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Clinical and Experimental Immunology
O R I G I N A L A RT I C L E
doi:10.1111/cei.12395
Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity
K. A. Ponto,*† D. Schuppan,‡ I. Zwiener,†§ H. Binder,§ A. Mirshahi,* T. Diana,‡ S. Pitz,* N. Pfeiffer* and G. J. Kahaly‡ Departments of *Ophthalmology, ‡Medicine I, § Biostatistics, and †Center of Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany
Accepted for publication 28 May 2014 Correspondence: G. J. Kahaly, Johannes Gutenberg University Medical Center, Langenbeckstreet 1, Mainz 55131, Germany. E-mail: [email protected]
Summary Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves’ disease (GD) and n = 533, 41% with Hashimoto’s thyroiditis (HT)] followed at a specialized joint thyroid–eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison’s disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison’s disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren’s syndrome were ‘protective’ for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison’s disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO. Keywords: autoimmune co-morbidity, autoimmune gastritis, autoimmune thyroid diseases, coeliac disease, thyroid-associated orbitopathy
Introduction Autoimmune thyroid diseases (AITD) encompass Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Their prevalence is fivefold higher in females than in males [1,2]. Diagnosis of AITD is based on clinical features, thyroid sonography and tests for anti-thyroid autoantibodies [3,4]. Thyroid-associated orbitopathy (TAO) is the most prevalent extrathyroidal manifestation of AITD [2,4,5] Common autoimmune disorders tend to co-exist in the same subjects, and cluster in families [6]. For GD and HT it has been shown that the relative risk of nearly all other rel-
evant autoimmune diseases is increased significantly [7]. However, clustering of associated autoimmunity is different between HT and GD [8]. The exact aetiology of the deregulated immune response of the thyroid in patients with AITD is still unknown, but patients usually have a complex genetic predisposition [e.g. human leucocyte antigen (HLA)-DR3/DR4 or HLA-DQ2/DQ8] [9]. Patients with AITD may also be affected by other autoimmune endocrine diseases [10], such as type 1 diabetes and autoimmune type A gastritis [6], but coeliac disease has also been frequently observed [11,12]. The aetiopathogenesis of AITD is multifactorial [13], and additional endogenous hormonal and
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 57–64
57
K. A. Ponto et al.
various exogenous factors are suspected triggers of disease manifestation. Exogenous factors comprise environmental influences such as smoking, iodine intake and infections [14]. The objective of this study was to provide data on the association between TAO versus non-TAO in consecutive and unselected patients with AITD and the prevalence of other autoimmune endocrine and non-endocrine diseases. We hypothesized that these different manifestations of AITD, affecting the periorbital extracellular matrix in GD, should be reflected by a variant spectrum of associated autoimmune co-morbidity.
Methods The medical records or files of 1310 consecutive unselected patients with AITD (n = 777 with GD and n = 533 with HT) were analysed within this retrospective cross-sectional study. No matching was performed. All patients were followed on a regular basis at a specialized out-patient clinic for autoimmune (endocrine) diseases of the Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany, between January 1999 and July 2012. The primary outcome measure was the prevalence of associated autoimmunity in patients with AITD with and without orbital disease. Complete endocrine investigation was performed in all patients; all patients were subsequently screened for signs and symptoms of orbital involvement. In the presence of clinical signs, patients were managed at our combined thyroid–eye clinic or (in the presence of a mild and inactive TAO) were seen by an ophthalmologist close to their home town on a regular basis. Diagnosis and clinical evaluation of TAO were performed according to the consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) [15,16]. A comprehensive interview regarding their medical history was performed, and blood samples were drawn for both functional and autoantibody testing in all patients. The standard reference ranges of the JGU Central Laboratory were used as cut-offs. Whenever suspected and if clinically indicated (positive autoantibodies and/or suggestive symptoms), endocrine function tests, measurement of specific autoantibodies and/or additional diagnostics (e.g. endoscopy of the gastrointestinal tract and/or magnetic resonance imaging) were performed. Data acquisition from patients with AITD was performed using standardized clinical and laboratory diagnostic criteria. The patients had clinically and biochemically confirmed AITD, either GD or HT. Cases that could not be defined clearly as GD or HT were not included into the analysis. A thyroid ultrasound was performed in all subjects with thyroid dysfunction, specific autoantibodies and in patients with a (family) history for thyroid diseases. The presence of thyroid stimulating hormone (TSH) receptor blocking autoantibodies (TBAb) in patients with HT was evaluated as published previously [17]. 58
The definitions and diagnostic criteria of the various autoimmune diseases are listed in Table 1. All subjects were tested for all autoimmune diseases that are listed in this table. The adult autoimmune polyglandular syndrome encompassed type II (Addison’s disease with another autoimmune endocrine disorder), type III (autoimmune thyroid disease and type 1 diabetes) as well as type IV (two autoimmune endocrine disorders excluding types I–III). The protocol was consistent with the principles of the Declaration of Helsinki. Because this study was observational, did not include any interventions aside from those commonly falling within the daily routine, and because no decoded patient-related data were passed to third parties, the responsible Ethics Committee of the Medical Association of the State Rhineland Palatinate, Germany, decided that no approval was required.
