ORIGINAL
ARTICLE
Organ Specificity in Autoimmune Diseases: Thyroid and Islet Autoimmunity in Alopecia Areata Shinsuke Noso,* Choongyong Park,* Naru Babaya, Yoshihisa Hiromine, Takeshi Harada, Hiroyuki Ito, Yasunori Taketomo, Kousei Kanto, Naoki Oiso, Akira Kawada, Tamio Suzuki, Yumiko Kawabata, and Hiroshi Ikegami Department of Endocrinology, Metabolism and Diabetes (S.N., C.P., N.B., Y.H., T.H., H.I., Y.T., K.K., Y.K., H.I.), Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan; Department of Dermatology (N.O., A.K.), Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan; and Department of Dermatology (T.S.), Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
Context: Multiple autoimmune diseases, such as autoimmunity against the thyroid gland and pancreatic islets, are often observed in a single patient. Although alopecia areata (AA) is one of the most frequent organ-specific autoimmune diseases, the association of AA with other autoimmune diseases and the genetic basis of the association remain to be analyzed. Objective: The aim of this study was to clarify the similarities and differences in HLA and clinical characteristics of thyroid and islet autoimmunity in patients with AA. Participants: A total of 126 patients with AA were newly recruited. Anti-islet and antithyroid autoantibodies were tested, and genotypes of HLA genes were determined. Results: Among the autoimmune diseases associated with AA, autoimmune thyroid disease was most frequent (10.0%), followed by vitiligo (2.7%) and rheumatoid arthritis (0.9%) but not type 1 diabetes (0.0%). The prevalence of thyroid-related autoantibodies in patients with AA was significantly higher than that in controls (TSH receptor antibody [TRAb]: 42.7% vs 1.2%, P ⫽ 1.6 ⫻ 10⫺46; thyroid peroxidase antibody: 29.1% vs 11.6%; P ⫽ 1.7 ⫻ 10⫺6), whereas the prevalence of islet-related autoantibodies was comparable between patients with AA and control subjects. The frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, was significantly higher in TRAb-positive (12.8%, P ⫽ .0028, corrected P value [Pc] ⫽ .02) but not TRAbnegative (7.1%, not significant) patients with AA than in control subjects (4.5%). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, was significantly lower in patients with AA (TRAb-positive: 8.5%; TRAb-negative: 11.9%) than in those with type 1 diabetes (29.5%, Pc ⬍ .0003 and Pc ⬍ .0008, respectively). Conclusion: AA was associated with thyroid autoimmunity but not islet autoimmunity, which correlated with class II HLA haplotypes susceptible or resistant to each autoimmune disease. (J Clin Endocrinol Metab 100: 1976 –1983, 2015)
rgan-specific autoimmune diseases against multiple target organs, such as type 1 diabetes and autoimmune thyroid disease (AITD), are often observed in a single patient (1), suggesting common etiology and genetic
O
susceptibility shared among different autoimmune diseases. Both type 1 diabetes (2) and AITD (Graves disease, and Hashimoto thyroiditis) (3) are multifactorial diseases, caused by exposure to environmental factors in genetically
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received November 3, 2014. Accepted February 26, 2015. First Published Online March 3, 2015
* S.N. and C.P. contributed equally to the study. Abbreviations: AITD, autoimmune thyroid disease; CI, confidence interval; GAD, glutamic acid decarboxylase; GAD Ab, glutamic acid decarboxylase antibody; IA-2 Ab, insulinomaassociated antigen 2 autoantibody; IAA, insulin autoantibody; NS, not significant; OR, odds ratio; RA, rheumatoid arthritis; rh, recombinant human; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TRAb, TSH (thyrotropin) receptor antibody.
