Abstract
Objectives
Celiac disease (CD) is an immune-mediated disorder that may present with gastrointestinal or extraintestinal manifestations or remain asymptomatic. Although an increased prevalence has been reported in some autoimmune diseases, data regarding CD frequency in pediatric rheumatologic diseases are limited, and routine screening remains controversial. This study aimed to evaluate the frequency of CD among children with rheumatologic diseases and the necessity of routine serological screening.
Methods
This cross-sectional study included 94 children with rheumatologic diseases who underwent systematic CD screening between January 2020 and November 2023. Screening was performed using anti–tissue transglutaminase immunoglobulin A and endomysial antibody tests regardless of symptoms. Patients with positive serology underwent upper gastrointestinal endoscopy and intestinal biopsy. The prevalence of biopsy-confirmed celiac disease was calculated with 95% confidence intervals.
Results
The median age was 171 months (Q1–Q3: 124.25–192.25), and 55.3% were female. Juvenile idiopathic arthritis (JIA) was the most common diagnosis (88.3%). Serological positivity suggestive of CD was detected in two patients (2.1%), both of whom were diagnosed with JIA. Biopsy-confirmed CD was identified in one patient, corresponding to a prevalence of 1.06% (95% confidence interval: 0.03–5.79), which was not significantly different from the prevalence reported in Turkish school children (two-proportion z-test, p=0.553). Both patients who underwent endoscopy had normal growth parameters and no classical gastrointestinal symptoms.
Conclusion
The prevalence of CD in children with rheumatologic diseases was low and similar to that of the general pediatric population. Routine screening for CD in asymptomatic patients with rheumatologic diseases may not be necessary, and a more individualized, risk-based approach may be more appropriate.
Keywords: Children, celiac disease, prevalence, rheumatologic diseases, screening
Celiac disease (CD) is a chronic immune-mediated enteropathy precipitated by dietary gluten exposure in genetically predisposed individuals.[1] Classically, CD was diagnosed among children presenting with gastrointestinal manifestations and failure to thrive. However, it is now recognized that CD may also present with extraintestinal symptoms or remain asymptomatic. The global prevalence of CD is estimated to range between 0.7% and 1.4%.[2] Among Turkish school children, the seroprevalence of CD has been reported as 2.5%, while the prevalence of biopsy-proven CD is 1/212.[3] Owing to its autoimmune nature, CD has been associated with several immune-mediated conditions, including type 1 diabetes mellitus, autoimmune thyroid disease, and selective immunoglobulin A (IgA) deficiency. Accordingly, international consensus statements recommend routine serological screening in these established high-risk groups, even in the absence of clinical symptoms.[4]
Several other conditions, including epilepsy and juvenile idiopathic arthritis (JIA), have been suspected to be associated with CD, although routine screening for these conditions remains controversial. Furthermore, several studies have reported cases of patients with rheumatic disorders who were concomitantly diagnosed with CD, suggesting that periodic screening for CD may be warranted in this population.[5] With the growing availability and use of serological tests, CD screening has become more widespread, including among children with rheumatologic diseases, even though no clear recommendations or guidelines have been published in this regard.[6-9]
The aim of this study is to investigate the frequency of CD among children with rheumatologic diseases to provide data that may help clarify the necessity of CD serological screening during follow-up.
Methods
We conducted this cross-sectional study between January 2020 and November 2023 at a tertiary pediatric rheumatology and gastroenterology center. Patients diagnosed with a rheumatologic disease (JIA, systemic lupus erythematosus, juvenile dermatomyositis (JDM), Sjögren syndrome, Behçet disease, and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis) by a pediatric rheumatologist and who underwent celiac disease screening at diagnosis and/or during follow-up, regardless of symptoms, were included. Patients with incomplete medical records or coexisting chronic conditions that could confound the evaluation were excluded. In addition, patients with previously diagnosed autoimmune diseases known to be associated with celiac disease (such as type 1 diabetes mellitus, autoimmune thyroiditis, and vitiligo) were excluded to minimize potential confounding effects on serological screening results. All participants had been followed in our clinic for a minimum of six months.
Growth parameters were evaluated using standard deviation scores (SDS), and chronic malnutrition was defined as weight-for-age and height-for-age SDS below −2.
