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The occurrence of other autoimmune diseases in celiac disease families has not been previously reported in a North American population. We investigated the familial aggregation of rheumatoid arthritis (RA), juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA), hypothyroidism, insulin dependent diabetes mellitus (IDDM), and alopecia areata (AA) among individuals in families with celiac disease (CD). Family history information, obtained from questionnaires from the University of California Irvine Celiac Disease study, was reviewed for reports of RA, JRA/JIA, hypothyroidism, IDDM, and AA in celiac disease cases and their first-degree relatives. Reports of disease were compared with prevalence data from the literature and analyzed by calculating the standardized ratio (SR) with 95% confidence limits. We analyzed: 1) subjects with confirmed celiac disease or dermatitis herpetiformis (205 probands and 203 affected first-degree relatives) and 2) first-degree relatives of celiac disease cases (n=1,272). We found a significantly increased number of cases, relative to the expected number, of IDDM in both groups and hypothyroidism among subjects with celiac disease. JRA/JIA was increased among first-degree relatives of celiacs. These results indicate that the presence of IDDM within our celiac disease families may be due to shared genetic susceptibility predisposing to these diseases or autoimmune diseases in general.
Celiac disease (CD, gluten-sensitive enteropathy, celiac sprue) is a common autoimmune disease, with estimates that the disease frequency is 0.75% (1:133) in the general population in the US , similar to European estimates. CD is caused by sensitivity to the dietary protein gliadin, which is present in wheat, and to the related prolamins, secalin in rye and hordein in barley. The term gluten-sensitive enteropathy (GSE) refers to the histologic abnormality of the small intestine, which ranges from minimal lymphocytic infiltration of the intestinal epithelium to severe atrophy of the villi . Occult disease is frequently present with minimal symptoms or signs. CD is familial, with significant morbidity if untreated. CD is one of the most significant causes of chronic malabsorption in children. Complications of CD include lymphoma, osteoporosis, anemia, and seizures.
There have been several reports of co-occurrence of CD and other autoimmune diseases in Europe, with no studies reported in the United States. A significantly increased prevalence of various autoimmune diseases has been reported in individuals with CD as compared to healthy controls [3–10], and a significantly increased prevalence of CD (10–30 fold) has been documented in individuals with varied autoimmune diseases (reviewed in Kumar ). The basis for these associations may be that CD and the other diseases share a similar pathogenic autoimmune mechanism or a genetic defect in the same responsible genes .
Most studies that have looked at the association of CD with autoimmune diseases have focused on individuals with CD rather than relatives of CD cases. Only two studies, conducted in Italy, specifically looked at the prevalence of autoimmune diseases in relatives of CD cases. In the first study, prevalence of autoimmune diseases was compared in children with CD matched to control children, and in all first- and second-degree relatives of the children with CD and the control children. There was a significantly higher prevalence of autoimmune diseases in the children with CD (7.2%) as compared to the controls (0.8%) and in the relatives of the CD subjects (4.9%) as compared to relatives of the controls (1.1%). Similarly, Cataldo and colleagues found a significantly higher prevalence of CD in 225 first-degree relatives of 66 children with CD (4.8%) as compared to 232 relatives of controls (0.86%) (p = 0.028). Furthermore, the prevalence of autoimmune diseases increased with increasing age of the relatives (p < 0.0001) .
Large family studies investigating the prevalence of other autoimmune diseases in relatives have not been performed in the US. In this study, we investigated whether RA, JRA/JIA, hypothyroidism, IDDM, and AA are increased in relatives of CD cases, as well as in CD cases themselves.
Families with CD were studied. These families were previously enrolled in a CD family study under Institutional Review Board (IRB) approvals at the University of California Irvine and the University of Utah. The participants were from the U.S. and Canada, and were ascertained from celiac newsletters, celiac support groups, and physician referral. A family qualified for enrollment if there were two members of the family, excluding parent-child pairs, with biopsy- and/or serology-proven CD. Participation in the study was extended to all first-degree family members of the probands, and then subsequently to all first-degree relatives of other CD cases found in the families. Participants were asked to complete a self-administered questionnaire containing demographic, personal, and family history information. Parents or guardians completed questionnaires for their children. Additional information that was not in the questionnaire was obtained through re-contact of participants and review of medical records, when available.