1976
jcem.endojournals.org
J Clin Endocrinol Metab, May 2015, 100(5):1976 –1983
doi: 10.1210/jc.2014-3985
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doi: 10.1210/jc.2014-3985
susceptible individuals. Type 1 diabetes is caused by “islet autoimmunity” characterized by specific infiltration of lymphocytes into pancreatic islets (4). Patients with type 1 diabetes frequently develop other organ-specific autoimmune diseases, of which AITD is the most frequent disorder (5, 6). We previously reported a high prevalence of islet autoimmunity in patients with AITD, as indicated by high positivity of glutamic acid decarboxylase antibody (GAD Ab) and high frequencies of type 1 diabetes-susceptible HLA haplotypes (7). All of these observations suggest a common etiology and genetic basis for islet and thyroid autoimmunity. Identification of the mechanisms and genes shared among different autoimmune diseases will provide important information on the common etiological pathways of autoimmune diseases, leading to effective methods for prevention and intervention in autoimmune diseases. Alopecia areata, which is characterized by specific infiltration of lymphocytes into the hair follicles, leading to hair loss, is one of the most frequent organ-specific autoimmune diseases. The overall incidence of alopecia areata is 20.2 per 100 000 person-years, and the lifetime risk was estimated to be 1.7% (1,700 per 100 000) as reported in a survey of hospital- and nonhospital-based data in the United States (8, 9). The autoimmune mechanisms as the basis for alopecia areata have emerged from accumulating lines of evidence. Hair follicles are protected from immune reaction due to lack of expression of HLA class I molecules under normal conditions (10). Despite this “immune privilege” around hair follicles, patients with alopecia areata show infiltration of lymphocytes, including T cells and natural killer cells, into hair follicles (11). Melanocytes were considered to be one of the candidates for target cells in alopecia areata (12), but specific autoantibodies have not been identified thus far. Patients with alopecia areata are also known to develop other autoimmune diseases, such as autoimmune thyroiditis, rheumatoid arthritis (RA), and vitiligo (9, 13, 14). However, the clinical and genetic characteristics of autoimmunity associated with alopecia areata are largely unknown. As a part of an ongoing project to clarify common etiology and genetic susceptibility shared among different autoimmune diseases, we studied the clinical and genetic characteristics of thyroid and islet autoimmunity in patients with alopecia areata.
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1977
tients with alopecia areata, for 110 patients data on detailed clinical characteristics, such as age, age at onset, duration of disease, other autoimmune diseases, and thyroid- and islet-related autoantibodies were available. A genetic association study of HLA genes with susceptibility to alopecia areata itself was performed in 126 patients with alopecia areata, and subanalysis using data of positivity for thyroid-related autoantibodies was performed in 110 patients. This study was approved by the appropriate ethics committees, and informed consent was obtained from all participants. Subjects were questioned about the age at onset, duration of the disease, and personal and familial medical history of AITD (Graves disease and Hashimoto thyroiditis), RA, type 1 diabetes mellitus, vitiligo, psoriasis, pernicious anemia, systemic lupus erythematosus, Addison disease, and other autoimmune diseases. To compare genotypes of HLA in alopecia areata with those of other autoimmune diseases, genotypic data of patients with type 1 diabetes (15) from our previous report were used.
Autoantibody assay TSH (thyrotropin) receptor antibody (TRAb) was measured with a commercially available radioreceptor assay kit using 125Ilabeled recombinant human (rh) TSH (DYNOtest TRAb human kit; Yamasa). Samples were defined as positive when the titer of antibody was higher than 1.0 IU/L. Thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) were measured with commercially available RIA kits using 125I-labeled rh thyroglobulin and thyroid peroxidase as tracer reagents, respectively (Cosmic). Samples were defined as positive when the titer of antibody was higher than the threshold of 0.3 U/mL. GAD Ab was measured with a commercially available RIA kit using 125Ilabeled rh GAD65 as a tracer reagent (Cosmic). Samples were defined as positive when the titer of antibody was higher than 1.5 U/mL, as recommended by the manufacturer. Autoantibody to insulinoma-associated antigen 2 (IA-2 Ab) was measured by an immunoprecipitation assay using 125I-labeled IA-2. Samples were defined as positive when the titer of antibody was higher than 1.0 U/mL. Insulin autoantibody (IAA) was measured with a commercially available RIA kit using 125I-labeled rh insulin as a tracer reagent (Yamasa). Samples were defined as positive when the titer of antibody was higher than 125 nU/mL.
