptom and diag-osis [�12 mo], ethnicity [Caucasian or not], family history ofD, family history of autoimmune disease, and smoking sta-

us), were tested using the log-rank test. Variables with a P valuef less than .10 were entered into a Cox model with a backwardlimination procedure. Results of the analyses are presented asazard ratios, with 95% confidence intervals.

The second part of the study analyzed the effect of gluten-ree diet on the development of autoimmune disease. Threenalyses were performed. First, an actuarial analysis was per-ormed. The outcome was the subsequent autoimmune diseaseate and the time to subsequent autoimmune disease. Patientsere classified into 2 groups on the basis of their adherence togluten-free diet during the first semester after diagnosis.

atients who started a gluten-free diet more than 6 monthsfter their diagnosis and patients who did not adhere initially togluten-free diet were included in the normal diet group until

hey started a strict gluten-free diet, which was used as the final

oint. Conversely, patients who stopped a gluten-free diet were F

ncluded in the gluten-free diet group until they transgressed oresumed a normal diet. The variables tested were those sus-ected to be possible predictors of autoimmune disease (seearlier), and a history of prior autoimmune disease. Multivari-te analyses were performed with Cox proportional hazardsegression to adjust for confounding. Because this analysis washe most determinant part of the study, it was used to calculatehe number of patients entering the study. According to anntermediary analysis performed after 2 years of recruitment, weypothesized that a gluten-free diet could decrease the 10-yearisk of subsequent autoimmune disease from 12% to 6%. Thised us to include a minimum of 558 patients (� � .05; � � .20).

The second analysis compared the annual incidence of au-oimmune diseases between 2 periods: the period after the CDiagnosis under a normal diet or poor compliance to a gluten-ree diet, and the period after the CD diagnosis under a strictluten-free diet. Incidence figures were given per 1000 patient-ears. Differences between frequencies were tested using thehi-squared test.

The third analysis was a paired comparison of the annualncidences that was performed in the subgroup of patients whodhered to a gluten-free diet for some time (5%–95% of time)fter their diagnosis.

These different analyses were performed in the whole groupf patients, then separately in the pediatric population (age atiagnosis of CD, �16 y) and in the adult population, and withnd without the classification of dermatitis herpetiformis as anutoimmune disease.

ResultsCumulative Risk of Autoimmune DiseaseA total of 178 patients (19.3%) had developed an auto-

mmune disease from birth to the inclusion visit (209 autoim-une diseases). In 95 patients, the diagnosis of autoimmune

isease was made more than 6 months before the CD diagnosis.n 38 patients, including 15 in whom serologic screening per-ormed for type 1 diabetes was positive and led to diagnose CD,he diagnoses of autoimmune disease and CD were madeithin the same 6-month period. The last 45 patients developed

heir first autoimmune disease more than 6 months after CDiagnosis. The number of autoimmune diseases per patientaried from 1 (157 patients) to 4 (3 patients). The cumulativeisk of autoimmune disease in the whole series was 8.1% � 1%t age 15, 15.7% � 1.5% at age 30, and 32.5% � 2.5% at age 50.onsidering dermatitis herpetiformis as an autoimmune dis-

ase changed the figures to 9.2% � 1%, 18.4% � 1.6%, and 36.3%2.6%, respectively, at the same ages.Table 1 shows the prevalence of specific autoimmune dis-

ases according to age at diagnosis of CD and date of diagnosis.nsulin-dependent diabetes mellitus (type 1 diabetes) and auto-mmune thyroiditis accounted for 29% and 26% of autoimmuneisorders, respectively, the former being observed mostly inhildren and the latter in adults.

