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Autoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease
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Autoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease Q28
Louise Emilsson,*,‡ Cisca Wijmenga,§ Joseph A. Murray,k and Jonas F. Ludvigsson¶,# *Primary Care Research Unit, Vårdcentralen Värmlands Nysäter, Värmland County, Sweden; ‡Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; §Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; kDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; ¶Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; #Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
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BACKGROUND & AIMS:
First-degree relatives of individuals with celiac disease are at increased risk for this disorder, but little is known about their risk for other autoimmune diseases. We assessed the risk of nonceliac autoimmune disease in first-degree relatives and spouses of people with celiac disease.
METHODS:
We identified individuals with celiac disease by searching computerized duodenal and jejunal biopsies, collected from 1969 through 2008, at 28 pathology departments in Sweden. Celiac disease was identified based on biopsy reports of villous atrophy (equal to Marsh grade 3; n [ 29,096). Individuals with celiac disease were matched with up to 5 controls (people without celiac disease) for sex, age, county, and calendar year (total, 144,522 controls). Through Swedish health care registries, we identified all first-degree relatives (fathers, mothers, siblings, and offspring) and spouses of individuals with celiac disease (n [ 84,648) and controls (n [ 430,942). We used Cox regression analysis to calculate hazard ratios (HRs) for nonceliac autoimmune disease (Crohn’s disease, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, psoriasis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, or ulcerative colitis) in these groups.
RESULTS:
During the follow-up period (median, 10.8 y), 3333 of the first-degree relatives of patients with celiac disease (3.9%) and 12,860 relatives of controls (3.0%) had an autoimmune disease other than celiac disease. First-degree relatives of people with celiac disease were at increased risk of nonceliac autoimmune disease, compared with controls (HR, 1.28; 95% confidence interval, 1.23–1.33), as were spouses (HR, 1.20; 95% confidence interval, 1.06–1.35). Risk estimates for nonceliac autoimmune disease did not differ between first-degree relatives and spouses of individuals with celiac disease (interaction test: P [ .11). HRs for celiac disease were highest in the first 2 years of follow-up evaluation.
CONCLUSIONS:
First-degree relatives and spouses of individuals with celiac disease are at increased risk of nonceliac autoimmune disease. In addition to genetic factors, environmental factors and ascertainment bias might contribute to the increased risk of autoimmunity in first-degree relatives of individuals with celiac disease.
Keywords: Population Study; Risk Factor; Genetics; Heredity; Celiac; Cohort; Shared Genetics; Autoimmune.
eliac disease (CD) is characterized by an immunemediated response to the intake of gluten, resulting in small intestinal villous atrophy.1 CD affects approximately 1% of the Western population.2 Earlier data suggested a concordance rate in monozygotic twins of approximately 75%, and development of CD is conditional on genetic background.3 CD also has been associated with several autoimmune diseases. Therefore, screening for CD is recommended in individuals with certain diseases, such as type I diabetes mellitus (T1DM) and autoimmune thyroid disease.4 In our recent
C
meta-analysis, approximately 6% of individuals with T1DM had CD, suggesting a more than 5-fold increased relative risk of CD in individuals with T1DM.5 The
Abbreviations used in this paper: CD, celiac disease; CI, confidence interval; FDR, first-degree relative; HR, hazard ratio; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1DM, type I diabetes mellitus; UC, ulcerative colitis. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.01.026
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association of CD and T1DM is explained partly by shared HLA genetics,6 and more than 60% of CD-associated loci outside the HLA region identified by genomewide association studies are shared with at least one other autoimmune disease.7 Loci within the HLA region also are shared with thyroid autoimmunity and systemic lupus erythematosus (SLE) and the risk loci outside of the HLA region have been shown to be shared primarily with T1DM, rheumatoid arthritis (RA), Crohn’s disease, and ulcerative colitis (UC).8 The prevalence of CD in first-degree relatives (FDRs) to individuals with CD is approximately 10%.9–11 Despite these findings, little is known about the risk of nonceliac autoimmune disease in FDRs to individuals with CD. One earlier study of 1272 FDRs showed an increased risk of T1DM but not thyroid autoimmunity or RA.12 Another smaller study showed that seemingly some autoimmune diseases were increased in 225 FDRs to CD children.13 However, the statistical power in both earlier studies was limited. Hence, we aimed to assess the risk of several autoimmune diseases in celiac FDRs compared with matched control FDRs (age, sex, county, and calendar year) in a nationwide population-based longitudinal cohort study. We hypothesized that celiac FDRs, in comparison with control FDRs, would have an excess risk of nonceliac autoimmune disease.
Methods Collection of Biopsy Data
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Data regarding CD were collected in 2006 to 2008 through computerized duodenal/jejunal biopsies performed at all Swedish Pathology Departments between 1969 and 2008. CD was defined as having a biopsy specimen classified with villous atrophy equal to histopathology, stage Marsh III,14 with date of first pathologic biopsy as the date of diagnosis and study entry. In total, there were 29,096 celiac individuals identified. Taking small intestinal biopsy samples is the clinical routine in Sweden,15 and more than 95% of individuals with Marsh III changes have CD in a Swedish setting.15
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First-Degree Relatives and Spouses Through the Swedish Multi-Generation Register18 we obtained data on all FDRs (father, mother, siblings, and offspring) to celiac individuals and controls; from the Total Population Register16 we obtained data on all registered spouses (defined through marriage) (Figure 1). Spouses should represent genetically different individuals sharing the same environment as the celiac/index individuals. Because we did not have access to dates of marriage or lengths of marriage, a person who was at some point married to a person with CD was classified as a spouse. All FDRs and spouses entered the study on the same date of the corresponding index individual’s study entry or at birth, whichever occurred latest (Figure 1). We defined exposure as being a celiac FDR or a celiac spouse. Celiac spouse was defined as a spouse to an individual with CD.
Outcome Measures Different autoimmune diseases, in which either the highest reported prevalence exceeding 50 or reported incidence exceeding 5 per 100,000 individuals in Western countries with a previously reported association to CD, were selected as outcome measures. Included diseases were defined according to relevant International Classification of Diseases codes (Supplementary Table 1). For Addison’s disease, the primary biliary cirrhosis, IgA deficiency, and chronic immune thrombocytopenia purpura prevalence figures were either approximately 15 to 25 per 100,000 individuals or unknown. We therefore calculated the incidence of these diseases in the Swedish Patient Register (containing inpatient and hospital-based outpatient data). Based on earlier data, the incidence in a control population of healthy individuals per 100,000 person-years was 7 for sarcoidosis,19 2 for IgA deficiency,20 1.5 for both Addison’s disease21 and chronic immune thrombocytopenia,22 and 0.3 for primary biliary cirrhosis.23 Given the high relative risk of sarcoidosis in
Reference Individuals: Controls By using the Swedish Total Population Register, all celiac individuals were matched with up to 5 reference individuals (controls) by the government agency Statistics Sweden.16 In all, there were 144,522 controls matched for sex, county, age, and calendar year of birth. All controls entered the study on the same date as their matched celiac individual (the date of positive biopsy). Patients with CD and their matched controls have been described in detail.17 Given the nationwide character of the study any individual selected as a control could have celiac FDRs. In this study about FDRs they were hence counted as control FDRs (with own CD).
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Figure 1. Linkage of registries.
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Autoimmunity in Celiac Relatives
CD (hazard ratio [HR], 4.03)19 and its higher incidence, this disease, but not the other 4 diseases, was included in our analysis of FDRs. Because research has shown no association with CD in a Swedish setting, we did not include multiple sclerosis24 and autoimmune hemolytic anemia25 among our outcomes. Furthermore, we did not include polymyalgia rheumatic and pernicious anemia because we found no studies indicating a relationship to CD (Supplementary Table).
Statistical Analyses
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We used Cox regression to estimate HRs adjusted for sex, age group, calendar year, and own celiac diagnosis in the relative/spouse. Follow-up evaluation started at study entry of the FDRs/spouses and ended at outcome (registration of any autoimmune disease: Crohn’s disease, hypothyroidism, hyperthyroidism, T1DM, psoriasis, RA, sarcoidosis, SLE, or UC), death, emigration, or on December 31, 2009, whichever occurred first (Figure 1). We excluded individuals with any of the earlierdescribed autoimmune diagnoses before study entry. In our main analysis we examined the future risk of all the included nonceliac autoimmune diseases in celiac FDRs together, but we also analyzed the risk stratified by relative (father, mother, sibling, brother, sister, offspring, son, and daughter). In other analyses we examined the risk of each autoimmune disease separately as well as the absolute and excess risk of each of the diseases. Similar analyses were performed for spouses. In secondary analyses we restricted our outcome to those individuals with at least 2 records of autoimmune disease and to those in whom the autoimmune disease had been listed as the main diagnosis. We also analyzed the risk of any autoimmune disease, excluding FDRs who themselves had CD. Autoimmune disease in FDRs and spouses also was examined according to follow-up evaluation (time since the date of diagnosis of the index individual with CD until autoimmune outcome, 2 or >2 y). In an attempt to assess the impact of genetics we used an interaction test to perform an analysis comparing biological FDRs with spouses. Statistical significance was defined as 95% confidence intervals (CIs) for risk estimates not including 1.0. We used SPSS version 21.0 (SPSS, Inc, Chicago, IL) for all analyses.