For this study, we restricted the analyses to families where 10 or more relatives were enrolled. Relatives not in the lineage (spouses) were excluded. The characteristics of the study sample are listed in Table 1. The study sample consisted of 1,680 individuals from 91 families meeting the criteria (median = 17 individuals per family, range 4–55).
The primary source of data for this study was a self-administered questionnaire, which included demographic information (date of birth, current age, sex, vital status), and medical history information on the respondent and first-degree family members for diagnoses including CD, RA, JRA/JIA, AA, hypothyroidism, and/or IDDM. Only data on blood relatives were included. A total of 1,014 questionnaires were reviewed from the 91 families (median = 9 questionnaires per family, range 1–38). Each questionnaire provided information on multiple family members, however not all individuals completed a questionnaire. Therefore, data were based on self-report, self-report and family history report; or only family history report. Of the questionnaires reporting an autoimmune disease, 60.5% were self-report or report of a parent on a minor child, 9.0% were a sibling report, 13.1% were an adult offspring report, 4.8% were a report from a parent of an adult offspring, and 12.6% were reports from two first-degree relatives. To ensure that family history and self-report data were as accurate as possible, participants were telephoned to verify each disease reported on a questionnaire. In the instances where reports from relatives differed, all family members reporting the diseases were contacted. We successfully reached 84% of those targeted for recontacting. Reports that could not be verified were excluded, so that we may have excluded some true diagnoses. Additional information was collected including age at diagnosis of the disease, symptoms, diagnostic modality, and type of treatment. This information enabled us to distinguish JRA/JIA from RA, and in a limited number of those with hypothyroidism, to identify those specifically diagnosed with Hashimoto’s thyroiditis.
We only included a diagnosis of CD if it was documented with a small bowel biopsy pathology report consistent with CD and/or a positive serological testing with IgA anti-endomysial antibody (EMA) and IgA tissue transglutaminase (tTG) antibody documented from medical records or diagnosed by our study. Other individuals in our study sample may have CD but did not have a verified diagnosis or were not yet identified as having CD. When date of birth or age was unknown, age was estimated based on ages of first-degree relatives (n=32, 1.9%).
Two groups were analyzed: 1) all subjects with confirmed CD (n = 408) and 2) all first-degree relatives of CD cases (n=1272). We compared the observed prevalence of RA, JRA/JIA, AA, hypothyroidism, and IDDM with expected prevalence based on available general population data (Table 2). These comparisons were performed separately for the two groups (CD group and first-degree relatives group). To test our hypotheses, we calculated standardized ratios (SR) as the ratio of observed cases in our two groups to the expected number based on prevalences in published reports (Table 2) and 95% confidence intervals (CI)..
We investigated the prevalence of IDDM, RA, JRA, AA, and hypothyroidism in celiac disease cases and their first degree relatives in North American families. A total of 184 autoimmune diseases were reported on questionnaires. We were able to verify 120 (65%) of these reports through telephone recontact and included these 120 in the analyses. For these 120 diagnoses, we were able to obtain medical records for 58 (48%) of the diagnoses (medical records were obtained from 1 of 10 RA, 1 of 4 JRA, 44 of 76 thyroid, 12 of 24 IDDM, and 0 of 7 alopecia cases). The medical records confirmed the diagnoses in 58 cases, suggesting that verified self-reports are reliable. We were unable to contact the subjects for 22 reports (12%) and for another 17 reports (9%), the family member had too little detail to confirm the diagnosis. Therefore, we may have under-reported the total number of autoimmune diseases, specifically by 22 cases for thyroiditis, 8 cases for RA, 5 cases for IDDM, and 4 cases for AA. For five questionnaire self-reports of RA and nine questionnaire reports of relatives, when we called to verify and asked specific questions, the initial report was incorrect (8%) and the contact reported it was osteoarthritis. There were an additional 9 questionnaire reports (5%) of relatives where the individual with the reported disease did not confirm the diagnosis, with the error for hypothyroidism (5 cases), AA (3 cases), and IDDM (1 case).