Genotyping of HLA (DRB1, DQB1, A, B, and C) Class II HLA-DRB1 and -DQB1, and class I A, B, and C alleles were genotyped in 126 patients with alopecia areata and 198 healthy control participants. HLA genotyping was performed by PCR-restriction fragment length polymorphism and PCR sequence-specific oligonucleotide and/or sequence-based typing methods as described previously (15). The most probable DRB1-DQB1 haplotypes were deduced according to known linkage disequilibria in the Japanese population.
Statistics Subjects and Methods Participants We studied 126 Japanese patients with alopecia areata and 198 healthy control participants. Patients were diagnosed with alopecia areata by board-certified dermatologists of Kinki University Hospital or Yamagata University Hospital. Of 126 pa-
2 and Fisher exact probability tests were used to determine the significance of differences in the distribution of the number of subjects and alleles. Corrected P values (Pc) were calculated by multiplying the nominal P value with the number of alleles or haplotypes studied. Student t test was used to compare clinical parameters. Statistical significance was defined as a P value of ⬍.05.
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1978
Noso et al
Thyroid and Islet Autoimmunity in Alopecia Areata
Table 1. Clinical Characteristics of Patients With Alopecia Areata
n Age ⬍10 y 10 –19 y 20 –29 y 30 –39 y 40 – 49 y 50 –59 y 60 – 69 y 70 –79 y ⱖ80 y Mean ⫾ SD Range Median Age at onset ⬍10 y 10 –19 y 20 –29 y 30 –39 y 40 – 49 y 50 –59 y 60 – 69 y 70 –79 y ⱖ80 y Mean ⫾ SD Range Median Duration of disease, y Mean ⫾ SD Range Median
Total, n (%)
Female, n (%)
Male, n (%)
110
76
34
8 (7.3) 14 (12.7) 15 (13.6) 30 (27.3) 14 (12.7) 11 (10.0) 11 (10.0) 6 (5.5) 1 (0.9) 37.5 ⫾ 19.4 5– 89 36
6 (7.9) 10 (13.2) 11 (14.5) 14 (18.4) 11 (14.5) 10 (13.2) 8 (10.5) 5 (6.6) 1 (1.3) 38.8 ⫾ 20.3 5– 89 36
2 (5.9) 4 (11.8) 4 (11.8) 16 (47.1) 3 (8.8) 1 (2.9) 3 (8.8) 1 (2.9) 0 (0.0) 34.6 ⫾ 16.7 5–79 35
22 (20.0) 11 (10.0) 15 (13.6) 26 (23.6) 13 (11.8) 8 (7.3) 9 (8.2) 5 (4.5) 1 (0.9) 34.3 ⫾ 20.4 0 – 88 35
16 (21.1) 9 (11.8) 11 (14.5) 12 (15.8) 10 (13.2) 6 (7.9) 7 (9.2) 4 (5.3) 1 (1.3) 35.3 ⫾ 21.3 0 – 88 35
6 (17.6) 2 (5.9) 4 (11.8) 14 (41.2) 3 (8.8) 2 (5.9) 2 (5.9) 1 (2.9) 0 (0.0) 32.2 ⫾ 18.0 2–79 32.5
3.1 ⫾ 6.6 0 –34 1
3.5 ⫾ 7.2 0 –34 1
2.5 ⫾ 4.8 0 –27 1
Results Clinical characteristics and family history of patients with alopecia areata A total of 110 patients with alopecia areata, including 34 men and 76 women, were newly recruited in the western part of Japan (Table 1). The mean age at onset was 34.3 ⫾ 20.4 years. The largest number of patients were aged 30 to 39 years, and the second largest number of patients were aged less than 10 years. Similar tendencies in the age and age at onset were observed between women and men. Autoimmune diseases and allergic diseases in patients with alopecia areata are shown in Table 2. Among these, AITD was observed in 10.0% of patients with alopecia areata (6.4% with Graves disease and 3.6% with Hashimoto thyroiditis), vitiligo was present in 2.7% and RA in 0.9%, and no patient had type 1 diabetes. Atopic dermatitis was observed in 30.9% of patients with alopecia areata, bronchial asthma in 12.7%, allergic rhinitis in 34.5%, and allergic conjunctivitis in 14.5%. The family history of patients with alopecia areata is shown in Supplemental Table 1. Thirty-eight subjects