Results Background Data We obtained data on 84,648 unique celiac FDRs and 430,942 control FDRs (Table 1). The majority of FDRs were male (61.1% in celiac FDRs vs 61.4% in control FDRs), which was expected because most CD patients are female. There were 3333 unique events of any nonceliac autoimmune disease in celiac FDRs compared with
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Table 1. Characteristics of Celiac and Control FDRs Celiac FDR Control FDR P N, (%) N, (%) value Total, n Relation Father Mother Sibling Offspring Spouse Sexb Female Male Age group, yb 1939 and earlier 1940–1963 1964–1986 1987–2010 Calendar year at study entryb 1989 and earlier 1990–1999 2000–2010 Celiac disease in the relative Father (to celiac patient) Mother Sibling Offspring Spouse Sex, spouses Female Male Events (any nonceliac autoimmune disease) Father Mother Sibling Offspring Spouse Total unique events Follow-up time, y Median Range
84,648 (100)a 430,942 (100)a <.001 17,641 9388 31,294 26,704 6712
(19.2) 86,461 (19.4) (10.2) 47,769 (10.7) (34.1) 147,256 (33.0) (29.1) 132,273 (29.6) (7.3) 32,877 (7.4) .12
30,622 (38.9) 154,531 (38.6) 48,130 (61.1) 245,896 (61.4) .001 11,631 26,522 19,608 20,991
(14.8) 58,344 (14.6) (33.7) 137,839 (34.4) (24.9) 98,856 (24.7) (26.7) 105,388 (26.7)
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.64 9911 (12.6) 50,634 (12.6) 30,986 (39.3) 158,038 (39.5) 37,855 (48.1) 191,755 (47.9) <.001 370 260 1695 908 11
(2.1) (2.8) (5.4) (3.4) (0.2)
130 149 513 412 87
(0.2) (0.3) (0.3) (0.3) (0.3) .14
1965 (29.3) 4747 (70.7)
9923 (30.2) 22,954 (69.8) <.001
614 747 1326 901 323 3631
(3.5) (8.0) (4.2) (3.4) (4.8) (4.3)
2388 3272 4354 3220 1353 14,126
(2.8) (6.8) (3.0) (2.4) (4.1) (3.3) N/A
10.7 0–42
10.8 0–42
a The sum is greater than the total number because you can be both a mother and a sibling, and so forth. b Not including spouse.
12,860 in the control relatives; for spouses, the corresponding figures were 323 for the celiac FDRs and 1353 for the control relatives (Table 1). CD increased in celiac FDRs but not in celiac spouses (Table 1). We had more data on fathers than on mothers. Exploring this unexpected finding, we found that more mothers (compared with fathers) died before the CD diagnosis of their offspring.
Any Nonceliac Autoimmunity The HR for any nonceliac autoimmune disease in celiac FDRs was 1.28 (95% CI, 1.23–1.33) (Table 2). The corresponding HRs in celiac spouses was 1.20 (95% CI, 1.06–1.35) (Table 3). The risk of any autoimmune
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291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348
349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 1.34 (1.16–1.55) 1.19 (1.05–1.34) 1.65 (1.41–1.93)
245 (0.3) 338 (0.4) 244 (0.3)
851 (0.2) 1404 (0.2) 631 (0.2)
1.35 (1.12–1.63) 1.14 (0.98–1.32) 1.65 (1.36–2.02)
1.33 (1.05–1.68) 1.29 (1.05–1.57) 1.65 (1.28–2.12)
26 36 26
7 6 10
1.25 1.39 1.16 1.16 1.60 1.81
330 841 889 515 139 64
1301 2961 3863 2222 435 171
1.45 1.46 1.22 1.25 1.68 2.02
1.18 1.37 1.08 1.11 1.42 1.76
(1.02–1.37) (1.26–1.50) (0.96–1.21) (0.98–1.26) (0.99–2.04) (1.26–2.46)
35 89 94 54 15 7
7 25 13 17 6 3
1.26 (1.19–1.33)
359
79
(1.11–1.41) (1.29–1.50) (1.08–1.25) (1.05–1.28) (1.32–1.95) (1.35–2.43)
1.28 (1.23–1.33)
(0.4) (1.1) (1.1) (0.7) (0.2) (0.1)
3333 (4.2)
(0.3) (0.7) (1.0) (0.6) (0.1) (0.0)
12,860 (3.2)
(1.15–1.82) (1.23–1.73) (1.11–1.34) (1.07–1.45) (1.34–2.12) (1.10–3.70)
1.30 (1.23–1.38)
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NOTE. All HRs were adjusted for age group, calendar year, own celiac disease, and sex of the relative. FDRs included fathers, mothers, siblings, and offspring. a The total number is lower than the sum because some individuals have more than 1 autoimmune disease.
Table 3. Risk for Autoimmune Disease in Celiac Spouses Versus Control Spouses
Disease Crohn’s disease Ulcerative colitis Type 1 diabetes mellitus Hyperthyroidism Hypothyroidism Psoriasis Rheumatoid arthritis Sarcoidosis Systematic lupus erythematosus Any of the abovea
HR (95% CI) 1.36 1.87 0.60 0.91 1.07 1.05 1.29 1.49 2.71
(0.80–2.33) (1.34–2.64) (0.14–2.64) (0.59–1.39) (0.82–1.40) (0.84–1.30) (0.99–1.68) (0.80–2.77) (1.26–5.84)
1.20 (1.06–1.35)
HR (95% CI) Absolute risk per 100,000 Excess risk per 100,000 HR (95% CI) Number of events in Number of events in person-years in celiac person-years in celiac Restricted to male Restricted to control spouses, celiac spouses, spouses spouses female spouses spouses n (%) n (%) 17 46 2 25 66 98 69 13 10
(0.3) (0.7) (0.0) (0.4) (1.0) (1.5) (1.0) (0.2) (0.1)
323 (4.8)
62 122 15 139 313 464 270 43 19
(0.2) (0.4) (0.0) (0.4) (1.0) (1.4) (0.8) (0.1) (0.1)
1353 (4.1)
1.14 1.67 0.60 0.97 1.14 0.95 1.04 1.38 0.87
(0.58–2.28) (1.12–2.50) (0.14–2.64) (0.49–1.91) (0.72–1.79) (0.72–1.26) (0.70–1.56) (0.66–2.89) (0.10–7.21)
1.84 (0.77–4.38) 2.69 (1.41–5.12) No events 0.87 (0.50–1.50) 1.04 (0.75–1.44) 1.23 (0.87–1.74) 1.54 (1.08–2.20) 1.80 (0.57–5.66) 3.64 (1.55–8.55)
20 53 3 29 76 114 79 15 11
6 25 1 3 5 5 18 5 7
1.09 (0.92–1.29)
1.33 (1.12–1.59)
380
63
NOTE. All HRs were adjusted for age group, calendar year, presence of CD, and sex of the spouse. a The total number is lower than the sum because some individuals have more than 1 autoimmune disease.
Clinical Gastroenterology and Hepatology Vol.
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Crohn’s disease Ulcerative colitis Type 1 diabetes mellitus Hyperthyroidism Hypothyroidism Psoriasis Rheumatoid arthritis Sarcoidosis Systematic lupus erythematosus Any of the abovea
HR (95% CI) Absolute risk per 100,000 Excess risks per 100,000 person-years in celiac person-years in celiac Restricted Number of events Number of events in HR (95% CI) Restricted relatives to female FDRs relatives HR (95% CI) in celiac FDRs, n (%) control FDRs, n (%) to male FDRs
Emilsson et al
Disease
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Table 2. Risk of Developing Autoimmune Diseases in Celiac FDRs Compared With Control FDRs
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Autoimmunity in Celiac Relatives
disease in celiac FDRs excluding those FDRs who themselves had a diagnosis of CD was highly similar (HR, 1.30; 95% CI, 1.25–1.35). The excess risk of any autoimmune diseases was 79 per 100,000 person-years in FDRs (Table 2) vs 63 in spouses (Table 3). The HRs for autoimmune disease were not statistically significantly different between biological relatives and spouses (P ¼ .11 for the interaction term). The risk of developing nonceliac autoimmune disease was highest in the first 2 years after CD diagnosis in the index individuals (HR, 1.42; 95% CI, 1.28–1.57), with slightly lower HRs thereafter, although still remaining statistically significant (HR, 1.26; 95% CI, 1.21–1.31). Sex did not influence the risk of nonceliac autoimmunity in FDRs (females: HR, 1.26; 95% CI, 1.19–1.33; males: HR, 1.30; 95% CI, 1.23–1.38) (Table 2), but was higher in female spouses than in male spouses (females: HR, 1.33; 95% CI, 1.12–1.59; males: HR, 1.09; 95% CI, 0.92–1.29) (Table 3), potentially suggesting that wives to husbands with newly diagnosed CD may test themselves for autoimmune diseases, whereas men are less likely to seek medical attention when their wife has a newly diagnosed CD.