Screening for CD was performed systematically by measuring serum anti-tissue transglutaminase immunoglobulin A (anti-tTG IgA) and anti-endomysium IgA (EMA) at the time of rheumatological disease diagnosis and every 2 years thereafter. Total serum IgA levels were assessed at baseline to identify IgA deficiency. In subjects with low serum IgA levels (total serum IgA <0.2 g/L), IgG-class antibodies against deamidated forms of anti-tTG immunoglobulin G (IgG) were determined. Upper gastrointestinal endoscopy and duodenal biopsy were performed in patients with positive serological findings, in accordance with standard clinical practice. The modified Marsh classification was used for histopathological staging.[10] This screening protocol reflects the pre-existing clinical practice at our institution, applied to all eligible patients as part of routine care independently of this study.
tTG-IgA was tested using a commercial enzyme-linked immunosorbent assay, and a titer above 20 relative units was evaluated as positive (Euroimmun, Lübeck, Germany). EMA was tested by an indirect immunofluorescence test, with a >1:10 titer determined as positive (Euroimmun, Lübeck, Germany). CD prevalence in patients with rheumatological disorders was compared with CD frequency in Turkish school children using a two-proportion z-test for the difference between two percentages.[3]
The study protocol was approved by the Istanbul Goztepe Prof. Dr. Suleyman Yalcin City Hospital ethics committee of our hospital (Decision no: 2023/0755, date: 29.11.2023). Written informed consent was obtained from the patients who agreed to take part in the study. The procedures used in this study adhered to the tenets of the Declaration of Helsinki.
Statistical Analysis
Statistical analyses were carried out using IBM SPSS Statistics for Windows, version 25.0 (SPSS; Chicago, IL, USA). Continuous variables were expressed as mean±standard deviation or median with interquartile range (Q1–Q3), depending on distribution. Categorical variables were summarized as numbers and percentages. The prevalence of biopsy-confirmed CD was calculated with 95% confidence intervals using the exact binomial method.
Results
A total of 94 pediatric patients with rheumatologic diseases were included in the study, of whom 52 (55.3%) were female. The median age of the patients at the time of investigation was 171 months (Q1–Q3: 124.25–192.25 months). The most common diagnosis was JIA (83 patients, 88.3%), followed by systemic lupus erythematosus (SLE) (5 patients, 5.3%). Demographic and anthropometric characteristics of the study population are summarized in Table 1, and the distribution of rheumatologic diagnoses is presented in Table 2. The median follow-up duration was 22.0 months (Q1–Q3: 14.9–37.1 months). Among patients with juvenile idiopathic arthritis, the most common subtype was oligoarticular JIA (42 patients, 50.6%), followed by enthesitis-related arthritis (23 patients, 27.7%).
Table 1.
Demographic and anthropometric characteristics of the study population (n=94)
| Characteristic | Value |
|---|---|
| Age, months, median (Q1-Q3) | 171 (124.25–192.25) |
| Female sex, n (%) | 52 (55.3) |
| Follow-up duration, months, median (Q1-Q3) | 22.0 (14.9–37.1) |
| Weight-for-age SDS, mean±SD | 0.18±1.50 |
| Height-for-age SDS, mean±SD | −0.01±0.98 |
| Chronic malnutrition, n (%) | 3 (3.2) |
| Receiving immunosuppressive therapy at time of screening, n (%) | 65 (69.1) |
| Methotrexate, n (%) | 29 (30.8) |
| Adalimumab, n (%) | 17 (18.1) |
| No pharmacologic therapy at time of study, n (%) | 21 (22.3) |
SDS: Standard deviation score; Q1-Q3: 25th–75th percentile (interquartile range).
Table 2.
Distribution of rheumatologic diagnoses in the study cohort
| Diagnosis | n (%) |
|---|---|
| Juvenile idiopathic arthritis | 83 (88.3) |
| Systemic lupus erythematosus | 5 (5.3) |
| Juvenile dermatomyositis | 2 (2.1) |
| ANCA-associated vasculitis | 2 (2.1) |
| Behçet disease | 1 (1.1) |
| Sjögren syndrome | 1 (1.1) |
ANCA: Anti-neutrophil cytoplasmic antibodies
The mean weight-for-age SDS was 0.18±1.50, and the mean height-for-age SDS was −0.01±0.98. Chronic malnutrition was present in 3 patients (3.2%), while the majority of patients had normal growth parameters.
Twenty-nine (30.8%) of our patients had been treated with methotrexate, 17 were receiving adalimumab, while 21 (22.3%) were receiving no therapy at the time of the study. At the time of celiac serological testing, 65 patients (69.1%) were receiving immunosuppressive therapy, whereas 29 patients (30.9%) were under non-immunosuppressive or drug-free follow-up.