J Clin Endocrinol Metab, May 2015, 100(5):1976 –1983
Table 2. Autoimmune Diseases and Allergic Diseases in Patients With Alopecia Areata
n Autoimmune disease AITD Graves disease Hashimoto thyroiditis Vitiligo RA Type 1 diabetes SLE Addison disease Pernicious anemia Psoriasis Allergic disease Atopic dermatitis Bronchial asthma Allergic rhinitis Allergic conjunctivitis
Total, n (%)
Female, n (%)
Male, n (%)
110
76
34
11 (10.0) 7 (6.4) 4 (3.6) 3 (2.7) 1 (0.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
10 (13.2) 7 (9.2) 3 (3.9) 3 (3.9) 1 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
1 (2.9) 0 (0.0) 1 (2.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
34 (30.9) 14 (12.7) 38 (34.5) 16 (14.5)
21 (27.6) 9 (11.8) 29 (38.2) 15 (19.7)
13 (38.2) 5 (14.7) 9 (26.5) 1 (2.9)
Abbreviation: SLE, systemic lupus erythematosus.
(34.9%) had a family history of alopecia areata, 7 (6.4%) had a family history of AITD (4.6% with Graves disease and 1.8% with Hashimoto thyroiditis), and 2 (1.8%) had a family history of RA. Regarding allergic diseases, a family history of atopic dermatitis was observed in 21.1% of patients with alopecia areata, bronchial asthma in 25.7%, allergic rhinitis in 18.3%, and allergic conjunctivitis in 1.8%. Organ-specific autoantibodies in patients with alopecia areata Regarding thyroid autoimmunity, the prevalence of positivity for TRAb in patients with alopecia areata was significantly higher than that in control subjects (42.7% vs 1.2%; odds ratio [OR], 60.9; 95% confidence interval [CI], 34.6 –107.2; P ⫽ 1.58 ⫻ 10⫺46) (Table 3). The prevalence of TPO Ab in patients with alopecia areata was also significantly higher than that in control subjects (29.1% vs 11.6%; OR, 3.1; 95% CI, 2.0 – 4.9; P ⫽ 1.68 ⫻ 10⫺6). No significant difference in the prevalence of TgAb was observed between patients with alopecia areata and control subjects (29.1% vs 22.2%; OR, 1.4; 95% CI, 0.9 –2.2; not significant [NS]). The positivity of islet-related autoantibodies (GAD Ab, IA-2 Ab, and IAA) in patients with alopecia areata was comparable to that in control subjects (Table 4). The titer of GAD Ab in antibody-positive patients with alopecia areata was significantly lower than that in GAD Ab–positive patients with AITD (2.4 vs 3176.8 U/mL; P ⫽ .008, Mann-Whitney U test) and comparable to that in control subjects (6.6 U/mL, NS) (Supplemental Figure 1).
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doi: 10.1210/jc.2014-3985
Table 3.
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Positivity of Antithyroid Antibodies in Healthy Control Subjects and Patients With Alopecia Areata
TRAb Total Male Female TPOAb Total Male Female TgAb Total Male Female
Alopecia Areata, n (%)
Control, n (%)a
OR (95% CI)
P
47/110 (42.7) 10/34 (29.4) 37/804 (48.7)
22/1818 (1.2) 7/804 (0.9) 15/1014 (1.5)
60.9 (34.6 –107.2) 47.4 (16.6 –135.3) 63.2 (32.0 –124.7)
1.58 ⫻ 10⫺46b 4.74 ⫻ 10⫺11 1.82 ⫻ 10⫺35b
32/110 (29.1) 6/34 (17.6) 26/76 (34.2)
210/1818 (11.6) 58/804 (7.2) 152/1014 (15.0)
3.1 (2.0 – 4.9) 2.8 (1.1– 6.9) 2.9 (1.8 – 4.9)
1.68 ⫻ 10⫺6 .039 3.98 ⫻ 10⫺5
32/110 (29.1) 8/34 (23.5) 24/76 (31.6)
403/1818 (22.2) 105/804 (13.1) 298/1014 (29.4)
1.4 (0.9 –2.2) 2.0 (0.9 – 4.6) 1.1 (0.7–1.8)
NS NS NS
a
Data from Kasagi et al (16).
b
One-tailed Fisher’s exact probability test; P ⬍ .0001 for two-tailed test.