Different Autoimmune Diseases Celiac FDRs were at increased risk for all the autoimmune diseases examined in our study, with highest HRs for T1DM, sarcoidosis, and SLE (Table 2 and Figure 2). HRs were comparable when we requested 2 records of autoimmune disease (for diagnosis), except that the relative risk of UC failed to attain statistical significance (Supplementary Table). Furthermore, HRs increased when we examined nonceliac autoimmune disease recorded as the main diagnosis (Supplementary Table 1). The absolute risks ranged from 7 (SLE) to 94 (psoriasis) per 100,000 person-years (Table 2). Celiac spouses were at significantly increased risk for SLE and UC only (Table 3 and Figure 2). The increased
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Figure 2. Risk of different autoimmune diseases in celiac FDRs (red) and celiac spouses (black).
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risk of SLE in spouses was seen only in female spouses, whereas the excess risk of UC was noted in both male and female spouses (Table 3).
Different Categories of First-Degree Relatives The risk of any autoimmune disease was very similar across different categories of FDRs, although siblings and offspring were at a slightly higher risk than parents of celiac individuals (Table 4). The spectrum of autoimmune diseases differed somewhat between categories: an excess of Crohn’s disease was observed in offspring, whereas psoriasis was more prevalent in only brothers and sons of celiac individuals. SLE increased only in parents and sisters of celiac individuals (Table 4).
Discussion In this nationwide, population-based longitudinal cohort study we examined the risk of nonceliac autoimmune disease in celiac FDRs. All outcomes were more common in celiac FDRs than in control FDRs, and hence we found a significantly increased risk of our composite measure “any included nonceliac autoimmune disease” in celiac FDRs. The highest HRs were observed for SLE, T1DM, and sarcoidosis. Although these diseases have been linked to CD, the HRs in individuals with CD have been substantially higher than what we found in celiac FDRs (eg, SLE: HR, 3.4926 vs 1.81 in FDRs; T1DM: HR, 2.427 vs 1.65 in FDRs; sarcoidosis: HR, 4.0319 vs 1.60 in FDRs). The literature suggests a strong genetic predisposition in CD and that shared genetics tend to overlap with other autoimmune diseases.8 Therefore, genetics seems like a plausible explanation for the excess risk found in celiac FDRs. Genome-wide association studies have suggested shared genetics with T1DM, UC, RA, and Crohn’s disease.8 Taking this into account, the HRs for RA and UC in this study are surprisingly low; however, loci outside of the HLA loci confer a very small proportion of the genetic risk in CD. However, because certain nonceliac autoimmune diseases also were more common in celiac spouses, genetics may not be the only explanation of the associations reported in this study. Naturally, spouses do not share genetics with each other from inheritance. Instead, they share the environment and possibly microbiome with their husband/wife, which also might impact the risk of developing and diagnosing other autoimmune diseases. Some studies have suggested that mate selection might not be totally genetically random because major histocompatibility complex class I appears to be more similar than expected between spouses, whereas major histocompatibility complex class II seemingly shows significant dissimilarity between spouses.28 If so, this possibility might have contributed to our findings. Another explanation is ascertainment bias, that is, both celiac FDRs and celiac spouses are
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NOTE. Hazard ratios and 95% CIs are shown. Results shown in italics are significant. a Because T1DM was defined as a diagnosis of DM registered before age 30 years (and not more than 2 parents were diagnosed with DM before the age of 30 years and after study entry ¼ the date their child was diagnosed with CD), the number of events was insufficient for statistical calculations.
(1.43–2.18) (1.42–2.42) (1.18–2.29) (1.28–2.00) (1.19–2.07) (1.15–2.43)
1.25 1.14 1.34 1.33 1.36 1.34 1.34 1.35
(1.14–1.37) (1.05–1.23) (1.26–1.43) (1.21–1.46) (1.25–1.48) (1.24–1.45) (1.21–1.48) (1.21–1.50)
1.32 1.18 1.12 1.16 1.07 1.66 1.62 1.73
(0.95–1.83) (0.76–1.84) (0.87–1.43) (0.84–1.59) (0.73–1.58) (1.32–2.10) (1.21–2.19) (1.19–2.53)
1.13 1.40 1.24 1.16 1.36 1.05 1.03 1.09
(0.88–1.46) (1.00–1.90) (1.02–1.50) (0.91–1.49) (0.99–1.88) (0.84–1.30) (0.79–1.34) (0.74–1.61)
1.76 1.85 1.65 1.60 1.57 1.68
a
a
1.50 1.10 1.34 1.71 1.23 1.36 1.27 1.40
(1.09–2.06) (0.89–1.36) (1.09–1.64) (1.16–2.53) (0.96–1.56) (1.05–1.76) (0.78–2.06) (1.03–1.91)
1.56 1.25 1.47 1.32 1.52 1.48 1.34 1.54
(1.25–1.95) (1.11–1.41) (1.28–1.70) (0.97–1.81) (1.30–1.77) (1.23–1.79) (0.91–1.97) (1.24–1.91)
1.14 0.98 1.22 1.28 1.15 1.19 1.25 1.09
(0.99–1.32) (0.80–1.19) (1.09–1.37) (1.10–1.50) (0.97–1.38) (1.03–1.37) (1.05–1.50) (0.86–1.37)
1.00 0.92 1.23 1.20 1.24 1.45 1.71 1.28
(0.79–1.27) (0.76–1.12) (1.05–1.43) (0.93–1.54) (1.02–1.52) (1.19–1.76) (1.28–2.28) (0.98–1.66)
1.70 1.16 1.77 1.61 2.10 1.71 1.69 1.79
(1.21–2.40) (0.67–2.00) (1.27–2.47) (1.06–2.45) (1.21–3.63) (1.20–2.43) (1.13–2.52) (0.84–3.81)
2.31 1.99 2.00 1.94 2.02 1.51 1.75 1.44
(1.02–5.24) (1.20–3.29) (1.22–3.28) (0.61–6.19) (1.17–3.49) (0.83–2.73) (0.47–6.47) (0.74–2.82)
Clinical Gastroenterology and Hepatology Vol.
Fathers Mothers Siblings Brothers Sisters Offspring Sons Daughters
Sarcoidosis Rheumatoid arthritis Psoriasis Hyperthyroidism Hypothyroidism Type 1 diabetes mellitus Ulcerative colitis, HR Crohn’s disease Any autoimmune disease
Table 4. Risk of Autoimmune Disease in Different Categories of Celiac FDRs
581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638
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more likely to be diagnosed with whatever disease (although the true prevalence is not different) simply because they might be more prone to seek medical advice or that doctors who are aware of the CD in the index individual are more likely to investigate FDRs and spouses for autoimmunity. The fact that the risk was higher within the first 2 years of diagnosis vs more than 2 years after the diagnosis indicates that ascertainment bias is present to some extent and therefore might inflate the estimates. That wives are more likely to seek health care and seek consultation for autoimmune disease when their husbands have CD than the other way around might explain why the risk of nonceliac autoimmunity differed by sex in spouses but not in biological FDRs. FDRs also are likely to undergo CD testing more often than the general population. The prevalence of diagnosed CD in control FDRs was 0.3% compared with 2.1% in fathers to celiac individuals and 5.4% in siblings to celiac individuals, which reflects both a genetic predisposition and more active case finding. Compared with previous studies in which the prevalence of CD in celiac FDRs has been reported to be as high as 11%,10 our finding of 5.4% in siblings is not particularly high. The CD prevalence in relatives, however, should not have affected our estimates because all analyses were adjusted for the presence of CD in the FDR. Although we cannot rule out the existence of bias, several findings suggest that there is a true genetic risk of autoimmunity in FDRs. For instance, in male FDRs the risks of all autoimmune diseases (except UC) were increased significantly, whereas only the risk of UC was increased significantly in male spouses. Accordingly, genetic predisposition might be less important and a shared environment might be more important in the conferred risk of UC, whereas it is possibly vice versa for some other autoimmune diseases. In all analyses we adjusted for CD in the FDRs and spouses. However, we cannot preclude the possibility that a number of (especially) FDRs had undiagnosed CD. Undiagnosed CD, however, would reduce our risk estimates toward the null.
Strengths and Limitations The large population-based setting, the reliable diagnostic procedure of CD,15 and our ability to identify more than 80,000 FDRs through the Swedish MultiGeneration Register were the major strengths of this study. The reliability of autoimmune outcomes is likely to be high in that positive predictive values for most diseases in the Swedish Patient Register range from 85% to 95%.29 Furthermore, risk estimates did not change when we requested 2 recordings of autoimmune disease for our outcome or restricted our outcome to individuals with a main listing of autoimmune disease. Some of the diseases, especially hypothyroidism, might be covered insufficiently by the Patient Register because many individuals with this condition only seek primary health care. The fact that only approximately 3%
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of FDRs had a record of nonceliac autoimmune disease in our study indicates that some diagnoses managed mainly in primary care are missing. For instance, hypothyroidism alone is thought to occur in approximately 5% of the general population (and any autoimmune disease is thought to occur in approximately 7%–8%). Still, low sensitivity should not lead to differential bias unless celiac FDRs are more likely to seek inpatient care than control FDRs.