Statistical analyses Statistical analyses were performed using spss (Statistical Package for the Social Sciences, version 18; SPSS Inc., Chicago, IL, USA). A χ2 test was used to calculate dependencies between two categorical variables. A binary regression analysis was used for multivariable analysis yielding odds ratios (OR), 95% confidence-intervals (OR and P-values, respectively). None of the autoimmune diseases was defined as the primary outcome measure, so all analyses that were performed were exploratory. No significance level was fixed.
Results Demographic data and associated co-morbidities Of 1310 consecutive and unselected patients with AITD followed regularly at the autoimmune out-patient clinic, a total of 777 had GD (59%) and 533 (41%) had HT. Of these 1310 AITD patients, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome (APS types II–IV), 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) autoimmune type A gastritis, 57 (4·4%) vitiligo and 25 (1·9%) had Addison’s disease. Listed in Table 2 are all associated autoimmune endocrine and non-endocrine diseases observed in patients with GD and HT. A positive association with GD was found for coeliac disease and for autoimmune gastritis, whereas type I diabetes, Addison’s disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis, autoimmune hepatitis and Sjögren’s syndrome were linked to HT.
Comparison of co-morbidities in patients with and without thyroid-associated orbitopathy Of 1310 patients with AITD, 610 (46·6%) had symptoms and signs of overt TAO and 700 (53·4%) did not have any orbital involvement. Median (range) age of patients with
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 57–64
Autoimmune co-morbidity in TAO Table 1. Definitions and diagnostic criteria of the various autoimmune diseases. Endocrine autoimmune diseases Graves’ disease
Hyperthyroidism, presence of thyroid-stimulating hormone (TSH) receptor autoantibodies, typical thyroid ultrasound pattern with enhanced vascularization of the thyroid gland Hashimoto’s thyroiditis At least fivefold increased serum level of thyroid peroxidase autoantibodies, a typical hypoechoic ultrasound pattern, and eu- or hypothyroidism Type I diabetes mellitus Insulin dependency; positive autoantibodies against the islet cell antigens and/or tyrosine phosphatase IA-2 (IA2A) and/or insulin (IAA) and/or glutamic acid decarboxylase-65 (GADA), a pathological serum glycaemic haemoglobin > 6·5% and fasting serum glucose > 120 mg/dl Addison’s disease Suppressed baseline serum cortisol levels ( 50 pg/ml) and the presence of cytochrome P450-21 hydroxylase autoantibodies Autoimmune primary Serum baseline parathyroid hormone levels < 15 pg/ml with positive anti-calcium-sensing receptor hypoparathyroidism autoantibodies, baseline serum calcium < 2 mmol/l and elevated serum phosphate levels > 5 mg/dl Autoimmune primary Suppressed serum peripheral sexual hormone levels, elevated serum gonadotrophic hormone levels hypogonadism (FSH > 15 IU/l, LH > 10 IU/l, pathological luteinizing hormone-releasing hormone stimulation test (delta FSH and LH > 10 IU/l) and positive 17-hydroxylase autoantibodies Autoimmune diseases of the gastrointestinal tract Coeliac disease Presence of serum immunoglobulin (Ig)A (in case of IgA-deficiency IgG) autoantibodies to tissue transglutaminase and histological confirmation by Marsh stage III (endoscopic biopsy of the small bowel) Autoimmune type A gastritis Presence of gastric parietal cell autoantibodies with