In the 408 CD cases (group 1), 59 autoimmune diseases were verified in 54 individuals. Five individuals reported two autoimmune diseases in addition to CD. As shown in Table 3, we observed a significantly increased prevalence of hypothyroidism (40 cases ≥12 years of age observed compared to 17.5 expected; SR of 2.3, CI 1.6–3.0), and of IDDM at any age and diagnosed at less than 20 years [SR of 10.0 (CI 5.3–16.7) and 10.9 (CI 5.1–19.8) respectively]. The prevalence of RA was not significantly different than expected. There were only three cases of AA reported, too few to adequately assess the prevalence, and no cases of JRA.
In the 1,272 first-degree relatives of CD cases, a total of 62 autoimmune diseases were reported in 58 individuals. Four individuals reported two autoimmune diseases. We observed a significant increase in IDDM at any age (SR 3.2, CI 1.7–5.3) and in those diagnosed at less than 20 years of age (SR 4.0, CI 2.0–7.0) (Table 4). The prevalence of JRA/JIA at any age was significantly higher than expected (SR 5.7; CI 1.5–12.7), and was higher at less than 17 years of age but the SR was not significant. There was no increase in the prevalence of RA, AA, or hypothyroidism. In fact, the observed number of individuals with hypothyroidism was lower than expected (Table 4).
The number of autoimmune diseases reported per family was evaluated to determine if some families carry a larger burden of disease than others. A total of 53 (58.2%) families reported having an autoimmune disease. In order to account for family size, the burden of disease in these families was calculated as the percent of family members with autoimmune diseases. The mean percentage of autoimmune diseases in these families was 10% with a range of 2–45% (Table 5). Therefore, some families had a much higher percentage of family members with autoimmune diseases than others.
The number of individual diseases reported per family was also evaluated. Out of 53 families reporting disease, 27 families had two or more individuals reported to have an autoimmune disease (Table 6).
In our study of CD families, we investigated whether there is an increase in the co-occurrence of other autoimmune diseases in individuals with CD and their first-degree relatives. The increased risk of acquiring an autoimmune disease may be due to genetic susceptibility for both diseases, an environmental trigger able to initiate both diseases, the presence of one autoimmune disease that alters or affects the body so that it is susceptible to another disease, or some undiscovered mechanism . We found a significantly increased number of observed cases of hypothyroidism and IDDM among individuals with CD. We also noted a larger number of cases of JRA/JIA and IDDM in first-degree relatives of CD cases than expected based on published prevalence studies. We did not observe an increased number of RA or AA cases than expected in either group.
In this study, the overall burden of the five autoimmune diseases (RA, JRA/JIA, AA, IDDM, hypothyroidism) in CD cases was 15%, which is higher than the estimated population prevalence of 3–5% [17, 18]. We only looked at a subset of the greater than 20 identified autoimmune diseases included in the total prevalence studies of autoimmune diseases, which likely resulted in an underestimate of total burden of autoimmune diseases in our sample. Our results are in agreement with previously published reports in which the prevalence of autoimmune diseases was significantly higher in CD cases than in healthy, age-matched controls. In one study of children, the prevalence of autoimmune disease was 14% in celiacs versus 2.8% in controls (p < 0.000001), with the most common autoimmune disease being IDDM . In adult CD patients and controls, the prevalence of autoimmunity was three-fold higher in one study , and there were significantly more endocrine disorders, IDDM, RA, and Sjögren’s syndrome in the cases than the controls in a second study .
Previous reports have found an increased prevalence of IDDM among CD patients in the range of 2.5–5% and of thyroid disease among CD patients of about 10–15% [7–9, 19–21]. The total observed number of reports of IDDM (12 cases) and hypothyroidism (42 cases) among CD cases in our study are significantly increased above the expected numbers based on prevalence studies from the literature, similar to what has been previously reported. The vast majority of cases of hypothyroidism were likely due to Hashimoto’s thyroiditis, as it has been reported that 90% of hypothyroid cases in an iodine sufficient area are due to Hashimoto’s thyroiditis . In this study, we did not have sufficient data to assign a diagnosis of Hashimoto’s thyroiditis except in six cases.
