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BRIEF REPORT |
Department of Pediatrics (P.E., J.F.L.) and Clinical Research Centre (S.M.M.), Örebro University Hospital, SE-701 85 Örebro, Sweden; Clinical Epidemiology Unit (S.M.M., A.E., J.F.L.), Department of Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden; Department of Medical Sciences (O.K.), Uppsala University, University Hospital, SE-751 05 Uppsala, Sweden; and Harvard School of Public Health (A.E.), Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Peter Elfström, Department of Pediatrics, Örebro University Hospital, SE-701 85 Örebro, Sweden. E-mail: peter.elfstrom{at}orebroll.se.
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Abstract |
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Methods: Through the Swedish national registers we identified 14,366 individuals with a diagnosis of CD (1964–2003) and 70,095 reference individuals matched for age, sex, calendar year, and county of residence. We used Cox regression to estimate hazard ratios (HRs) for subsequent AD. Analyses were restricted to individuals with more than 1 yr of follow-up and without AD prior to study entry or within 1 yr after study entry. Conditional logistic regression estimated the odds ratio for CD in individuals with prior AD.
Results: There was a statistically significantly positive association between CD and subsequent AD [HR = 11.4; 95% confidence interval (CI) = 4.4–29.6]. This risk increase was seen in both children and adults and did not change with adjustment for diabetes mellitus or socioeconomic status. When we restricted reference individuals to inpatients, the adjusted HR for AD was 4.6 (95% CI = 1.9–11.4). Individuals with prior AD were at increased risk of CD (odds ratio = 8.6; 95% CI = 3.4–21.8).
Conclusions: This study found a highly increased risk of AD in individuals with CD. This relationship was independent of temporal sequence. We therefore recommend that individuals with AD should be screened for CD. We also suggest an increased awareness of AD in individuals with CD.
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Introduction |
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Celiac disease (CD) is a chronic inflammatory intestinal disease induced by dietary gluten in genetically susceptible individuals (4). CD has increasingly become recognized as a multi-organ disorder and has been linked to a number of diseases (5). Several studies have indicated an increased risk of CD in patients with AD (6, 7, 8, 9). These studies were, however, limited in size, based on screening for CD in individuals with AD (6, 7, 8, 9), and none of the authors estimated the risk of AD in CD (6, 7, 8, 9). The rarity of AD makes such analyses difficult without access to large datasets.
In this study, we investigated the risk of AD in a cohort of 14,366 individuals with CD and 70,095 age- and sex-matched reference individuals.
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Subjects and Methods |
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In short, the Swedish National Board of Health used the Swedish national inpatient register (IPR) to identify all individuals with a hospital discharge diagnosis of CD between 1964 and 2003. CD was defined according to relevant international classification of disease (ICD) codes (ICD-7, 286.00; ICD-8, 269.00, 269.98; ICD-9, 579A; ICD-10, K90.0). The IPR was also used to identify individuals with AD (ICD-7, 274.4; ICD-8, 255.1; ICD-9, 255E; ICD-10, E27.1-2) and diabetes mellitus (DM).
Individuals with CD were matched with up to five reference individuals for age, sex, calendar year, and county at time of CD diagnosis. Reference individuals were identified through the Total Population Register. In a subset of individuals (n = 45,526; 8,815 with CD), we had data from Statistics Sweden on socioeconomic index (SEI).
We identified 15,533 individuals with CD diagnosed between 1964 and 2003. Of these, 1049 individuals with CD were excluded due to a shorter follow-up than 1 yr and 94 due to data irregularities. We then excluded 24 individuals with AD occurring before diagnosis of CD (n = 14) or within the first year of such diagnosis (n = 10). Similar exclusion criteria were used for the reference cohort. Hence, this study was based on 14,366 individuals with CD and 70,095 individuals without a diagnosis of CD; all study participants were free of AD 1 yr after study entry. Follow-up time was started 1 yr after study entry (equal to the date of first inpatient diagnosis of CD or corresponding date in matched reference individuals). Follow-up time ended on date of first discharge diagnosis of AD, emigration, death, or end of the study period (December 31, 2003), whichever occurred first.
Statistics
Cox regression estimated the hazard ratios (HRs) for subsequent AD in CD. These analyses were conditioned on risk-set so that an individual with CD was compared only with his/her age- and sex-matched reference individuals.
In separate analyses, we stratified for sex and age at study entry (
15 or 
16 yr). To increase the specificity of our outcome measure, we specifically calculated HRs for AD when 1) AD was listed as the main diagnosis, 2) the same individual had received a diagnosis of AD at least twice, and 3) AD had been recorded in a department where diagnostic investigations for AD are usually carried out (pediatrics or internal medicine).
We estimated the risk of AD after adjusting for DM and after excluding all individuals who had a diagnosis of DM before the end of follow-up. We also calculated crude and adjusted risk estimates for AD in individuals with data on SEI. In a separate analysis, we included the first year after study entry in the follow-up.
In a post hoc analysis, we estimated the risk of subsequent AD in individuals with CD compared with reference individuals who had been admitted to hospital within less than 1 yr before or after the first diagnosis of CD in the matched individual with CD. To maximize the power, we included the first year of follow-up in the post hoc analyses. We chose to adjust for sex, age, and calendar period instead of using internal stratification because some strata contained no reference individuals.