Factors associated with an increased risk of autoimmuneisease in univariate analysis were a long interval between therst symptom and the diagnosis of CD, an absence of digestiveymptoms at diagnosis, younger age at diagnosis, and familyistory of autoimmune disease (171 patients [19%] had at leastfirst- or second-degree relative with autoimmune disease).

amily history of CD (86 patients [9%] had at least 1 first- or

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July 2008 CELIAC DISEASE AND AUTOIMMUNITY 755

econd-degree relative with CD) was not associated with anncreased risk of autoimmune disease. The Cox model selectedamily history of autoimmunity, diagnosis of CD before 36ears of age, and absence of digestive symptoms (Table 2).

ithin the pediatric population, family history and absence ofigestive and nutritional symptoms at diagnosis were associ-ted with an increased risk of autoimmune disease. In patientsiagnosed with CD in adulthood, family history and young aget diagnosis were associated with an increased risk of autoim-une disease (Table 2). Figure 1 gives the cumulative risk of

utoimmune disease in 3 groups defined by the age at diagnosisf CD. Diagnosis of CD later in life was associated with a lesserisk of autoimmune disease, whereas the risk was not signifi-

able 1. Autoimmune Diseases by Age and Date of Occurren

Diagnos

Date of occurrence Ever

o. of patients 924edian age at diagnosis, y (IQR) 11 (1–35)edian follow-up period, y (IQR) 4 (1–12)

ype 1 diabetes mellitus 60utoimmune thyroiditis 55soriasis 17nflammatory bowel disease 14utoimmune hepatitis 11itiligo 11lopecia areata 7heumatoid disease 6iant aphthosis 4pilepsy and calcification 2jögren’s syndrome 2ystemic lupus 2utoimmune neutropenia 2ddison’s disease 2ernicious anemia 2ntiphospholipid syndrome 2yasthenia gravis 2

hrombopenic purpura 2olymyositis 1emolytic anemia 1ultiple sclerosis 1rimary biliary cirrhosis 1ullous pemphigoid 1

mmunoglobulin A nephropathy 1otal 209ermatitis herpetiformis 29otal (dermatitis herpetiformis included) 238

QR, interquartile range.

able 2. Factors Associated With an Increased Risk of Autoim

Whole population(n � 924)

HR 95%

amily history of autoimmune disease 2.36 1.71–3D diagnosis �36 y 2.65 1.79–3o digestive symptoms 1.60 1.18–2o nutritional symptoms

I, confidence interval; HR, hazard ratio.

antly different in those diagnosed in childhood and youngdulthood. Similar results were obtained when considering der-atitis herpetiformis as an autoimmune disease (data not

hown).

Subsequent Autoimmune Disease in Relationto Gluten-Free DietFifty-five patients developed an autoimmune disease

ore than 6 months after the diagnosis of CD (59 autoimmuneiseases). Those are indicated in Table 1. The cumulative risk ofutoimmune disease subsequent to diagnosis of CD, irrespec-ive of compliance or interruption of the gluten-free diet, was.3% � 0.6% at 5 years and 6.4% � 1.2% at 10 years.

t Diagnosis of CD

fore age 16 y Diagnosis at or after age 16 y

or Subsequent Prior Subsequent

2 441 422 347–4) — 36 (29–50) —

9 (4–20) — 4 (2–9)7 5 27 10 7 36 120 3 14 02 2 6 42 2 3 41 1 6 30 2 4 10 0 5 11 0 2 11 1 0 01 0 1 00 2 0 00 1 1 00 1 1 00 1 1 00 0 2 00 0 1 10 0 1 10 0 0 10 1 0 00 0 1 00 0 1 00 0 1 00 0 1 05 29 115 305 3 18 30 32 133 33

ne Disease (Cox Model)

Diagnosis of CD beforeage 16 y (n � 502)

Diagnosis of CD at orafter age 16 y (n � 422)

HR 95% CI HR 95% CI

2.84 1.58–5.11 2.23 1.49–3.342.45 1.60–3.75

2.52 1.45–4.352.40 1.37–4.18

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756 COSNES ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 7