Serological positivity suggestive of celiac disease was identified in 2 patients (2.1%), both of whom were diagnosed with juvenile idiopathic arthritis. One patient demonstrated isolated EMA positivity, while the other showed positivity for both anti-tTG IgA and EMA. Neither patient was receiving any therapy at the time of serological screening. IgA deficiency was detected in six patients, in whom tTG IgG was tested, and no positivity was found. Upper gastrointestinal endoscopy was performed in two patients with positive serology; one patient was diagnosed with celiac disease (Marsh 3A), whereas the other had normal histopathological findings. Both patients who underwent endoscopy had normal growth parameters. Biopsy-confirmed celiac disease was identified in one patient, corresponding to a prevalence of 1.06% (1/94; 95% confidence interval: 0.03–5.79), which was comparable to the prevalence reported in Turkish school children, where biopsy-confirmed celiac disease was identified in 1 out of 212 children (0.47%); this difference was not statistically significant (two-proportion z-test, z=0.59, p=0.553).
Discussion
In the present study, the prevalence of biopsy-confirmed CD among children with rheumatologic diseases was low and comparable to that reported in the general pediatric population. Only one patient was diagnosed with biopsy-confirmed CD despite systematic serological screening performed independently of clinical symptoms. This prevalence was similar to that previously reported in Turkish school children, where biopsy-confirmed CD was identified in approximately 1 in 212 children.[3] These findings suggest that the coexistence of CD and pediatric rheumatologic conditions may reflect shared autoimmune susceptibility rather than a disease-specific increased risk and do not suggest a clearly increased prevalence of CD in pediatric rheumatologic diseases. Although designed as a cross-sectional study, screening was performed within a longitudinal clinical follow-up setting, which may partially mitigate the limitations inherent to a single time-point assessment.
Previous studies investigating the association between CD and pediatric rheumatologic conditions have reported heterogeneous results. In patients with JIA, some studies have suggested a higher prevalence of CD compared with the general population, whereas others have demonstrated similar rates, particularly when biopsy-confirmed cases were considered.[6,11] Variability among studies may be explained by differences in study design, screening strategies, and the inclusion of serology-only cases without histological confirmation. Similarly, evidence from systemic autoimmune diseases does not consistently support an increased prevalence of CD. A recent systematic review and meta-analysis evaluating patients with SLE reported a pooled prevalence of biopsy-confirmed celiac disease comparable to that of the general population, suggesting that coexistence may reflect shared autoimmune mechanisms rather than a direct disease-specific association.[9] Taken together, these findings are consistent with our results and support the notion that routine screening for CD in all patients with pediatric rheumatologic diseases remains debatable.
Most available data originate from studies focusing on individual diseases, particularly JIA, whereas evidence regarding other pediatric rheumatologic diseases, such as SLE and JDM, remains limited.[12-14] In contrast to disease-specific studies, the present study evaluated a spectrum of pediatric rheumatologic diseases within a single cohort using a systematic screening approach, providing a preliminary estimate of celiac disease frequency across a heterogeneous pediatric rheumatology cohort. Given the predominance of JIA cases and the modest sample size, this estimate should not be regarded as a comprehensive assessment of the overall burden of celiac disease in pediatric rheumatology practice but rather as a starting point for larger, multicenter studies.
Another important finding of our study was that both patients who underwent endoscopic evaluation, including the patient with biopsy-confirmed celiac disease, demonstrated normal growth parameters and lacked classical gastrointestinal manifestations. This observation supports previous reports indicating that CD in patients with rheumatologic disorders may present without typical clinical findings, such as growth failure or overt gastrointestinal symptoms.[6,8] Therefore, reliance solely on clinical suspicion may lead to missed diagnoses in selected cases. On the other hand, the relatively low prevalence observed in our cohort suggests that routine screening of all patients may not be justified.
In addition, a substantial proportion of patients in our study were receiving immunosuppressive therapy at the time of serological testing. In accordance with ESPGHAN guidelines, duodenal biopsy is not routinely indicated in patients with negative serological testing due to the high sensitivity and specificity of combined anti-tTG IgA and EMA assays.[4,7] However, despite this high diagnostic accuracy, false-negative results cannot be completely excluded, particularly in patients receiving immunosuppressive therapy. Therefore, the possibility of undetected cases should be taken into account when interpreting our findings. Immunosuppressive agents may potentially attenuate autoimmune responses and influence antibody production, which could contribute to lower serological detection rates. This may have contributed to an underestimation of the true prevalence of celiac disease in our cohort. Although this effect could not be directly evaluated in the present study, it should be considered when interpreting negative serological results in pediatric rheumatology populations. However, all patients in the present study were screened regardless of treatment status, and biopsy confirmation was performed in seropositive cases, which may reduce the likelihood of substantial underestimation.