histological atrophy of the gastric mucosa and intestinal metaplasia Autoimmune hepatitis Elevated anti-nuclear and/or anti-alpha smooth muscle actin or anti-soluble liver antigen antibodies in the presence of usually ≥2-fold elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values and subsequent histological confirmation Dermatological autoimmune diseases Vitiligo Clinical inspection Alopecia Clinical picture and root hair analysis Urticaria Clinical phenotype Further autoimmune diseases Rheumatoid arthritis Clinical criteria (e.g. morning stiffness); laboratory tests: positive rheumatoid factor and cyclic citrullinated peptide (CCP) Sjögren′s Syndrome Dry eye syndrome and positive anti-SS-A-and SS-B-antibodies. If clinically required an additional positive biopsy of the salivary gland was performed Systemic lupus erythematosus Presence of DNS and ds-DNS- and anti-smooth-muscle antibodies together with a classical phenotype Scleroderma Clinical phenotype and biopsy; laboratory tests: positive serum anti-nuclear, anti-SCL 70 and anti-centromere autoantibodies Sarcoidosis Laboratory tests: elevated angiotensin converting enzyme (ACE), elevated blood sedimentation rate; clinical and radiological criteria, i.e. swelling of lymph nodes and lung fibrosis Myasthenia gravis Positive serum acetylcholine receptor autoantibodies, Simpson’s (ice-pack) test and tensilon test
and without TAO was 50 years (4–85·5 years) and 43 years (4–83), respectively. Of patients with TAO, 491 of 610 (80·5%) were females versus 576 of 700 (82·3%) in nonTAO. The rate of smokers was 30 and 29·3% of patients with versus without TAO. TAO was far more prevalent in patients with GD than in those with HT: 584 (95·7%) and 26 (4·3%) of the patients with GD and HT had TAO (P < 0·001), respectively. The same holds true for autoimmune diseases of the gastrointestinal tract, namely coeliac disease and autoimmune type A gastritis (Fig. 1). TSH receptor-blocking autoantibodies (TBAb) were positive in 133 of 533 (25%) patients with HT. Of these TBAb-positive patients, nine (6·8%) had coeliac disease versus 18 of 400 (4·5%) TBAb-negative HT patients (P = 0·302). Smoking was not associated with the presence
of coeliac disease in TAO, as 59 of 72 (81·9%) patients with TAO and coeliac disease were non-smokers (P = 0·019). Complete and detailed ophthalmic findings were available in a large subgroup of patients. Almost all patients with coeliac disease and TAO (23 of 24, 96%) had diplopia, of whom five (42%) showed constant diplopia. In 18 (75%) of these patients, a moderate-to-severe TAO was present. In contrast, in 10 of 15 cases (67%), patients with type 1 diabetes had a mild TAO and constant diplopia in one (7%) patient only. However, there were no statistically significant differences pertaining to ophthalmic findings between the various groups. Table 3 illustrates the frequencies of the different co-morbidities in AITD patients with and without TAO. A higher rate of TAO was found, especially in GD patients
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 57–64
59
K. A. Ponto et al. Table 2. Associated autoimmune diseases in patients with autoimmune thyroid diseases. Frequencies of co-morbidities in patients with Graves’ disease and Hashimoto’s thyroiditis, respectively, with P-values according to χ2 test and odds ratios (ORs), 95% confidence intervals (CIs) and P-values according to binary logistic regression analysis. ORs >1 indicate a positive association with ‘Graves’ disease.
