A total of 924 patients were included in the study, 378 from pediatric centers and 546 from adult gastroenterology centers, including 124 patients who had been diagnosed with CD during childhood. The diagnosis of CD was made more than 6 months before the inclusion visit in 788 patients (85%). These 788 patients were included in the study of the effect of gluten-free diet.

Patients were recruited over a 5-year period (2003–2007) from 27 French centers of Gastroenterology and Pediatric Gastroenterology. Physicians in these centers were asked to include all patients with a diagnosis of CD that they saw consecutively as inpatients or outpatients during the period of recruitment. A diagnosis of CD required a duodenal biopsy showing increased intraepithelial lymphocyte count, crypt hypertrophy, and villous atrophy.Recruitment was ended when the predefined number of patients included in the study was reached.

The presence of autoimmune disease in patients and in their first- and second-degree relatives was evaluated by use of a structured questionnaire and a review of patient charts. The questionnaire was completed by the physician during the inclusion visit in the presence of the patient. The presence of one of the autoimmune disorders belonging to a prefixed list was searched for in all subjects. The date of the diagnosis of autoimmune disease was recorded using medical charts. Only clinically patent autoimmune disorders were taken into account, and at the time of clinical evaluation there was no particular search for biological abnormalities.

The adherence to a gluten-free diet was evaluated retrospectively by the physician in charge of the patient. In addition, the patient (or his/her parents) was interviewed during the inclusion visit to ascertain compliance and the absence of unintentional gluten ingestions. There was no systematic clinical, immunologic, or histologic monitoring of the compliance to the diet, and the physician used his own criteria to assess compliance. Finally, the time that elapsed between the diagnosis of CD and inclusion in the study was divided into periods with good compliance to the diet, periods under gluten-free diet but with poor compliance, and periods under normal diet. These 2 latter periods were pooled in further analyses.

Statistical Analysis

The all-life cumulative risk of autoimmune disease was assessed using the Kaplan–Meier method with the date of birth as the starting point. Variables suspected to be associated with autoimmune disease (diagnosis of CD in childhood [<16 y], or late adulthood [older than the median age at diagnosis in adults], sex, main symptoms revealing CD [digestive, nutritional, hematologic], interval between first symptom and diagnosis [<12 mo], ethnicity [Caucasian or not], family history of CD, family history of autoimmune disease, and smoking status), were tested using the log-rank test. Variables with a P value of less than .10 were entered into a Cox model with a backward elimination procedure. Results of the analyses are presented as hazard ratios, with 95% confidence intervals.

The second part of the study analyzed the effect of gluten-free diet on the development of autoimmune disease. Three analyses were performed. First, an actuarial analysis was performed. The outcome was the subsequent autoimmune disease rate and the time to subsequent autoimmune disease. Patients were classified into 2 groups on the basis of their adherence to a gluten-free diet during the first semester after diagnosis. Patients who started a gluten-free diet more than 6 months after their diagnosis and patients who did not adhere initially to a gluten-free diet were included in the normal diet group until they started a strict gluten-free diet, which was used as the final point. Conversely, patients who stopped a gluten-free diet were included in the gluten-free diet group until they transgressed or resumed a normal diet. The variables tested were those suspected to be possible predictors of autoimmune disease (see earlier), and a history of prior autoimmune disease. Multivariate analyses were performed with Cox proportional hazards regression to adjust for confounding. Because this analysis was the most determinant part of the study, it was used to calculate the number of patients entering the study. According to an intermediary analysis performed after 2 years of recruitment, we hypothesized that a gluten-free diet could decrease the 10-year risk of subsequent autoimmune disease from 12% to 6%. This led us to include a minimum of 558 patients (α = .05; β = .20).

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

The third analysis was a paired comparison of the annual incidences that was performed in the subgroup of patients who adhered to a gluten-free diet for some time (5%–95% of time) after their diagnosis.

These different analyses were performed in the whole group of patients, then separately in the pediatric population (age at diagnosis of CD, <16 y) and in the adult population, and with and without the classification of dermatitis herpetiformis as an autoimmune disease.