In this study, the only patient diagnosed with biopsy-confirmed CD had JIA. This observation is consistent with previous literature suggesting a relatively stronger association between CD and JIA compared with other rheumatologic conditions. A recent systematic review and meta-analysis reported a pooled prevalence of biopsy-confirmed celiac disease of approximately 1.4% among patients with JIA, which is comparable to that of the general population but higher than that observed in several other rheumatologic disorders. Furthermore, the same analysis suggested that while routine screening may not be justified for all rheumatologic diseases, serological screening in JIA patients could be considered in the presence of additional risk factors or clinical suspicion.[8] Our findings support this interpretation, as CD was not identified among other rheumatologic diseases included in the cohort, despite systematic screening. Although the small number of cases precludes definitive conclusions, this finding may indicate that screening strategies in pediatric rheumatologic diseases should be individualized, with particular attention to patients with JIA.
Limitations
This study has several limitations. First, the single-center design and relatively small sample size limit the generalizability of the findings. The relatively small sample size and wide confidence interval limit the precision of the prevalence estimate and raise the possibility of a type II error, precluding definitive conclusions. Therefore, a true increase in prevalence cannot be definitively excluded. Second, the cross-sectional nature of the study does not allow assessment of the long-term incidence of celiac disease during follow-up, and patients who may develop seropositivity later in the disease course could not be identified. Another important consideration is the potential impact of immunosuppressive therapy. A substantial proportion of patients in our cohort were receiving immunosuppressive treatment at the time of screening. These agents may attenuate autoimmune responses and suppress antibody production, potentially leading to false-negative serological results and underestimation of the true prevalence of CD. Notably, seropositivity was observed only in patients not receiving immunosuppressive therapy; however, no definitive conclusions can be drawn due to the small number of cases. In addition, the predominance of JIA in our cohort limits the generalizability of the findings to other pediatric rheumatologic diseases. Therefore, the results should be interpreted primarily within the context of JIA-predominant populations.
This study also has several notable strengths. First, screening was performed systematically in all patients regardless of clinical symptoms, avoiding the selection bias inherent in symptom-triggered testing and providing a more representative estimate of CD frequency in this population. Second, the cohort encompassed a heterogeneous spectrum of pediatric rheumatologic diseases evaluated within a single, standardized screening protocol, rather than being restricted to a single diagnosis. Third, the diagnosis was confirmed histologically by duodenal biopsy in all seropositive patients, in line with the diagnostic gold standard, rather than relying on serology alone. Finally, the embedding of cross-sectional screening within a longitudinal clinical follow-up setting provides real-world data on the clinical utility of periodic CD screening in children with rheumatologic diseases.
Conclusion
The prevalence of biopsy-confirmed celiac disease in this predominantly JIA cohort was low and comparable to that of the general pediatric population. However, due to methodological limitations, including the small sample size, wide confidence intervals, immunosuppressive therapy, and limited generalizability, routine universal screening cannot be definitively recommended. A risk-based, individualized screening strategy may be more appropriate.
Footnotes
Please cite this article as ”Kalaycik Sengul O, Dizman EN, Aktas I, Sencan ED, Kucuk E, et al. Frequency of Celiac Disease in a Cross-Sectional, JIA-Predominant Cohort of Children with Rheumatologic Diseases. <sayfa numarası>”.
Disclosures
Ethics Approval
Ethics committee approval for this study was obtained from the Istanbul Goztepe Prof. Dr. Suleyman Yalcin City Hospital (Approval no: 2023/0755; date: November 29, 2023)
Informed consent
Written informed consent was obtained from the patients who agreed to take part in the study.
Conflict of Interest
The authors declare that there is no conflict of interest.
Financial Disclosure
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Use of AI for Writing Assistance
No artificial intelligence-assisted technologies were used in any section of the study.
Authorship Contributions
Concept – O.K.S., K.O.; Design – O.K.S., K.O., S.C.; Supervision – O.K.S.; Fundings − O.K.S.; Materials − O.K.S., E.N.O., I.A., E.D.S., E.K., F.H., K.O., S.C.; Data collection &/or processing – O.K.S., E.N.O., I.A., E.D.S., E.K., F.H., K.O., S.C.; Analysis and/or interpretation – O.K.S.; Literature search – O.K.S., K.O., S.C.; Writing – O.K.S., K.O., S.C.; Critical review – O.K.S., K.O., S.C.
Peer-review
Externally peer-reviewed.
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