Actuarial AnalysisThe effect of gluten-free diet first was examined using

ctuarial curves comparing patients who adhered to a gluten-ree diet after CD diagnosis with those who started the diet laterr did not adhere. Adherence to a gluten-free diet was associ-ted with a decreased risk of subsequent autoimmune diseaseFigure 2). However, in multivariate analysis this factor was notignificant (P � .07); the CD diagnosis in childhood was thenly variable retained (hazard ratio, 0.33; 95% confidence inter-al, 0.15– 0.73). The 10-year cumulative risk of autoimmuneisease was 4.2% � 1.7% in the children who followed theluten-free diet (n � 397), versus 7.1% � 4.9% in those who didot (n � 44). This difference was not significant. In this pop-lation, the only factor associated with an increased risk ofubsequent autoimmune disease was a prior autoimmune dis-ase at the diagnosis of CD. In the patients diagnosed with CDn adulthood, adherence to a gluten-free diet was protective10-year cumulative risk of autoimmune disease 9.1% � 3.3% inompliant vs 21.1% � 9.4% in noncompliant; P � .05), and dietas the only significant predictor of subsequent autoimmuneisease.

Comparison of Annual IncidencesAmong the 59 autoimmune diseases diagnosed after

he diagnosis of CD (Table 1), 24 developed while the patientas following a gluten-free diet, and 35 during normal diet oruring nonadherence to the diet. The number of severe auto-

mmune diseases (diabetes, inflammatory bowel disease, con-

igure 2. Cumulative risk of autoimmune dis-ase subsequent to the diagnosis of CD accord-

ng to compliance to a gluten-free diet (GFD).

ective tissue diseases, hepatitis, hematologic disorders) thateveloped under a gluten-free diet was 8, and without a gluten-ree diet was 20. In total, the incidence of autoimmune diseasesas 5.4 per 1000 patient-years under a gluten-free diet versus1.3 per 1000 patient-years under a normal diet or duringonadherence to the diet (P � .002). This difference still wasignificant in the patients diagnosed in childhood (3.1 vs 8.3 per000 patient-years, respectively; P � .01) and within the adultopulation (9.5 vs 21.8 per 1000 patient-years, respectively;� .02).

Paired Comparison of Annual IncidencesIn the group of 364 patients who followed a gluten free

iet intermittently, the incidence of autoimmune diseases was.4 per 1000 patient-years under a gluten-free diet (2065 pa-ient-years) versus 9.6 per 1000 patient-years under a normaliet or during poor adherence to the diet (2494 patient-years) (P

.01). This difference still was significant in the patientsiagnosed in childhood (1.3 vs 6.8 per 1000 patient-years,espectively; P � .01), but did not reach the level of significancen the adult population (10.7 vs 23.6 per 1000 patient-years,espectively; P � .13).

Similar results were obtained when considering dermatitiserpetiformis as an autoimmune disease (data not shown).

DiscussionThis study shows that the risk of development of an

utoimmune disease in celiac patients is increased in patients

Figure 1. Cumulative risk of autoimmune dis-ease during life according to the age at diagnosisof CD. Diagnosis after 36 years of age was as-sociated with a decreased risk of associated au-toimmune diseases when compared with the 2other groups (P � .001). The difference betweenthe 2 other groups was not significant.

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July 2008 CELIAC DISEASE AND AUTOIMMUNITY 757

ith a family history of autoimmune disease and when a diag-osis of CD is made in childhood or young adulthood com-ared with later in life. More importantly, after diagnosis ofD, strict adherence to a gluten-free diet was associated with aecreased risk of subsequent autoimmune disease.

The present study had several limitations. First, althoughonsecutive patients were included prospectively, the data wereollected retrospectively. The date of diagnosis of autoimmuneisease was a major point in the analysis, and there may beome uncertainty regarding this item. In fact, most autoim-

une diseases that were diagnosed years before inclusion wereighly symptomatic or needed treatment (thyroid disease, typediabetes, inflammatory bowel disease, and alopecia) and their