13. Cataldo F, Marino V. Increased prevalence of autoimmune diseases in first-degree relatives of patients with celiac disease. J Pediatr Gastroenterol Nutr 2003;36:470–473. 14. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992;102:330–354. 15. Ludvigsson JF, Brandt L, Montgomery SM, et al. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009;9:19. 16. Johannesson I. The Total Population Register of Statistics Sweden. New Possibilities and Better Quality. Statistics Sweden, 2002.
Conclusions
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We found an increased risk of nonceliac autoimmune disease in FDRs and celiac spouses. This risk probably represents a mixture of genetic, environmental, and ascertainment bias mechanisms.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2015.01.026.
References 1. Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009; 373:1480–1493. 2. Dube C, Rostom A, Sy R, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology 2005;128:S57–S67. 3. Greco L, Romino R, Coto I, et al. The first large population based twin study of coeliac disease. Gut 2002;50:624–628. 4. Green PH, Cellier C. Celiac disease. N Engl J Med 2007;357: 1731–1743. 5. Elfstrom P, Sundstrom J, Ludvigsson JF. Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes. Aliment Pharmacol Ther 2014;40:1123–1132. 6. Bao F, Yu L, Babu S, et al. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J Autoimmun 1999;13: 143–148. 7. Troncone R, Discepolo V. Celiac disease and autoimmunity. J Pediatr Gastroenterol Nutr 2014;59(Suppl 1):S9–S11. 8. Ricano-Ponce I, Wijmenga C. Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet 2013;14: 325–353. 9. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286–292. 10. Rubio-Tapia A, Van Dyke CT, Lahr BD, et al. Predictors of family risk for celiac disease: a population-based study. Clin Gastroenterol Hepatol 2008;6:983–987. 11. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology 2006; 131:1981–2002. 12. Neuhausen SL, Steele L, Ryan S, et al. Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives. J Autoimmun 2008;31:160–165.
17. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–1178. 18. Ekbom A. The Swedish Multi-generation Register. Methods Mol Biol 2011;675:215–220. 19. Ludvigsson JF, Wahlstrom J, Grunewald J, et al. Coeliac disease and risk of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2007;24:121–126. 20. Marild K, Fredlund H, Ludvigsson JF. Increased risk of hospital admission for influenza in patients with celiac disease: a nationwide cohort study in Sweden. Am J Gastroenterol 2010;105:2465–2473. 21. Elfstrom P, Montgomery SM, Kampe O, et al. Risk of primary adrenal insufficiency in patients with celiac disease. J Clin Endocrinol Metab 2007;92:3595–3598. 22. Olen O, Montgomery SM, Elinder G, et al. Increased risk of immune thrombocytopenic purpura among inpatients with coeliac disease. Scand J Gastroenterol 2008;43:416–422. 23. Ludvigsson JF, Elfstrom P, Broome U, et al. Celiac disease and risk of liver disease: a general population-based study. Clin Gastroenterol Hepatol 2007;5:63–69 e1. 24. Ludvigsson JF, Olsson T, Ekbom A, et al. A population-based study of coeliac disease, neurodegenerative and neuroinflammatory diseases. Aliment Pharmacol Ther 2007;25:1317–1327. 25. Gabrielli M, Candelli M, Franceschi F, et al. Primary autoimmune haemolytic anaemia and coeliac disease. Scand J Gastroenterol 2004;39:605–606. 26. Ludvigsson JF, Rubio-Tapia A, Chowdhary V, et al. Increased risk of systemic lupus erythematosus in 29,000 patients with biopsyverified celiac disease. J Rheumatol 2012;39:1964–1970. 27. Ludvigsson JF, Ludvigsson J, Ekbom A, et al. Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. Diabetes Care 2006; 29:2483–2488. 28. Khankhanian P, Gourraud PA, Caillier SJ, et al. Genetic variation in the odorant receptors family 13 and the MHC loci influence mate selection in a multiple sclerosis dataset. BMC Genomics 2010;11:626. 29. Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011;11:450. 30. Staii A, Mirocha S, Todorova-Koteva K, et al. Hashimoto thyroiditis is more frequent than expected when diagnosed by cytology which uncovers a pre-clinical state. Thyroid Res 2010;3:11. 31. Elfstrom P, Montgomery SM, Kampe O, et al. Risk of thyroid disease in individuals with celiac disease. J Clin Endocrinol Metab 2008;93:3915–3921. 32. Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury,
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traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil 2014;95:986–995.e1. 33. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011; 365:1713–1725. 34. Peters U, Askling J, Gridley G, et al. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch Intern Med 2003;163:1566–1572. 35. Chakravarty EF, Bush TM, Manzi S, et al. Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data. Arthritis Rheum 2007;56:2092–2094. 36. Ronnblom A, Samuelsson SM, Ekbom A. Ulcerative colitis in the county of Uppsala 1945-2007: incidence and clinical characteristics. J Crohns Colitis 2010;4:532–536. 37. Braathen LR, Botten G, Bjerkedal T. Prevalence of psoriasis in Norway. Acta Derm Venereol Suppl (Stockh) 1989;142:5–8. 38. Ludvigsson JF, Lindelof B, Zingone F, et al. Psoriasis in a nationwide cohort study of patients with celiac disease. J Invest Dermatol 2011;131:2010–2016.
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871 872 873 874 40. Devereaux D, Tewelde SZ. Hyperthyroidism and thyrotoxicosis. 875 Emerg Med Clin North Am 2014;32:277–292. 876 877 878 879 Reprint requests Address requests for reprints to: Louise Emilsson, MD, Vårdcentralen Värm880 lands Nysäter, Nyströms väg 5, 66195 Värmlands Nysäter, Sweden. e-mail: Q2Q3 881 [email protected]; fax: (46) (0) 533-30214. Q4 882 Q5 Acknowledgments 883 This project (2006/633-31/3) was approved by the Research Ethics Committee 884 of the Karolinska Institutet, Sweden, on June 14, 2006. 885 Conflicts of interest Q6 886 The authors disclose no conflicts. 887 888 Funding Q7 This study was funded by the Swedish Research Council. 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 39. Karvonen M, Viik-Kajander M, Moltchanova E, et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23:1516–1526.
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8.e1
Q27
Autoimmunity in Celiac Relatives
Crohn’s disease Ulcerative colitis Type 1 diabetes mellitus Hyperthyroidism Hypothyroidism Psoriasis Rheumatoid arthritis Sarcoidosis Systematic lupus erythematosus
120040
140037
Disease
27
39
25 1936
Supplementary Table 2. Risk of Having at Least Two Listings of Autoimmune Disease in Celiac FDRs Versus Control FDRs 2 listings of autoimmune diagnosis
Main diagnosis of autoimmune disease
HR (95% CI)
HR (95% CI)
1.30 1.12 1.59 1.25 1.38 1.17 1.17 1.65 2.02
(1.09–1.57) (0.97–1.29) (1.35–1.88) (1.08–1.46) (1.24–1.55) (1.06–1.29) (1.04–1.30) (1.32–2.06) (1.46–2.80)
1.31 1.18 1.64 1.29 1.59 1.16 1.16 1.76 1.77
(1.12–1.52) (1.04–1.33) (1.40–1.93) (1.12–1.47) (1.35–1.87) (1.07–1.25) (1.05–1.29) (1.44–2.15) (1.28–2.45)
L40 E10 (age, <30 y) E05 696 250 (age, <30 y) 242
ICD, International Classification of Diseases.
696 250 (age, <30 y) 242 706 260 (age, <30 y) 252 Psoriasis Type 1 diabetes mellitus Grave’s/hyperthyroidism
705.4 572.00, 572.09
734.1 563.00
710A 555
M32 K50
NOTE. HRs were adjusted for age group, calendar year, presence of CD, and sex of the relative.
Systemic lupus erythematosus Crohn’s disease
12,000 10,00032 24633 41 20
30
719
D86 E00–E03, E06.3 M05, M06, M08.0, M08.2 K51 135 245C, 243, 244 714, excluded 714E, 714X 556 135 245.1, 243, 244 712.1, 712.3 563.10, 569.02 138.00–138.10 253 722, excluded 722.1 572.20, 572.21 Sarcoidosis Hashimoto’s/ hypothyroidism Rheumatoid arthritis Ulcerative colitis
15035
4.0 (2.3–7.0)19 4.4 (3.4–5.6)31 Unpublished data Increased SMR compared with controls34 3.5 (2.5–4.9)26 Increased SMR compared with controls34 1.7 (1.5–1.9)38 2.4 (1.9–3.0)27 2.9 (2.0–4.1)31
Celiac association HR (95% CI) Prevalence/ 100,000 Incidence/ 100,000 ICD-10 ICD-9 ICD-8 ICD-7 Autoimmune condition
Supplementary Table 1. ---
929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991
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Autoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease Q28
Louise Emilsson,*,‡ Cisca Wijmenga,§ Joseph A. Murray,k and Jonas F. Ludvigsson¶,# *Primary Care Research Unit, Vårdcentralen Värmlands Nysäter, Värmland County, Sweden; ‡Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; §Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; kDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; ¶Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; #Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
Q8
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Q10 Q11 Q12
BACKGROUND & AIMS:
First-degree relatives of individuals with celiac disease are at increased risk for this disorder, but little is known about their risk for other autoimmune diseases. We assessed the risk of nonceliac autoimmune disease in first-degree relatives and spouses of people with celiac disease.
