Coeliac disease re-screening among once seronegative at-risk relatives: A long-term follow-up study.

BACKGROUND: Serological screening of the relatives of coeliac disease patients is widely endorsed. However, the need for and the optimal timing of possible re-testing of once seronegative at-risk individuals for coeliac disease remain unclear. OBJECTIVE: We investigated this issue by inviting a large cohort of previously screening-negative relatives of patients with coeliac disease to participate in a follow-up study. METHODS: Altogether 599 relatives of coeliac disease index patients not diagnosed with coeliac disease in a screening study carried out in 2006-2010 were asked about possible later diagnosis or re-tested with coeliac disease autoantibodies in 2017-2021. Besides incidence, the possible impact of various patient-related clinical factors and HLA haplotype on the later diagnosis or screening positivity was examined. RESULTS: Fifteen (2.5%) relatives were either diagnosed with a coeliac disease (n = 8) during the follow-up period or were found to be screening-positive in the re-testing (n = 7), giving a combined annual incidence of 221/100,000 person-years in all relatives and 336/100,000 among those carrying coeliac disease-associated HLA DQ2/DQ8. The new cases more often carried the high-risk (DQ2.5/2.5 or DQ2.5/2.2; 35.7% vs. 7.4%, respectively, p < 0.001) HLA and were younger at initial screening (23.3 vs. 40.5 years, p = 0.028) and - in spite of a negative screening outcome - had higher median transglutaminase antibody level in the first study than those not affected. There were no significant differences between the affected and non-affected relatives in other demographic data, degree of kinship with the index, current symptoms or frequency of chronic co-morbidities. CONCLUSION: The incidence rate for later coeliac disease diagnosis or new seropositivity in relatives who had been tested once was 221/100,000 person-years in all and 336/100,000 among those carrying at-risk HLA genetics after ∼10 years of follow-up. HLA-typing could help to target a subgroup of relatives who would benefit most from re-testing.

Presence of high-risk HLA genotype is the most important individual risk factor for coeliac disease among at-risk relatives.

BACKGROUND: Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure. AIMS: To investigate the individual risk of coeliac disease among patients' relatives. METHODS: Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression. RESULTS: There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18 years at diagnosis (odds ratio 1.60, 95% CI 1.04-2.45) in index, and age 41-60 years (1.73, 1.10-2.73), being a sibling (1.65, 1.06-2.59) and having the high-risk genotype (3.22, 2.01-5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80-4.78) in multivariable analysis. CONCLUSIONS: Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. ClinicalTrials.gov identifier NCT03136731.