ate of diagnosis could be ascertained without difficulty. Weid not include any subclinical autoimmune disease. Second,he duration of recruitment lasted 5 years, which may be con-idered a very long period. A possible explanation is that symp-omatic CD is not as frequent in France when compared withther European countries.13 Alternatively, because only univer-ity centers participated, a high proportion of celiac patientsollowed up by general practitioners or private gastroenterolo-ists may not have been included, which could lead to a bias toore severe cases. The aim of our study was not to assess the

requency of autoimmune disease in CD but to analyze theactors associated with an increased risk. It should be noted,owever, that the prevalence of autoimmune disease in ouropulation (19.3%) was not different from that of other impor-ant series from Italy5,6 or Finland.7 Third, the definition ofompliance to a gluten-free diet was not based on a systematicrotocol but was assessed by the physician using his ownriteria. However, a specific inquiry was performed during thenclusion visit to assess compliance and unintentional errors,nd in most centers the disappearance of anti-endomysiumntibodies and histologic recovery were required to ascertainompliance.

Some factors associated with an increased risk of autoim-une disease during life in celiac patients could be expected.he absence of digestive and nutritional symptoms may be aonsequence of the recruitment of celiac patients because theyad autoimmune disease. For example, the diagnosis of CD washe result of screening using antibody testing in some patientsith diabetes who had no digestive symptoms. The fact thatutoimmune diseases were more frequent in patients with aamily history of autoimmunity favors the hypothesis of ainkage disequilibrium between the genes responsible for CDnd those responsible for the co-expressed autoimmune diseas-s.14 A more striking observation was that late diagnosis of CDn adulthood was associated with a decreased risk of autoim-

une disease. This result is in contradiction with those ofentura et al,5 obtained in a pediatric population, but compat-

ble with those of Sategna Guidetti et al.6 Indeed, in the lattertudy, the risk of autoimmune disease tended to decrease withhe duration of gluten exposure. This apparent paradox may be

consequence of the delayed development of CD in patientsiagnosed after 36 years. It may be hypothesized that comparedith other celiac patients, these patients have a weaker suscep-

ibility to autoimmunity, and late CD is one of the variousanifestations of this dysregulation. Alternatively, in these pa-

ients, CD remains latent for years and the loss of the intestinalarrier function develops only in late adulthood; the increase of

he antigen load, a possible trigger of various autoimmune B

iseases, occurs later in life. In addition to the variability ofutoimmune susceptibility with age, differences in the durationf latent CD may explain in part why the duration of glutenxposure is a risk factor for autoimmune diseases in children5

ho have a short period of latency, but not in adults.6,7 It is notn contradiction with the apparent protective effect of a gluten-ree diet after a diagnosis of CD if we admit that in mostatients patent CD developed a short time before being diag-osed.

In the present study, a gluten-free diet appeared protectivegainst the development of an autoimmune disease both re-arding the cumulative risk and annual incidences in the wholeopulation. However, the effect of a gluten-free diet on theumulative risk of an autoimmune disease did not reach theevel of significance in the multivariate analysis nor within theediatric population. This lack of significance may be linked tohe much lower proportion of children not adhering to aluten-free diet when compared with adults. The effect of aluten-free diet on the development of subsequent autoim-une disease or on the course of a prior one is a matter of

ebate. Both Sategna Guidetti et al6 and Viljamaa et al7 ob-erved that many celiac patients developed autoimmune dis-ases despite a strict adherence to a gluten-free diet. Kaukinent al15 did not find that a gluten-free diet was followed by betterontrol of glycemia in patients with both CD and diabetes, and

Danish study showed that a gluten-free diet improves thelinical status but not diabetes of celiac patients with diabetes.16

n a prospective study of 7 first-degree relatives of patients withype 1 diabetes, diabetes-associated autoantibody levels at thend of a 12-month gluten-free– diet period were not signifi-antly different from those before starting the diet or at the endf the gluten re-exposure period.17 On the other hand, thelimination of dietary gluten reduces the frequency of diabetesn nonobese diabetic mice18 and increases the acute insulinesponse to the intravenous glucose tolerance test in first-egree relatives at risk for type 1 diabetes.19 In celiac children,iabetes serum antibodies tend to disappear under a gluten-freeiet,20 and antibodies against thyroid peroxidase are less fre-uent under a gluten-free diet than under a normal diet.21 Ourtudy compares the incidence of any autoimmune disease inompliant versus noncompliant patients with a gluten-free diet.t showed that a gluten-free diet does not give total protectionecause some celiac patients developed an autoimmune diseaseven though they were strictly compliant, but this risk wasiminished by a factor of two compared with noncompliantatients.