METHODS:
We identified individuals with celiac disease by searching computerized duodenal and jejunal biopsies, collected from 1969 through 2008, at 28 pathology departments in Sweden. Celiac disease was identified based on biopsy reports of villous atrophy (equal to Marsh grade 3; n [ 29,096). Individuals with celiac disease were matched with up to 5 controls (people without celiac disease) for sex, age, county, and calendar year (total, 144,522 controls). Through Swedish health care registries, we identified all first-degree relatives (fathers, mothers, siblings, and offspring) and spouses of individuals with celiac disease (n [ 84,648) and controls (n [ 430,942). We used Cox regression analysis to calculate hazard ratios (HRs) for nonceliac autoimmune disease (Crohn’s disease, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, psoriasis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, or ulcerative colitis) in these groups.
RESULTS:
During the follow-up period (median, 10.8 y), 3333 of the first-degree relatives of patients with celiac disease (3.9%) and 12,860 relatives of controls (3.0%) had an autoimmune disease other than celiac disease. First-degree relatives of people with celiac disease were at increased risk of nonceliac autoimmune disease, compared with controls (HR, 1.28; 95% confidence interval, 1.23–1.33), as were spouses (HR, 1.20; 95% confidence interval, 1.06–1.35). Risk estimates for nonceliac autoimmune disease did not differ between first-degree relatives and spouses of individuals with celiac disease (interaction test: P [ .11). HRs for celiac disease were highest in the first 2 years of follow-up evaluation.
CONCLUSIONS:
First-degree relatives and spouses of individuals with celiac disease are at increased risk of nonceliac autoimmune disease. In addition to genetic factors, environmental factors and ascertainment bias might contribute to the increased risk of autoimmunity in first-degree relatives of individuals with celiac disease.
Keywords: Population Study; Risk Factor; Genetics; Heredity; Celiac; Cohort; Shared Genetics; Autoimmune.
eliac disease (CD) is characterized by an immunemediated response to the intake of gluten, resulting in small intestinal villous atrophy.1 CD affects approximately 1% of the Western population.2 Earlier data suggested a concordance rate in monozygotic twins of approximately 75%, and development of CD is conditional on genetic background.3 CD also has been associated with several autoimmune diseases. Therefore, screening for CD is recommended in individuals with certain diseases, such as type I diabetes mellitus (T1DM) and autoimmune thyroid disease.4 In our recent
C
meta-analysis, approximately 6% of individuals with T1DM had CD, suggesting a more than 5-fold increased relative risk of CD in individuals with T1DM.5 The
Abbreviations used in this paper: CD, celiac disease; CI, confidence interval; FDR, first-degree relative; HR, hazard ratio; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1DM, type I diabetes mellitus; UC, ulcerative colitis. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.01.026
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association of CD and T1DM is explained partly by shared HLA genetics,6 and more than 60% of CD-associated loci outside the HLA region identified by genomewide association studies are shared with at least one other autoimmune disease.7 Loci within the HLA region also are shared with thyroid autoimmunity and systemic lupus erythematosus (SLE) and the risk loci outside of the HLA region have been shown to be shared primarily with T1DM, rheumatoid arthritis (RA), Crohn’s disease, and ulcerative colitis (UC).8 The prevalence of CD in first-degree relatives (FDRs) to individuals with CD is approximately 10%.9–11 Despite these findings, little is known about the risk of nonceliac autoimmune disease in FDRs to individuals with CD. One earlier study of 1272 FDRs showed an increased risk of T1DM but not thyroid autoimmunity or RA.12 Another smaller study showed that seemingly some autoimmune diseases were increased in 225 FDRs to CD children.13 However, the statistical power in both earlier studies was limited. Hence, we aimed to assess the risk of several autoimmune diseases in celiac FDRs compared with matched control FDRs (age, sex, county, and calendar year) in a nationwide population-based longitudinal cohort study. We hypothesized that celiac FDRs, in comparison with control FDRs, would have an excess risk of nonceliac autoimmune disease.
Methods Collection of Biopsy Data
Q14
Data regarding CD were collected in 2006 to 2008 through computerized duodenal/jejunal biopsies performed at all Swedish Pathology Departments between 1969 and 2008. CD was defined as having a biopsy specimen classified with villous atrophy equal to histopathology, stage Marsh III,14 with date of first pathologic biopsy as the date of diagnosis and study entry. In total, there were 29,096 celiac individuals identified. Taking small intestinal biopsy samples is the clinical routine in Sweden,15 and more than 95% of individuals with Marsh III changes have CD in a Swedish setting.15
Q15
No.
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First-Degree Relatives and Spouses Through the Swedish Multi-Generation Register18 we obtained data on all FDRs (father, mother, siblings, and offspring) to celiac individuals and controls; from the Total Population Register16 we obtained data on all registered spouses (defined through marriage) (Figure 1). Spouses should represent genetically different individuals sharing the same environment as the celiac/index individuals. Because we did not have access to dates of marriage or lengths of marriage, a person who was at some point married to a person with CD was classified as a spouse. All FDRs and spouses entered the study on the same date of the corresponding index individual’s study entry or at birth, whichever occurred latest (Figure 1). We defined exposure as being a celiac FDR or a celiac spouse. Celiac spouse was defined as a spouse to an individual with CD.
Outcome Measures Different autoimmune diseases, in which either the highest reported prevalence exceeding 50 or reported incidence exceeding 5 per 100,000 individuals in Western countries with a previously reported association to CD, were selected as outcome measures. Included diseases were defined according to relevant International Classification of Diseases codes (Supplementary Table 1). For Addison’s disease, the primary biliary cirrhosis, IgA deficiency, and chronic immune thrombocytopenia purpura prevalence figures were either approximately 15 to 25 per 100,000 individuals or unknown. We therefore calculated the incidence of these diseases in the Swedish Patient Register (containing inpatient and hospital-based outpatient data). Based on earlier data, the incidence in a control population of healthy individuals per 100,000 person-years was 7 for sarcoidosis,19 2 for IgA deficiency,20 1.5 for both Addison’s disease21 and chronic immune thrombocytopenia,22 and 0.3 for primary biliary cirrhosis.23 Given the high relative risk of sarcoidosis in
Reference Individuals: Controls By using the Swedish Total Population Register, all celiac individuals were matched with up to 5 reference individuals (controls) by the government agency Statistics Sweden.16 In all, there were 144,522 controls matched for sex, county, age, and calendar year of birth. All controls entered the study on the same date as their matched celiac individual (the date of positive biopsy). Patients with CD and their matched controls have been described in detail.17 Given the nationwide character of the study any individual selected as a control could have celiac FDRs. In this study about FDRs they were hence counted as control FDRs (with own CD).
-,
Figure 1. Linkage of registries.
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233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
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CD (hazard ratio [HR], 4.03)19 and its higher incidence, this disease, but not the other 4 diseases, was included in our analysis of FDRs. Because research has shown no association with CD in a Swedish setting, we did not include multiple sclerosis24 and autoimmune hemolytic anemia25 among our outcomes. Furthermore, we did not include polymyalgia rheumatic and pernicious anemia because we found no studies indicating a relationship to CD (Supplementary Table).
Statistical Analyses
Q17
Q18
We used Cox regression to estimate HRs adjusted for sex, age group, calendar year, and own celiac diagnosis in the relative/spouse. Follow-up evaluation started at study entry of the FDRs/spouses and ended at outcome (registration of any autoimmune disease: Crohn’s disease, hypothyroidism, hyperthyroidism, T1DM, psoriasis, RA, sarcoidosis, SLE, or UC), death, emigration, or on December 31, 2009, whichever occurred first (Figure 1). We excluded individuals with any of the earlierdescribed autoimmune diagnoses before study entry. In our main analysis we examined the future risk of all the included nonceliac autoimmune diseases in celiac FDRs together, but we also analyzed the risk stratified by relative (father, mother, sibling, brother, sister, offspring, son, and daughter). In other analyses we examined the risk of each autoimmune disease separately as well as the absolute and excess risk of each of the diseases. Similar analyses were performed for spouses. In secondary analyses we restricted our outcome to those individuals with at least 2 records of autoimmune disease and to those in whom the autoimmune disease had been listed as the main diagnosis. We also analyzed the risk of any autoimmune disease, excluding FDRs who themselves had CD. Autoimmune disease in FDRs and spouses also was examined according to follow-up evaluation (time since the date of diagnosis of the index individual with CD until autoimmune outcome, 2 or >2 y). In an attempt to assess the impact of genetics we used an interaction test to perform an analysis comparing biological FDRs with spouses. Statistical significance was defined as 95% confidence intervals (CIs) for risk estimates not including 1.0. We used SPSS version 21.0 (SPSS, Inc, Chicago, IL) for all analyses.
