A new algorithm may be able to predict which children with potential celiac disease will go on to develop villous atrophy, according to investigators writing in.
The risk model was developed from the largest cohort of its kind, with the longest follow-up to date, reported lead author, of University Federico II in Naples, Italy, and colleagues. Using the algorithm, which relies most heavily on a baseline number of intraepithelial lymphocytes (IELs) in mucosa, followed by age at diagnosis and genetic profile, clinicians may now consider prescribing gluten-free diets to only the highest-risk patients, instead of all suspected cases, noting that more than half of potential cases do not develop flat mucosa within 12 years.
Development of the algorithm began with enrollment of 340 children aged 2-18 years who were positive for endomysial antibodies immunoglobulin A antibodies and had tested positive twice consecutively for antitissue transglutaminase antibodies. Additionally, children were required to possess HLA DQ2- or DQ8-positive haplotypes and have normal duodenal architecture in five biopsy samples. Because of symptoms suggestive of celiac disease or parental discretion, 60 patients were started on a gluten-free diet and excluded from the study, leaving 280 patients in the final cohort. These patients were kept on a gluten-containing diet and followed for up to 12 years. Every 6 months, the investigators checked antibodies and clinical status, and every 2 years, small bowel biopsy was performed, if symptoms had not necessitated this earlier.
After a median follow-up of 60 months, ranging from 18 months to 12 years, 39 patients (13.9%) developed symptoms of celiac disease and were placed on a gluten-free diet, although they declined confirmatory biopsy, disallowing classification of celiac disease. Another 33 patients (11.7%) were lost to follow-up and 89 (32%) stopped producing antibodies, with none going on to develop villous atrophy. In total, 42 patients (15%) developed flat mucosa during the follow-up period, with an estimated cumulative incidence of 43% at 12 years. The investigators noted that patients most frequently progressed within two time frames; at 24-48 months after enrollment, or at 96-120 months.
To develop the algorithm, the investigators performed multivariable analysis with several potential risk factors, including age, sex, genetic profile, mucosal characteristics, and concomitant autoimmune diseases. Of these, a high number of IELs upon first biopsy was most highly correlated with progression to celiac disease. Patients who developed villous atrophy had a mean value of 11.9 IELs at first biopsy, compared with 6.44 among those who remained potential (P = .05). The next strongest predictive factors were age and genetic profile. Just 7% of children less than 3 years developed flat mucosa, compared with 51% of patients aged 3-10 years and 55% of those older than 10 years (P = .007). HLA status was predictive in the group aged 3-10 years but not significant in the youngest or oldest patients. Therefore, HLA haplotype was included in the final algorithm, but with smaller contribution than five non-HLA genes, namely, IL12a, SH2B3, RGS1, CCR, and IL2/IL21.
“Combining these risk factors, we set up a model to predict the probability for a patient to evolve from potential celiac disease to villous atrophy,” the investigators wrote. “Overall, the discriminant analysis model allows us to correctly classify, at entry, 80% of the children who will not develop a flat mucosa over follow-up, while approximately 69% of those who will develop flat mucosa are correctly classified by the parameters we analyzed. This system is then more accurate to predict a child who will not develop flat mucosa and then can be monitored on a gluten-containing diet than a child who will become celiac.”
The investigators noted that IEL count may be an uncommon diagnostic; however, they recommended the test, even if it necessitates referral. “The [IEL] count turned out to be crucial for the prediction power of the discriminant analysis,” the investigators wrote.
“The long-term risks of potential celiac disease have never been accurately evaluated. Thus, before adopting a wait-and-see strategy on a gluten-containing diet, a final decision should always be shared with the family.”
Still, the investigators concluded that gluten-free diet “should not be prescribed indistinctly to all patients” with potential celiac disease, as it is a “very heterogenic condition and is not necessarily the first step of overt disease.”
The investigators disclosed no funding or conflicts of interest.
SOURCE: Auricchio R et al. Gastroenterology. 2019 Apr 9.