In conclusion, celiac patients most at risk for autoimmuneisease are those diagnosed early in life and having a familyistory of autoimmunity. Although in most cases a diagnosis ofutoimmune disease precedes a diagnosis of CD, the presenttudy argues in favor of a protective effect of the gluten-free dietn the development of autoimmune disease. This effect shoulde added to the benefits of the diet in celiac patients, as thereventions of malignancy22–24 and osteoporosis.25

AppendixThe following investigators also participated in the Ce-

iac Disease and Autoimmunity study: members of the Groupe’Etude et de Recherche sur la Maladie Coeliaque: Hôpitalt-Antoine, Paris: L. Beaugerie and P. Baumer; Montpellier: A.

oyer; Hôpital Louis Mourier, Colombes: B. Coffin; Paris: M. P.

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758 COSNES ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 7

ordier; Hôpital Henri Mondor, Créteil: A. Cosnes; Hôpitallaude Huriez, Lille: S. Couignoux and F. Gonzales; Hôpitalmbroise Paré, Boulogne: P. Crenn; Centre Hospitalier Univer-

itaire Hautepierre, Strasbourg: B. Duclos; Centre Hospitalierniversitaire Amiens Nord: J. L. Dupas; Centre Hospitalier Lyonud, Pierre Bénite: B. Flourié; Hôpital St-Louis, Paris: J. M.ornet and M. Lémann; Hôpital Européen Georges Pompidou,aris: G. Malamut; Centre Hospitalier Universitaire Rangueil,oulouse: J. Moreau; Hôtel Dieu, Nantes: S. Sacher-Huvelin;nd Hôpital de l’Archet 2, Nice: S. Schneider.

Members of the Groupe Francophone d’Hépatologie Gastro-ntérologie et Nutrition Pédiatriques: Hôpital Trousseau, Paris:. J. Baudon; Centre Hospitalier Universitaire, Clermont-Fer-and: C. Borderon; American Memorial Hospital, Reims: D.upouy; Hôpital Trousseau, Paris: J. P. Girardet; Hôpitallocheville, Tours: C. Maurage; Centre Hospitalier Universitaireancy Brabois, Vandoeuvre: A. Morali; Centre Hospitalier, Leans: C. Pelatan; Hôpital Jeanne de Flandre, Lille: D. Turck;

nd Hôpital d’Enfants de la Timone, Marseille: M. Zairi.

References

1. Collin P, Salmi J, Hallstrom O, et al. Autoimmune thyroid disor-ders and coeliac disease. Eur J Endocrinol 1994;130:137–140.

2. Not T, Tommasini A, Tonini G, et al. Undiagnosed coeliac diseaseand risk of autoimmune disorders in subjects with type I diabetesmellitus. Diabetologia 2001;44:151–155.

3. Barker JM. Clinical review: type 1 diabetes-associated autoimmu-nity: natural history, genetic associations, and screening. J ClinEndocrinol Metab 2006;91:1210–1217.

4. Collin P, Reunala T, Pukkala E, et al. Coeliac disease–associateddisorders and survival. Gut 1994;35:1215–1218.

5. Ventura A, Magazzu G, Greco L. Duration of exposure to glutenand risk for autoimmune disorders in patients with celiac dis-ease. SIGEP Study Group for Autoimmune Disorders in CeliacDisease. Gastroenterology 1999;117:297–303.

6. Sategna Guidetti C, Solerio E, Scaglione N, et al. Duration ofgluten exposure in adult coeliac disease does not correlate withthe risk for autoimmune disorders. Gut 2001;49:502–505.