Results Background Data We obtained data on 84,648 unique celiac FDRs and 430,942 control FDRs (Table 1). The majority of FDRs were male (61.1% in celiac FDRs vs 61.4% in control FDRs), which was expected because most CD patients are female. There were 3333 unique events of any nonceliac autoimmune disease in celiac FDRs compared with
3
Q1
Table 1. Characteristics of Celiac and Control FDRs Celiac FDR Control FDR P N, (%) N, (%) value Total, n Relation Father Mother Sibling Offspring Spouse Sexb Female Male Age group, yb 1939 and earlier 1940–1963 1964–1986 1987–2010 Calendar year at study entryb 1989 and earlier 1990–1999 2000–2010 Celiac disease in the relative Father (to celiac patient) Mother Sibling Offspring Spouse Sex, spouses Female Male Events (any nonceliac autoimmune disease) Father Mother Sibling Offspring Spouse Total unique events Follow-up time, y Median Range
84,648 (100)a 430,942 (100)a <.001 17,641 9388 31,294 26,704 6712
(19.2) 86,461 (19.4) (10.2) 47,769 (10.7) (34.1) 147,256 (33.0) (29.1) 132,273 (29.6) (7.3) 32,877 (7.4) .12
30,622 (38.9) 154,531 (38.6) 48,130 (61.1) 245,896 (61.4) .001 11,631 26,522 19,608 20,991
(14.8) 58,344 (14.6) (33.7) 137,839 (34.4) (24.9) 98,856 (24.7) (26.7) 105,388 (26.7)
Q23
.64 9911 (12.6) 50,634 (12.6) 30,986 (39.3) 158,038 (39.5) 37,855 (48.1) 191,755 (47.9) <.001 370 260 1695 908 11
(2.1) (2.8) (5.4) (3.4) (0.2)
130 149 513 412 87
(0.2) (0.3) (0.3) (0.3) (0.3) .14
1965 (29.3) 4747 (70.7)
9923 (30.2) 22,954 (69.8) <.001
614 747 1326 901 323 3631
(3.5) (8.0) (4.2) (3.4) (4.8) (4.3)
2388 3272 4354 3220 1353 14,126
(2.8) (6.8) (3.0) (2.4) (4.1) (3.3) N/A
10.7 0–42
10.8 0–42
a The sum is greater than the total number because you can be both a mother and a sibling, and so forth. b Not including spouse.
12,860 in the control relatives; for spouses, the corresponding figures were 323 for the celiac FDRs and 1353 for the control relatives (Table 1). CD increased in celiac FDRs but not in celiac spouses (Table 1). We had more data on fathers than on mothers. Exploring this unexpected finding, we found that more mothers (compared with fathers) died before the CD diagnosis of their offspring.
Any Nonceliac Autoimmunity The HR for any nonceliac autoimmune disease in celiac FDRs was 1.28 (95% CI, 1.23–1.33) (Table 2). The corresponding HRs in celiac spouses was 1.20 (95% CI, 1.06–1.35) (Table 3). The risk of any autoimmune
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291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348
349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 1.34 (1.16–1.55) 1.19 (1.05–1.34) 1.65 (1.41–1.93)
245 (0.3) 338 (0.4) 244 (0.3)
851 (0.2) 1404 (0.2) 631 (0.2)
1.35 (1.12–1.63) 1.14 (0.98–1.32) 1.65 (1.36–2.02)
1.33 (1.05–1.68) 1.29 (1.05–1.57) 1.65 (1.28–2.12)
26 36 26
7 6 10
1.25 1.39 1.16 1.16 1.60 1.81
330 841 889 515 139 64
1301 2961 3863 2222 435 171
1.45 1.46 1.22 1.25 1.68 2.02
1.18 1.37 1.08 1.11 1.42 1.76
(1.02–1.37) (1.26–1.50) (0.96–1.21) (0.98–1.26) (0.99–2.04) (1.26–2.46)
35 89 94 54 15 7
7 25 13 17 6 3
1.26 (1.19–1.33)
359
79
(1.11–1.41) (1.29–1.50) (1.08–1.25) (1.05–1.28) (1.32–1.95) (1.35–2.43)
1.28 (1.23–1.33)
(0.4) (1.1) (1.1) (0.7) (0.2) (0.1)
3333 (4.2)
(0.3) (0.7) (1.0) (0.6) (0.1) (0.0)
12,860 (3.2)
(1.15–1.82) (1.23–1.73) (1.11–1.34) (1.07–1.45) (1.34–2.12) (1.10–3.70)
1.30 (1.23–1.38)
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NOTE. All HRs were adjusted for age group, calendar year, own celiac disease, and sex of the relative. FDRs included fathers, mothers, siblings, and offspring. a The total number is lower than the sum because some individuals have more than 1 autoimmune disease.
Table 3. Risk for Autoimmune Disease in Celiac Spouses Versus Control Spouses
Disease Crohn’s disease Ulcerative colitis Type 1 diabetes mellitus Hyperthyroidism Hypothyroidism Psoriasis Rheumatoid arthritis Sarcoidosis Systematic lupus erythematosus Any of the abovea
HR (95% CI) 1.36 1.87 0.60 0.91 1.07 1.05 1.29 1.49 2.71
(0.80–2.33) (1.34–2.64) (0.14–2.64) (0.59–1.39) (0.82–1.40) (0.84–1.30) (0.99–1.68) (0.80–2.77) (1.26–5.84)
1.20 (1.06–1.35)
HR (95% CI) Absolute risk per 100,000 Excess risk per 100,000 HR (95% CI) Number of events in Number of events in person-years in celiac person-years in celiac Restricted to male Restricted to control spouses, celiac spouses, spouses spouses female spouses spouses n (%) n (%) 17 46 2 25 66 98 69 13 10
(0.3) (0.7) (0.0) (0.4) (1.0) (1.5) (1.0) (0.2) (0.1)
323 (4.8)
62 122 15 139 313 464 270 43 19
(0.2) (0.4) (0.0) (0.4) (1.0) (1.4) (0.8) (0.1) (0.1)
1353 (4.1)
1.14 1.67 0.60 0.97 1.14 0.95 1.04 1.38 0.87
(0.58–2.28) (1.12–2.50) (0.14–2.64) (0.49–1.91) (0.72–1.79) (0.72–1.26) (0.70–1.56) (0.66–2.89) (0.10–7.21)
1.84 (0.77–4.38) 2.69 (1.41–5.12) No events 0.87 (0.50–1.50) 1.04 (0.75–1.44) 1.23 (0.87–1.74) 1.54 (1.08–2.20) 1.80 (0.57–5.66) 3.64 (1.55–8.55)
20 53 3 29 76 114 79 15 11
6 25 1 3 5 5 18 5 7
1.09 (0.92–1.29)
1.33 (1.12–1.59)
380
63
NOTE. All HRs were adjusted for age group, calendar year, presence of CD, and sex of the spouse. a The total number is lower than the sum because some individuals have more than 1 autoimmune disease.
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Crohn’s disease Ulcerative colitis Type 1 diabetes mellitus Hyperthyroidism Hypothyroidism Psoriasis Rheumatoid arthritis Sarcoidosis Systematic lupus erythematosus Any of the abovea
HR (95% CI) Absolute risk per 100,000 Excess risks per 100,000 person-years in celiac person-years in celiac Restricted Number of events Number of events in HR (95% CI) Restricted relatives to female FDRs relatives HR (95% CI) in celiac FDRs, n (%) control FDRs, n (%) to male FDRs
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Table 2. Risk of Developing Autoimmune Diseases in Celiac FDRs Compared With Control FDRs
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Autoimmunity in Celiac Relatives
disease in celiac FDRs excluding those FDRs who themselves had a diagnosis of CD was highly similar (HR, 1.30; 95% CI, 1.25–1.35). The excess risk of any autoimmune diseases was 79 per 100,000 person-years in FDRs (Table 2) vs 63 in spouses (Table 3). The HRs for autoimmune disease were not statistically significantly different between biological relatives and spouses (P ¼ .11 for the interaction term). The risk of developing nonceliac autoimmune disease was highest in the first 2 years after CD diagnosis in the index individuals (HR, 1.42; 95% CI, 1.28–1.57), with slightly lower HRs thereafter, although still remaining statistically significant (HR, 1.26; 95% CI, 1.21–1.31). Sex did not influence the risk of nonceliac autoimmunity in FDRs (females: HR, 1.26; 95% CI, 1.19–1.33; males: HR, 1.30; 95% CI, 1.23–1.38) (Table 2), but was higher in female spouses than in male spouses (females: HR, 1.33; 95% CI, 1.12–1.59; males: HR, 1.09; 95% CI, 0.92–1.29) (Table 3), potentially suggesting that wives to husbands with newly diagnosed CD may test themselves for autoimmune diseases, whereas men are less likely to seek medical attention when their wife has a newly diagnosed CD.