We did not find an increased number of observed cases of CD with RA, JRA/JIA, or AA, relative to expected numbers. There have been a few studies focused on the prevalence of RA among CD patients, but similar to our results, the rates have been similar to those in the general population [10, 23–26]. The majority of patients with RA have the HLA-DR4 subtype (associated with the HLA-DQB1*0302 allele of DQ8) [27, 28]. Because the number of CD patients with DQ8 is only about 5%, an association with RA in our smaller sample of CD patients with DR4 may not have been evident. In addition, some studies have reported that the incidence of RA is decreasing and both comparison studies may be an overestimate of the true disease burden [29, 30]. In our sample, no individuals with CD reported being diagnosed with JRA/JIA. Previous studies have reported a prevalence of JRA/JIA co-occurring with CD in children of approximately 3–7% [31, 32]. CD may be diagnosed at any age and given the young age of onset of JRA/JIA it is possible that some individuals in our study sample with JRA/JIA have not yet developed or been diagnosed with CD. It is also possible that children in our sample have been diagnosed with CD, but have yet to be diagnosed with JRA/JIA. JRA/JIA is rare and the study sample is small, so it is very possible that there will be cases in this set. We found no association of AA and CD, even though AA is associated with the CD susceptibility allele, HLA-DQB1*0201 . There have been a few case reports of the co-occurrence of AA and CD [34, 35].
Family studies allow for the opportunity to study the aggregation of disease and assist in the determination of disease etiology. Aggregation of disease in families may be explained by the sharing of genetic susceptibility factors or environmental factors, which predispose to disease. Some studies have found a positive association of probands with a specific autoimmune disease, such as IDDM, and autoimmune diseases as a whole among their first- and second-degree family members [36, 37]. Among our first-degree family members, we had an overall burden of the studied autoimmune diseases of 4.9%, which is similar to the population prevalence of 3–5%. However, we only studied a subset of autoimmune diseases and therefore may have underestimated the total burden of autoimmune disease. We found a significantly increased number of relatives than expected for IDDM (SR = 3.2 and SR = 4.0) in comparison to expected numbers derived from the two published studies, Table 3. We found a significantly increased number of observed cases relative to expected in all ages for JRA/JIA (SR = 5.7).
Standardized ratios less than 1.0 were found for RA in two of the three comparisons, and we identified no males with JRA/JIA. There are several reasons this may have occurred. Given that many autoimmune diseases are rare, our study may have been underpowered to evaluate these diseases. The lack of knowledge and understanding about these conditions in our families may have resulted in underreporting. Issues of bias in reporting and selection, as outlined in the limitations sections, may have resulted in an under identification of additional disease cases. It is also possible that there is not an association of these conditions in CD families.
The burden of disease was not the same in all of our families. Out of 91 families that met inclusion criteria, approximately half reported autoimmune diseases (58%). When the families reporting disease were examined, the size of the family was not related to the number of diseases reported. We had a range of 2–45% of individuals reported with disease in these families. It appears that some families may be more susceptible to autoimmune diseases than other families.
We also evaluated whether the specific disease or diseases reported were different within a family. Within families, the number of different autoimmune diseases reported was most often one or two. In the 27 families with more than one relative reporting disease, the specific autoimmune disease in the family members was the same in 10 families. In 16 families, there were two autoimmune diseases and in 1 family there were 4 autoimmune diseases. There may have been other autoimmune diseases that were not investigated in this study.
It is well-documented that many autoimmune diseases are associated with alleles in genes in the major histocompatibility complex (MHC) . In many of these diseases, an association with specific alleles of either MHC class I or class II genes has been documented, as with the association of DQ2 (DQA1*05/DQB1*02) and DQ8 (DQA1*0301/DQB*302) in CD and DR4 (HLA-DRB1*0401, *0404, *0405, *0408) in RA [27, 28, 38–41]. However, these genetic associations only predispose a person to the development of disease but are not sufficient by themselves to cause the disease.