7. Viljamaa M, Kaukinen K, Huhtala H, et al. Coeliac disease, auto-immune diseases and gluten exposure. Scand J Gastroenterol2005;40:437–443.

8. Green A. The EURODIAB studies on childhood diabetes 1988-1999. Europe and Diabetes. Diabetologia 2001;44(Suppl 3):B1–B2.

9. Vanderpump MP, Tunbridge WM. Epidemiology and prevention ofclinical and subclinical hypothyroidism. Thyroid 2002;12:839–847.

0. Kumar PJ, Walker-Smith J, Milla P, et al. The teenage coeliac:follow up study of 102 patients. Arch Dis Child 1988;63:916–

920. j

1. Mayer M, Greco L, Troncone R, et al. Compliance of adolescentswith coeliac disease with a gluten free diet. Gut 1991;32:881–885.

2. Marsh MN. Gluten, major histocompatibility complex, and thesmall intestine. Gastroenterology 1992;102:330–354.

3. Baudon JJ, Dabadie A, Cardona J, et al. [Incidence of symptom-atic celiac disease in French children.] Presse Med 2001;30:107–110.

4. Fasano A. Systemic autoimmune disorders in celiac disease.Curr Opin Gastroenterol 2006;22:674–679.

5. Kaukinen K, Salmi J, Lahtela J, et al. No effect of gluten-free dieton the metabolic control of type 1 diabetes in patients withdiabetes and celiac disease. Retrospective and controlled pro-spective survey. Diabetes Care 1999;22:1747–1748.

6. Hansen D, Brock-Jacobsen B, Lund E, et al. Clinical benefit of agluten-free diet in type 1 diabetic children with screening-de-tected celiac disease: a population-based screening study with 2years’ follow-up. Diabetes Care 2006;29:2452–2456.

7. Hummel M, Bonifacio E, Naserke HE, et al. Elimination of dietarygluten does not reduce titers of type 1 diabetes-associated au-toantibodies in high-risk subjects. Diabetes Care 2002;25:1111–1116.

8. Funda DP, Kaas A, Bock T, et al. Gluten-free diet prevents dia-betes in NOD mice. Diabetes Metab Res Rev 1999;15:323–327.

9. Pastore MR, Bazzigaluppi E, Belloni C, et al. Six months ofgluten-free diet do not influence autoantibody titers, but improveinsulin secretion in subjects at high risk for type 1 diabetes. J ClinEndocrinol Metab 2003;88:162–165.

0. Ventura A, Neri E, Ughi C, et al. Gluten-dependent diabetes-related and thyroid-related autoantibodies in patients with celiacdisease. J Pediatr 2000;137:263–265.

1. Toscano V, Conti FG, Anastasi E, et al. Importance of gluten inthe induction of endocrine autoantibodies and organ dysfunctionin adolescent celiac patients. Am J Gastroenterol 2000;95:1742–1748.

2. Silano M, Volta U, Mecchia AM, et al. Delayed diagnosis ofcoeliac disease increases cancer risk. BMC Gastroenterol 2007;7:8.

3. Brousse N, Meijer JW. Malignant complications of coeliac dis-ease. Best Pract Res Clin Gastroenterol 2005;19:401–412.

4. Holmes GK, Prior P, Lane MR, et al. Malignancy in coeliac dis-ease—effect of a gluten free diet. Gut 1989;30:333–338.

5. Cellier C, Flobert C, Cormier C, et al. Severe osteopenia insymptom-free adults with a childhood diagnosis of coeliac dis-ease. Lancet 2000;355:806.

Address requests for reprints to: Professor Jacques Cosnes, Servicee Gastroentérologie et Nutrition, Hôpital St-Antoine, 184 Rue duaubourg St-Antoine, 75571 Paris Cedex 12, France. e-mail:

acques.cosnes@sat.aphp.fr; ; fax: (33) 1-49-28-31-88.