Prior AD and subsequent CD
Conditional logistic regression estimated the odds ratio for CD in individuals with a prior diagnosis of AD. We performed this analysis to evaluate whether the positive association between CD and AD was restricted to patients with CD preceding AD. The end of follow-up was defined as date of first CD diagnosis and the same date for the matched reference individuals without CD. Those with 1 yr or less between the date of first AD diagnosis and CD diagnosis (or study entry), and corresponding data in matched reference individuals, were excluded.
Ethics
This study was approved by the Research Ethics Committee of the Karolinska Institute. None of the participants was contacted. Subject information was anonymized before the analyses.
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Results |
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Overall, 39 of 15,439 (0.25%) individuals with CD had a diagnosis of AD before or after diagnosis of CD. In reference individuals, 19 of 76,910 (0.02%) had a diagnosis of AD be-fore or after study entry.
Individuals with CD were at an 11-fold increased risk of subsequent AD [HR = 11.4; 95% confidence interval (CI) = 4.4–29.6] (Table 1
). This risk increase was also seen when adjusting for DM or SEI (Table 1). The HR for AD was 24.1 in individuals entering the study before the age of 16 yr and 8.9 in individuals entering the study as adults. This difference was not statistically significant (formal interaction test: P = 0.274).
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). Six individuals with CD and five reference individuals had at least two subsequent diagnoses of AD (Table 1). When we included the first year of follow-up, the HR for subsequent AD increased to 19.4 (Table 1). When we limited reference individuals to inpatients, the risk estimate decreased but nevertheless remained statistically significantly increased (adjusted HR = 4.6; 95% CI = 1.9–11.4; P = 0.001; based on 25 and six positive events in 15,425 individuals with CD and 14,370 inpatient reference individuals, respectively).
The incidence rate for AD was 15 per 191,780 person-years in individuals with CD and nine per 971,639 in reference individuals (Table 2).
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Individuals with AD were at an 8-fold increased risk of subsequent CD (odds ratio = 8.6; 95% CI = 3.4–21.8; P < 0.001).
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Discussion |
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This study confirms earlier studies on CD and AD (6, 7, 8, 9). These studies were, however, limited in size and lack data on potential confounders (6, 7, 8, 9). In contrast, our study included more than 14,000 patients with CD and 70,000 reference individuals. This gives the study considerable power to identify infrequent events and enabled us to examine the risk of AD in various strata. Stratified analyses revealed that risk estimates were similar in males and females. High risk estimates for AD were seen both in childhood and adulthood CD. We do, however, urge caution when interpreting risk estimates for AD in childhood CD because positive events were few in this stratum.
The positive association between CD and AD was seen both before and after diagnosis of CD, and we do not believe that one disease causes the other. Instead we suggest that our findings might be explained by the presence of shared genetic traits, as e.g. HLA DQ2 and DQ8 are common both in AD (12) and CD (4). In the study by Myhre et al. (12), all six individuals with both AD and CD carried the HLA DR3-DQ2 haplotype.
The misclassification rate for CD, in a subset of individuals with both CD and lymphoma, was recently estimated at less than 15% in the IPR (13). This partly stems from the well-established practice in Sweden to perform a small-bowel biopsy before confirming CD (14). However, not all individuals with CD will be identified through a hospital-based register. This should be no major drawback because we nevertheless had access to morbidity data in more than 14,000 individuals with CD. There is also a risk that individuals with CD identified through a hospital-based register have more severe disease than the average individual with CD and therefore are at increased risk of any disease. Nevertheless, when using inpatient reference individuals, this study found a 4.6-fold risk increase for AD in individuals with CD. This means that the association between CD and AD is unlikely to be due to ascertainment bias or hospitalization in individuals with CD. Although not all individuals with AD are admitted to hospital, our incidence figures in reference individuals was 0.9/100,000 person-years; compare with 0.62 of 100,000 person-years in a recent Norwegian study (15) and signal for a high sensitivity for AD in the IPR.
A weakness of the study is the lack of data on 21-hydroxylase autoantibodies, and therefore we cannot rule out the existence of false-negative cases of AD in our study. Although the lack of 21-hydroxylase antibody data may introduce bias, it is unlikely to explain our results because the use of this antibody test in individuals suspected of having AD should not differ by CD status.
A second weakness is that data on, for example, medication (such as steroid treatment in AD) and performed investigations could not be obtained through patient charts because all registry data were anonymized before the analyses (in accordance with requirements from the ethics committee).
In conclusion, we found a highly increased risk of AD in individuals with CD. This relationship was independent of temporal sequence. Methods for autoantibody testing of AD and CD have improved recently with better sensitivity and specificity using 21-hydroxylase (2) and transglutaminase (16) autoantibody testing for AD and CD, respectively. We therefore recommend that individuals with AD should be screened for CD. We also suggest an increased awareness of AD in individuals with CD.
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Footnotes |
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This project (04-030/1) was approved by the Research Ethics Committee of the Karolinska Institute, Stockholm, Sweden on March 18, 2004.
J.F.L. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of Interest: No conflict of interest is declared.
First Published Online June 26, 2007
Abbreviations: AD, Addison’s disease; CD, celiac disease; CI, confidence interval; DM, diabetes mellitus; HR, hazard ratio; ICD, International Classification of Disease; IPR, Swedish national inpatient register; SEI, socioeconomic index.
Received April 30, 2007.
Accepted June 18, 2007.
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  L. Leelarathna, J.K. Powrie, and P.V. Carroll Thomas Addison's disease after 154 years: modern diagnostic perspectives on an old condition QJM, August 1, 2009; 102(8): 569 - 573. [Abstract] [Full Text] [PDF]
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