In our families, individuals with CD and their first-degree relatives reported significantly more cases of IDDM than expected. The individuals in our families with IDDM may share HLA alleles and other unknown genetic susceptibility factors, which may predispose them to both IDDM and CD. CD and IDDM are reported to be associated with the same HLA susceptibility alleles, but not all individuals with these susceptibility alleles develop both diseases. Greater than 90% of individuals with CD or IDDM have the DQ2 (DQA1*0501/DQB1*0201) or DQ8 (DQA1*0301/DQB*302) haplotype, which are reported to be susceptibility loci for CD and IDDM, but in studies of patients with IDDM only about 2.5–5% of patients also developed CD [19–21, 39, 42, 43]. This demonstrates that there are other unidentified susceptibility factors.
A pathogenetic model proposed for some autoimmune diseases is that multiple genes may act independently of each other or may interact through functionally related pathways to lead to the pathogenesis of the disease . It is possible that individuals with autoimmune diseases also share non-MHC genes predisposing to autoimmune conditions. For example, the PTPN22 gene has been reported to be associated with susceptibility to RA and JRA/JIA and the MDR1 gene has been shown to confer risk for Crohn’s disease and ulcerative colitis [44–46]. A combination of MHC and non-MHC genes in the etiology of CD and autoimmune diseases is likely, but the precise interaction of these to increase disease susceptibility is still unclear. The disease associations in our study could also be related to common environmental exposure or a combination of factors . Environmental factors that have been implicated as risk factors for autoimmune disease are infection, vaccines, smoking, diet, exposure to ultraviolet light, and stress .
We were limited by the availability of prevalence studies for the diseases we studied and the ethnicity of the CD families (99.7% non-Hispanic Caucasian) may not have been well-matched to published populations for the specific disease. Second, with low prevalence rates for a disease and/or age group, SR estimates were not precise. For most of the diseases, we relied on self-reports and reports from first-degree relatives rather than medical records, which may have resulted in some inaccuracies. However, in general, studies have shown that self-report and family history are accurate [49–52]. When the first-degree relative is a parent versus a sibling, the reporting accuracy typically is higher . We found that for the 58 cases for whom we had medical records, the diagnoses were confirmed, suggesting that verified self-reports are reliable. The questionnaires were not designed to be a specific tool for the assessment of autoimmune diseases other than CD, and a number of diagnoses may have been missed or erroneously reported. To decrease the likelihood of over-reporting, we did not include reports about first-degree relatives if we were unable to re-contact the family member reporting. Therefore, some reports of disease were omitted. We had medical records to verify diagnoses for 48% of disease reports. These records were primarily for hypothyroidism and IDDM, so reports of these diseases may be more accurate than reports of RA, JRA, and AA.
The results of this first North American study support the hypothesis that there is an increased occurrence of autoimmune diseases in CD families relative to the general population. In the set of CD cases (group 1), 13.2% of individuals had at least one autoimmune disease. In the first-degree relatives of CD cases (group 2), 4.6% of individuals had at least one autoimmune disease. Individuals with CD are more likely to report an autoimmune disease than first-degree relatives. It may be that individuals with CD are more susceptible to autoimmune diseases due to a shared genetic factor(s). An individual with one autoimmune disease also may be more susceptible to develop additional disease(s). For IDDM, the observed number of affecteds was significantly higher than expected among both CD cases and first-degree relatives. In addition, an increased number of cases of hypothyroidism were observed in individuals with CD (SR > 1.0 with 95% CI excluding unity for 3 of the 4 estimates). A significant increase in the number of first-degree relatives with JRA/JIA was observed (SR = 5.7). Given these findings, a genetic association with other autoimmune diseases in our CD families is plausible. Further studies to evaluate our entire study sample and replication in another set of celiac families are needed.
This study was funded by NIH DK50678. We thank the families for participating in our study.
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