Different Autoimmune Diseases Celiac FDRs were at increased risk for all the autoimmune diseases examined in our study, with highest HRs for T1DM, sarcoidosis, and SLE (Table 2 and Figure 2). HRs were comparable when we requested 2 records of autoimmune disease (for diagnosis), except that the relative risk of UC failed to attain statistical significance (Supplementary Table). Furthermore, HRs increased when we examined nonceliac autoimmune disease recorded as the main diagnosis (Supplementary Table 1). The absolute risks ranged from 7 (SLE) to 94 (psoriasis) per 100,000 person-years (Table 2). Celiac spouses were at significantly increased risk for SLE and UC only (Table 3 and Figure 2). The increased
print & web 4C=FPO
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Figure 2. Risk of different autoimmune diseases in celiac FDRs (red) and celiac spouses (black).
5
risk of SLE in spouses was seen only in female spouses, whereas the excess risk of UC was noted in both male and female spouses (Table 3).
Different Categories of First-Degree Relatives The risk of any autoimmune disease was very similar across different categories of FDRs, although siblings and offspring were at a slightly higher risk than parents of celiac individuals (Table 4). The spectrum of autoimmune diseases differed somewhat between categories: an excess of Crohn’s disease was observed in offspring, whereas psoriasis was more prevalent in only brothers and sons of celiac individuals. SLE increased only in parents and sisters of celiac individuals (Table 4).
Discussion In this nationwide, population-based longitudinal cohort study we examined the risk of nonceliac autoimmune disease in celiac FDRs. All outcomes were more common in celiac FDRs than in control FDRs, and hence we found a significantly increased risk of our composite measure “any included nonceliac autoimmune disease” in celiac FDRs. The highest HRs were observed for SLE, T1DM, and sarcoidosis. Although these diseases have been linked to CD, the HRs in individuals with CD have been substantially higher than what we found in celiac FDRs (eg, SLE: HR, 3.4926 vs 1.81 in FDRs; T1DM: HR, 2.427 vs 1.65 in FDRs; sarcoidosis: HR, 4.0319 vs 1.60 in FDRs). The literature suggests a strong genetic predisposition in CD and that shared genetics tend to overlap with other autoimmune diseases.8 Therefore, genetics seems like a plausible explanation for the excess risk found in celiac FDRs. Genome-wide association studies have suggested shared genetics with T1DM, UC, RA, and Crohn’s disease.8 Taking this into account, the HRs for RA and UC in this study are surprisingly low; however, loci outside of the HLA loci confer a very small proportion of the genetic risk in CD. However, because certain nonceliac autoimmune diseases also were more common in celiac spouses, genetics may not be the only explanation of the associations reported in this study. Naturally, spouses do not share genetics with each other from inheritance. Instead, they share the environment and possibly microbiome with their husband/wife, which also might impact the risk of developing and diagnosing other autoimmune diseases. Some studies have suggested that mate selection might not be totally genetically random because major histocompatibility complex class I appears to be more similar than expected between spouses, whereas major histocompatibility complex class II seemingly shows significant dissimilarity between spouses.28 If so, this possibility might have contributed to our findings. Another explanation is ascertainment bias, that is, both celiac FDRs and celiac spouses are
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NOTE. Hazard ratios and 95% CIs are shown. Results shown in italics are significant. a Because T1DM was defined as a diagnosis of DM registered before age 30 years (and not more than 2 parents were diagnosed with DM before the age of 30 years and after study entry ¼ the date their child was diagnosed with CD), the number of events was insufficient for statistical calculations.
(1.43–2.18) (1.42–2.42) (1.18–2.29) (1.28–2.00) (1.19–2.07) (1.15–2.43)
1.25 1.14 1.34 1.33 1.36 1.34 1.34 1.35
(1.14–1.37) (1.05–1.23) (1.26–1.43) (1.21–1.46) (1.25–1.48) (1.24–1.45) (1.21–1.48) (1.21–1.50)
1.32 1.18 1.12 1.16 1.07 1.66 1.62 1.73
(0.95–1.83) (0.76–1.84) (0.87–1.43) (0.84–1.59) (0.73–1.58) (1.32–2.10) (1.21–2.19) (1.19–2.53)
1.13 1.40 1.24 1.16 1.36 1.05 1.03 1.09
(0.88–1.46) (1.00–1.90) (1.02–1.50) (0.91–1.49) (0.99–1.88) (0.84–1.30) (0.79–1.34) (0.74–1.61)
1.76 1.85 1.65 1.60 1.57 1.68
a
a
1.50 1.10 1.34 1.71 1.23 1.36 1.27 1.40
(1.09–2.06) (0.89–1.36) (1.09–1.64) (1.16–2.53) (0.96–1.56) (1.05–1.76) (0.78–2.06) (1.03–1.91)
1.56 1.25 1.47 1.32 1.52 1.48 1.34 1.54
(1.25–1.95) (1.11–1.41) (1.28–1.70) (0.97–1.81) (1.30–1.77) (1.23–1.79) (0.91–1.97) (1.24–1.91)
1.14 0.98 1.22 1.28 1.15 1.19 1.25 1.09
(0.99–1.32) (0.80–1.19) (1.09–1.37) (1.10–1.50) (0.97–1.38) (1.03–1.37) (1.05–1.50) (0.86–1.37)
1.00 0.92 1.23 1.20 1.24 1.45 1.71 1.28
(0.79–1.27) (0.76–1.12) (1.05–1.43) (0.93–1.54) (1.02–1.52) (1.19–1.76) (1.28–2.28) (0.98–1.66)
1.70 1.16 1.77 1.61 2.10 1.71 1.69 1.79
(1.21–2.40) (0.67–2.00) (1.27–2.47) (1.06–2.45) (1.21–3.63) (1.20–2.43) (1.13–2.52) (0.84–3.81)
2.31 1.99 2.00 1.94 2.02 1.51 1.75 1.44
(1.02–5.24) (1.20–3.29) (1.22–3.28) (0.61–6.19) (1.17–3.49) (0.83–2.73) (0.47–6.47) (0.74–2.82)
Clinical Gastroenterology and Hepatology Vol.
Fathers Mothers Siblings Brothers Sisters Offspring Sons Daughters
Sarcoidosis Rheumatoid arthritis Psoriasis Hyperthyroidism Hypothyroidism Type 1 diabetes mellitus Ulcerative colitis, HR Crohn’s disease Any autoimmune disease
Table 4. Risk of Autoimmune Disease in Different Categories of Celiac FDRs
581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638
Emilsson et al Systemic lupus erythematosus
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-,
No.
-
more likely to be diagnosed with whatever disease (although the true prevalence is not different) simply because they might be more prone to seek medical advice or that doctors who are aware of the CD in the index individual are more likely to investigate FDRs and spouses for autoimmunity. The fact that the risk was higher within the first 2 years of diagnosis vs more than 2 years after the diagnosis indicates that ascertainment bias is present to some extent and therefore might inflate the estimates. That wives are more likely to seek health care and seek consultation for autoimmune disease when their husbands have CD than the other way around might explain why the risk of nonceliac autoimmunity differed by sex in spouses but not in biological FDRs. FDRs also are likely to undergo CD testing more often than the general population. The prevalence of diagnosed CD in control FDRs was 0.3% compared with 2.1% in fathers to celiac individuals and 5.4% in siblings to celiac individuals, which reflects both a genetic predisposition and more active case finding. Compared with previous studies in which the prevalence of CD in celiac FDRs has been reported to be as high as 11%,10 our finding of 5.4% in siblings is not particularly high. The CD prevalence in relatives, however, should not have affected our estimates because all analyses were adjusted for the presence of CD in the FDR. Although we cannot rule out the existence of bias, several findings suggest that there is a true genetic risk of autoimmunity in FDRs. For instance, in male FDRs the risks of all autoimmune diseases (except UC) were increased significantly, whereas only the risk of UC was increased significantly in male spouses. Accordingly, genetic predisposition might be less important and a shared environment might be more important in the conferred risk of UC, whereas it is possibly vice versa for some other autoimmune diseases. In all analyses we adjusted for CD in the FDRs and spouses. However, we cannot preclude the possibility that a number of (especially) FDRs had undiagnosed CD. Undiagnosed CD, however, would reduce our risk estimates toward the null.
Strengths and Limitations The large population-based setting, the reliable diagnostic procedure of CD,15 and our ability to identify more than 80,000 FDRs through the Swedish MultiGeneration Register were the major strengths of this study. The reliability of autoimmune outcomes is likely to be high in that positive predictive values for most diseases in the Swedish Patient Register range from 85% to 95%.29 Furthermore, risk estimates did not change when we requested 2 recordings of autoimmune disease for our outcome or restricted our outcome to individuals with a main listing of autoimmune disease. Some of the diseases, especially hypothyroidism, might be covered insufficiently by the Patient Register because many individuals with this condition only seek primary health care. The fact that only approximately 3%
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697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754
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Autoimmunity in Celiac Relatives
of FDRs had a record of nonceliac autoimmune disease in our study indicates that some diagnoses managed mainly in primary care are missing. For instance, hypothyroidism alone is thought to occur in approximately 5% of the general population (and any autoimmune disease is thought to occur in approximately 7%–8%). Still, low sensitivity should not lead to differential bias unless celiac FDRs are more likely to seek inpatient care than control FDRs.