Coeliac disease Autoimmune type A gastritis Autoimmune hepatitis Type 1 diabetes Addison’s disease Primary hypogonadism Primary hypopara-thyroidism Alopecia areata Vitiligo Rheumatoid arthritis Sjögren’s syndrome Systemic lupus erythematosus Sarcoidosis Scleroderma Myasthenia gravis
Frequency in 777 patients with Graves’ disease n (%)
Frequency in 533 patients with Hashimoto’s thyroiditis n (%)
P-value (χ2 test)
84 (10·8) 53 (6·8) 3 (0·4) 55 (7·1) 2 (0·3) 11 (1·4) 1 (0·1) 11 (1·4) 27 (3·5) 12 (1·5) 13 (1·7) 5 (0·6) 3 (0·4) 1 (0·1) 4 (0·5)
27 (5·0) 7 (1·3) 9 (1·7) 74 (13·8) 23 (4·3) 25 (4·7) 3 (0·6) 29 (5·4) 30 (5·6) 18 (3·4) 26 (4·9) 10 (1·9) 1 (0·2) 2 (0·4) 0
Clinical and Experimental Immunology
O R I G I N A L A RT I C L E
doi:10.1111/cei.12395
Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity
K. A. Ponto,*† D. Schuppan,‡ I. Zwiener,†§ H. Binder,§ A. Mirshahi,* T. Diana,‡ S. Pitz,* N. Pfeiffer* and G. J. Kahaly‡ Departments of *Ophthalmology, ‡Medicine I, § Biostatistics, and †Center of Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany
Accepted for publication 28 May 2014 Correspondence: G. J. Kahaly, Johannes Gutenberg University Medical Center, Langenbeckstreet 1, Mainz 55131, Germany. E-mail: [email protected]
Summary Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves’ disease (GD) and n = 533, 41% with Hashimoto’s thyroiditis (HT)] followed at a specialized joint thyroid–eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison’s disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison’s disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren’s syndrome were ‘protective’ for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison’s disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO. Keywords: autoimmune co-morbidity, autoimmune gastritis, autoimmune thyroid diseases, coeliac disease, thyroid-associated orbitopathy
Introduction Autoimmune thyroid diseases (AITD) encompass Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Their prevalence is fivefold higher in females than in males [1,2]. Diagnosis of AITD is based on clinical features, thyroid sonography and tests for anti-thyroid autoantibodies [3,4]. Thyroid-associated orbitopathy (TAO) is the most prevalent extrathyroidal manifestation of AITD [2,4,5] Common autoimmune disorders tend to co-exist in the same subjects, and cluster in families [6]. For GD and HT it has been shown that the relative risk of nearly all other rel-
evant autoimmune diseases is increased significantly [7]. However, clustering of associated autoimmunity is different between HT and GD [8]. The exact aetiology of the deregulated immune response of the thyroid in patients with AITD is still unknown, but patients usually have a complex genetic predisposition [e.g. human leucocyte antigen (HLA)-DR3/DR4 or HLA-DQ2/DQ8] [9]. Patients with AITD may also be affected by other autoimmune endocrine diseases [10], such as type 1 diabetes and autoimmune type A gastritis [6], but coeliac disease has also been frequently observed [11,12]. The aetiopathogenesis of AITD is multifactorial [13], and additional endogenous hormonal and
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 57–64
57
K. A. Ponto et al.
various exogenous factors are suspected triggers of disease manifestation. Exogenous factors comprise environmental influences such as smoking, iodine intake and infections [14]. The objective of this study was to provide data on the association between TAO versus non-TAO in consecutive and unselected patients with AITD and the prevalence of other autoimmune endocrine and non-endocrine diseases. We hypothesized that these different manifestations of AITD, affecting the periorbital extracellular matrix in GD, should be reflected by a variant spectrum of associated autoimmune co-morbidity.
Methods The medical records or files of 1310 consecutive unselected patients with AITD (n = 777 with GD and n = 533 with HT) were analysed within this retrospective cross-sectional study. No matching was performed. All patients were followed on a regular basis at a specialized out-patient clinic for autoimmune (endocrine) diseases of the Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany, between January 1999 and July 2012. The primary outcome measure was the prevalence of associated autoimmunity in patients with AITD with and without orbital disease. Complete endocrine investigation was performed in all patients; all patients were subsequently screened for signs and symptoms of orbital involvement. In the presence of clinical signs, patients were managed at our combined thyroid–eye clinic or (in the presence of a mild and inactive TAO) were seen by an ophthalmologist close to their home town on a regular basis. Diagnosis and clinical evaluation of TAO were performed according to the consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) [15,16]. A comprehensive interview regarding their medical history was performed, and blood samples were drawn for both functional and autoantibody testing in all patients. The standard reference ranges of the JGU Central Laboratory were used as cut-offs. Whenever suspected and if clinically indicated (positive autoantibodies and/or suggestive symptoms), endocrine function tests, measurement of specific autoantibodies and/or additional diagnostics (e.g. endoscopy of the gastrointestinal tract and/or magnetic resonance imaging) were performed. Data acquisition from patients with AITD was performed using standardized clinical and laboratory diagnostic criteria. The patients had clinically and biochemically confirmed AITD, either GD or HT. Cases that could not be defined clearly as GD or HT were not included into the analysis. A thyroid ultrasound was performed in all subjects with thyroid dysfunction, specific autoantibodies and in patients with a (family) history for thyroid diseases. The presence of thyroid stimulating hormone (TSH) receptor blocking autoantibodies (TBAb) in patients with HT was evaluated as published previously [17]. 58
The definitions and diagnostic criteria of the various autoimmune diseases are listed in Table 1. All subjects were tested for all autoimmune diseases that are listed in this table. The adult autoimmune polyglandular syndrome encompassed type II (Addison’s disease with another autoimmune endocrine disorder), type III (autoimmune thyroid disease and type 1 diabetes) as well as type IV (two autoimmune endocrine disorders excluding types I–III). The protocol was consistent with the principles of the Declaration of Helsinki. Because this study was observational, did not include any interventions aside from those commonly falling within the daily routine, and because no decoded patient-related data were passed to third parties, the responsible Ethics Committee of the Medical Association of the State Rhineland Palatinate, Germany, decided that no approval was required.
Statistical analyses Statistical analyses were performed using spss (Statistical Package for the Social Sciences, version 18; SPSS Inc., Chicago, IL, USA). A χ2 test was used to calculate dependencies between two categorical variables. A binary regression analysis was used for multivariable analysis yielding odds ratios (OR), 95% confidence-intervals (OR and P-values, respectively). None of the autoimmune diseases was defined as the primary outcome measure, so all analyses that were performed were exploratory. No significance level was fixed.
Results Demographic data and associated co-morbidities Of 1310 consecutive and unselected patients with AITD followed regularly at the autoimmune out-patient clinic, a total of 777 had GD (59%) and 533 (41%) had HT. Of these 1310 AITD patients, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome (APS types II–IV), 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) autoimmune type A gastritis, 57 (4·4%) vitiligo and 25 (1·9%) had Addison’s disease. Listed in Table 2 are all associated autoimmune endocrine and non-endocrine diseases observed in patients with GD and HT. A positive association with GD was found for coeliac disease and for autoimmune gastritis, whereas type I diabetes, Addison’s disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis, autoimmune hepatitis and Sjögren’s syndrome were linked to HT.
Comparison of co-morbidities in patients with and without thyroid-associated orbitopathy Of 1310 patients with AITD, 610 (46·6%) had symptoms and signs of overt TAO and 700 (53·4%) did not have any orbital involvement. Median (range) age of patients with
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 57–64
Autoimmune co-morbidity in TAO Table 1. Definitions and diagnostic criteria of the various autoimmune diseases. Endocrine autoimmune diseases Graves’ disease
Hyperthyroidism, presence of thyroid-stimulating hormone (TSH) receptor autoantibodies, typical thyroid ultrasound pattern with enhanced vascularization of the thyroid gland Hashimoto’s thyroiditis At least fivefold increased serum level of thyroid peroxidase autoantibodies, a typical hypoechoic ultrasound pattern, and eu- or hypothyroidism Type I diabetes mellitus Insulin dependency; positive autoantibodies against the islet cell antigens and/or tyrosine phosphatase IA-2 (IA2A) and/or insulin (IAA) and/or glutamic acid decarboxylase-65 (GADA), a pathological serum glycaemic haemoglobin > 6·5% and fasting serum glucose > 120 mg/dl Addison’s disease Suppressed baseline serum cortisol levels ( 50 pg/ml) and the presence of cytochrome P450-21 hydroxylase autoantibodies Autoimmune primary Serum baseline parathyroid hormone levels < 15 pg/ml with positive anti-calcium-sensing receptor hypoparathyroidism autoantibodies, baseline serum calcium < 2 mmol/l and elevated serum phosphate levels > 5 mg/dl Autoimmune primary Suppressed serum peripheral sexual hormone levels, elevated serum gonadotrophic hormone levels hypogonadism (FSH > 15 IU/l, LH > 10 IU/l, pathological luteinizing hormone-releasing hormone stimulation test (delta FSH and LH > 10 IU/l) and positive 17-hydroxylase autoantibodies Autoimmune diseases of the gastrointestinal tract Coeliac disease Presence of serum immunoglobulin (Ig)A (in case of IgA-deficiency IgG) autoantibodies to tissue transglutaminase and histological confirmation by Marsh stage III (endoscopic biopsy of the small bowel) Autoimmune type A gastritis Presence of gastric parietal cell autoantibodies with histological atrophy of the gastric mucosa and intestinal metaplasia Autoimmune hepatitis Elevated anti-nuclear and/or anti-alpha smooth muscle actin or anti-soluble liver antigen antibodies in the presence of usually ≥2-fold elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values and subsequent histological confirmation