13. Cataldo F, Marino V. Increased prevalence of autoimmune diseases in first-degree relatives of patients with celiac disease. J Pediatr Gastroenterol Nutr 2003;36:470–473. 14. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992;102:330–354. 15. Ludvigsson JF, Brandt L, Montgomery SM, et al. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009;9:19. 16. Johannesson I. The Total Population Register of Statistics Sweden. New Possibilities and Better Quality. Statistics Sweden, 2002.
Conclusions
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We found an increased risk of nonceliac autoimmune disease in FDRs and celiac spouses. This risk probably represents a mixture of genetic, environmental, and ascertainment bias mechanisms.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2015.01.026.
References 1. Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009; 373:1480–1493. 2. Dube C, Rostom A, Sy R, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology 2005;128:S57–S67. 3. Greco L, Romino R, Coto I, et al. The first large population based twin study of coeliac disease. Gut 2002;50:624–628. 4. Green PH, Cellier C. Celiac disease. N Engl J Med 2007;357: 1731–1743. 5. Elfstrom P, Sundstrom J, Ludvigsson JF. Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes. Aliment Pharmacol Ther 2014;40:1123–1132. 6. Bao F, Yu L, Babu S, et al. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J Autoimmun 1999;13: 143–148. 7. Troncone R, Discepolo V. Celiac disease and autoimmunity. J Pediatr Gastroenterol Nutr 2014;59(Suppl 1):S9–S11. 8. Ricano-Ponce I, Wijmenga C. Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet 2013;14: 325–353. 9. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286–292. 10. Rubio-Tapia A, Van Dyke CT, Lahr BD, et al. Predictors of family risk for celiac disease: a population-based study. Clin Gastroenterol Hepatol 2008;6:983–987. 11. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology 2006; 131:1981–2002. 12. Neuhausen SL, Steele L, Ryan S, et al. Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives. J Autoimmun 2008;31:160–165.
17. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–1178. 18. Ekbom A. The Swedish Multi-generation Register. Methods Mol Biol 2011;675:215–220. 19. Ludvigsson JF, Wahlstrom J, Grunewald J, et al. Coeliac disease and risk of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2007;24:121–126. 20. Marild K, Fredlund H, Ludvigsson JF. Increased risk of hospital admission for influenza in patients with celiac disease: a nationwide cohort study in Sweden. Am J Gastroenterol 2010;105:2465–2473. 21. Elfstrom P, Montgomery SM, Kampe O, et al. Risk of primary adrenal insufficiency in patients with celiac disease. J Clin Endocrinol Metab 2007;92:3595–3598. 22. Olen O, Montgomery SM, Elinder G, et al. Increased risk of immune thrombocytopenic purpura among inpatients with coeliac disease. Scand J Gastroenterol 2008;43:416–422. 23. Ludvigsson JF, Elfstrom P, Broome U, et al. Celiac disease and risk of liver disease: a general population-based study. Clin Gastroenterol Hepatol 2007;5:63–69 e1. 24. Ludvigsson JF, Olsson T, Ekbom A, et al. A population-based study of coeliac disease, neurodegenerative and neuroinflammatory diseases. Aliment Pharmacol Ther 2007;25:1317–1327. 25. Gabrielli M, Candelli M, Franceschi F, et al. Primary autoimmune haemolytic anaemia and coeliac disease. Scand J Gastroenterol 2004;39:605–606. 26. Ludvigsson JF, Rubio-Tapia A, Chowdhary V, et al. Increased risk of systemic lupus erythematosus in 29,000 patients with biopsyverified celiac disease. J Rheumatol 2012;39:1964–1970. 27. Ludvigsson JF, Ludvigsson J, Ekbom A, et al. Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. Diabetes Care 2006; 29:2483–2488. 28. Khankhanian P, Gourraud PA, Caillier SJ, et al. Genetic variation in the odorant receptors family 13 and the MHC loci influence mate selection in a multiple sclerosis dataset. BMC Genomics 2010;11:626. 29. Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011;11:450. 30. Staii A, Mirocha S, Todorova-Koteva K, et al. Hashimoto thyroiditis is more frequent than expected when diagnosed by cytology which uncovers a pre-clinical state. Thyroid Res 2010;3:11. 31. Elfstrom P, Montgomery SM, Kampe O, et al. Risk of thyroid disease in individuals with celiac disease. J Clin Endocrinol Metab 2008;93:3915–3921. 32. Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury,
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traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil 2014;95:986–995.e1. 33. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011; 365:1713–1725. 34. Peters U, Askling J, Gridley G, et al. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch Intern Med 2003;163:1566–1572. 35. Chakravarty EF, Bush TM, Manzi S, et al. Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data. Arthritis Rheum 2007;56:2092–2094. 36. Ronnblom A, Samuelsson SM, Ekbom A. Ulcerative colitis in the county of Uppsala 1945-2007: incidence and clinical characteristics. J Crohns Colitis 2010;4:532–536. 37. Braathen LR, Botten G, Bjerkedal T. Prevalence of psoriasis in Norway. Acta Derm Venereol Suppl (Stockh) 1989;142:5–8. 38. Ludvigsson JF, Lindelof B, Zingone F, et al. Psoriasis in a nationwide cohort study of patients with celiac disease. J Invest Dermatol 2011;131:2010–2016.
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871 872 873 874 40. Devereaux D, Tewelde SZ. Hyperthyroidism and thyrotoxicosis. 875 Emerg Med Clin North Am 2014;32:277–292. 876 877 878 879 Reprint requests Address requests for reprints to: Louise Emilsson, MD, Vårdcentralen Värm880 lands Nysäter, Nyströms väg 5, 66195 Värmlands Nysäter, Sweden. e-mail: Q2Q3 881 [email protected]; fax: (46) (0) 533-30214. Q4 882 Q5 Acknowledgments 883 This project (2006/633-31/3) was approved by the Research Ethics Committee 884 of the Karolinska Institutet, Sweden, on June 14, 2006. 885 Conflicts of interest Q6 886 The authors disclose no conflicts. 887 888 Funding Q7 This study was funded by the Swedish Research Council. 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 39. Karvonen M, Viik-Kajander M, Moltchanova E, et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23:1516–1526.
FLA 5.2.0 DTD YJCGH54156_proof 20 March 2015 9:05 pm ce DVC
8.e1
Q27
Autoimmunity in Celiac Relatives
Crohn’s disease Ulcerative colitis Type 1 diabetes mellitus Hyperthyroidism Hypothyroidism Psoriasis Rheumatoid arthritis Sarcoidosis Systematic lupus erythematosus
120040
140037
Disease
27
39
25 1936
Supplementary Table 2. Risk of Having at Least Two Listings of Autoimmune Disease in Celiac FDRs Versus Control FDRs 2 listings of autoimmune diagnosis
Main diagnosis of autoimmune disease
HR (95% CI)
HR (95% CI)
1.30 1.12 1.59 1.25 1.38 1.17 1.17 1.65 2.02
(1.09–1.57) (0.97–1.29) (1.35–1.88) (1.08–1.46) (1.24–1.55) (1.06–1.29) (1.04–1.30) (1.32–2.06) (1.46–2.80)
1.31 1.18 1.64 1.29 1.59 1.16 1.16 1.76 1.77
(1.12–1.52) (1.04–1.33) (1.40–1.93) (1.12–1.47) (1.35–1.87) (1.07–1.25) (1.05–1.29) (1.44–2.15) (1.28–2.45)
L40 E10 (age, <30 y) E05 696 250 (age, <30 y) 242
ICD, International Classification of Diseases.
696 250 (age, <30 y) 242 706 260 (age, <30 y) 252 Psoriasis Type 1 diabetes mellitus Grave’s/hyperthyroidism
705.4 572.00, 572.09
734.1 563.00
710A 555
M32 K50
NOTE. HRs were adjusted for age group, calendar year, presence of CD, and sex of the relative.
Systemic lupus erythematosus Crohn’s disease
12,000 10,00032 24633 41 20
30
719
D86 E00–E03, E06.3 M05, M06, M08.0, M08.2 K51 135 245C, 243, 244 714, excluded 714E, 714X 556 135 245.1, 243, 244 712.1, 712.3 563.10, 569.02 138.00–138.10 253 722, excluded 722.1 572.20, 572.21 Sarcoidosis Hashimoto’s/ hypothyroidism Rheumatoid arthritis Ulcerative colitis
15035
4.0 (2.3–7.0)19 4.4 (3.4–5.6)31 Unpublished data Increased SMR compared with controls34 3.5 (2.5–4.9)26 Increased SMR compared with controls34 1.7 (1.5–1.9)38 2.4 (1.9–3.0)27 2.9 (2.0–4.1)31
Celiac association HR (95% CI) Prevalence/ 100,000 Incidence/ 100,000 ICD-10 ICD-9 ICD-8 ICD-7 Autoimmune condition
Supplementary Table 1. ---
929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991
2015
Q26
-
FLA 5.2.0 DTD YJCGH54156_proof 20 March 2015 9:05 pm ce DVC
992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054