Dermatological autoimmune diseases Vitiligo Clinical inspection Alopecia Clinical picture and root hair analysis Urticaria Clinical phenotype Further autoimmune diseases Rheumatoid arthritis Clinical criteria (e.g. morning stiffness); laboratory tests: positive rheumatoid factor and cyclic citrullinated peptide (CCP) Sjögren′s Syndrome Dry eye syndrome and positive anti-SS-A-and SS-B-antibodies. If clinically required an additional positive biopsy of the salivary gland was performed Systemic lupus erythematosus Presence of DNS and ds-DNS- and anti-smooth-muscle antibodies together with a classical phenotype Scleroderma Clinical phenotype and biopsy; laboratory tests: positive serum anti-nuclear, anti-SCL 70 and anti-centromere autoantibodies Sarcoidosis Laboratory tests: elevated angiotensin converting enzyme (ACE), elevated blood sedimentation rate; clinical and radiological criteria, i.e. swelling of lymph nodes and lung fibrosis Myasthenia gravis Positive serum acetylcholine receptor autoantibodies, Simpson’s (ice-pack) test and tensilon test
and without TAO was 50 years (4–85·5 years) and 43 years (4–83), respectively. Of patients with TAO, 491 of 610 (80·5%) were females versus 576 of 700 (82·3%) in nonTAO. The rate of smokers was 30 and 29·3% of patients with versus without TAO. TAO was far more prevalent in patients with GD than in those with HT: 584 (95·7%) and 26 (4·3%) of the patients with GD and HT had TAO (P < 0·001), respectively. The same holds true for autoimmune diseases of the gastrointestinal tract, namely coeliac disease and autoimmune type A gastritis (Fig. 1). TSH receptor-blocking autoantibodies (TBAb) were positive in 133 of 533 (25%) patients with HT. Of these TBAb-positive patients, nine (6·8%) had coeliac disease versus 18 of 400 (4·5%) TBAb-negative HT patients (P = 0·302). Smoking was not associated with the presence
of coeliac disease in TAO, as 59 of 72 (81·9%) patients with TAO and coeliac disease were non-smokers (P = 0·019). Complete and detailed ophthalmic findings were available in a large subgroup of patients. Almost all patients with coeliac disease and TAO (23 of 24, 96%) had diplopia, of whom five (42%) showed constant diplopia. In 18 (75%) of these patients, a moderate-to-severe TAO was present. In contrast, in 10 of 15 cases (67%), patients with type 1 diabetes had a mild TAO and constant diplopia in one (7%) patient only. However, there were no statistically significant differences pertaining to ophthalmic findings between the various groups. Table 3 illustrates the frequencies of the different co-morbidities in AITD patients with and without TAO. A higher rate of TAO was found, especially in GD patients
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 57–64
59
K. A. Ponto et al. Table 2. Associated autoimmune diseases in patients with autoimmune thyroid diseases. Frequencies of co-morbidities in patients with Graves’ disease and Hashimoto’s thyroiditis, respectively, with P-values according to χ2 test and odds ratios (ORs), 95% confidence intervals (CIs) and P-values according to binary logistic regression analysis. ORs >1 indicate a positive association with ‘Graves’ disease.
Coeliac disease Autoimmune type A gastritis Autoimmune hepatitis Type 1 diabetes Addison’s disease Primary hypogonadism Primary hypopara-thyroidism Alopecia areata Vitiligo Rheumatoid arthritis Sjögren’s syndrome Systemic lupus erythematosus Sarcoidosis Scleroderma Myasthenia gravis
Frequency in 777 patients with Graves’ disease n (%)
Frequency in 533 patients with Hashimoto’s thyroiditis n (%)
P-value (χ2 test)
84 (10·8) 53 (6·8) 3 (0·4) 55 (7·1) 2 (0·3) 11 (1·4) 1 (0·1) 11 (1·4) 27 (3·5) 12 (1·5) 13 (1·7) 5 (0·6) 3 (0·4) 1 (0·1) 4 (0·5)
27 (5·0) 7 (1·3) 9 (1·7) 74 (13·8) 23 (4·3) 25 (4·7) 3 (0·6) 29 (5·4) 30 (5·6) 18 (3·4) 26 (4·9) 10 (1·9) 1 (0·2) 2 (0·4) 0