Genetic analysis in patients with alopecia areata Regarding HLA class II genes, the haplotype frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes (15), tended to be higher in patients with alopecia areata than in control subjects (9.1% vs 4.5%; OR, 2.11; 95% CI, 1.11–3.99; P ⫽ .03) (Table 5). When the patients with alopecia areata were stratified by the presence or absence of TRAb, a positive association with DRB1*15:01-DQB1*06:02 was observed in TRAbpositive but not TRAb-negative patients with alopecia areata (Table 5). The frequency of the DRB1*15:01DQB1*06:02 haplotype in TRAb-positive patients with alopecia areata was significantly higher than that in control subjects (12.8% vs 4.5%; OR, 2.05; 95% CI, 1.01– 4.16; P ⫽ .0028, Pc ⬍ .02) (Table 5). To compare haplotype frequencies with those in other autoimmune diseases, the frequency of the DRB1*15:01-DQB1*06:02 haplotype in alopecia areata was compared with that in type 1 Table 4. Positivity of Anti-Islet Antibodies in Healthy Control Subjects and Patients With Alopecia Areata
GAD Ab Total Male Female IA-2 Ab Total Male Female IAA Total Male Female
1979
Alopecia Areata, n (%)
Control, n (%)a
4/110 (3.6) 1/34 (2.9) 3/76 (3.9)
OR (95% CI)
P
6/282 (2.1) 0/80 (0.0) 6/202 (3.0)
1.74 (0.5– 6.3) 1.34 (0.3–5.5)
NS NS NS
2/110 (1.8) 0/34 (0.0) 2/76 (2.6)
1/78 (1.3) ND ND
1.43 (0.1–16.0)
NS
1/110 (0.9) 0/34 (0.0) 1/76 (1.3)
2/150 (1.3) ND ND
0.68 (0.1–7.6)
NS
Abbreviation: ND, no data. a Data for GAD Ab were from Moriguchi (7), data for IA-2Ab were from Kasuga et al (17), and data for IAA were from Murayama et al. (18).
diabetes in our previous study (Figure 1, left panel). As reported previously, the frequency of DRB1*15:01DQB1*06:02 was significantly lower in patients with type 1 diabetes than in control participants (15), indicating that this haplotype is protective against type 1 diabetes (Figure 1, left panel). Even in TRAb-negative patients with alopecia areata, the haplotype frequency was significantly higher than that in patients with type 1 diabetes (7.1% vs 0.4%; Pc ⫽ .002) (Figure 1, left panel). The haplotype frequency of DRB1*08:03-DQB1*06:01, another susceptible haplotype for AITD as reported in our previous study (7), showed no difference between TRAb-positive patients with alopecia areata and control subjects (6.4% vs 7.3%; OR, 0.86; 95% CI, 0.35–2.14; NS) (Table 5). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes (15), was significantly higher in patients with type 1 diabetes than in control subjects (29.5% vs 15.7%; Pc ⫽ .0001) (Figure 1, right panel). The frequency of DRB1*04:05-DQB1*04:01 in patients with alopecia areata tended to be lower than that in control subjects (10.3% vs 15.7%; OR, 0.62; 95% CI, 0.38 –1.01; P ⫽ .05) (Table 5). In comparison with persons with type 1 diabetes (29.5%), the haplotype frequency was significantly lower in patients with alopecia areata, regardless of TRAb positivity (TRAb-positive patients with alopecia areata: 8.5%, Pc ⬍ .0003; TRAbnegative patients with alopecia areata:11.9%, Pc ⬍ .0008) (Figure 1, right panel). As for HLA class I genes, the allele frequency of A*33:03 was significantly lower in patients with alopecia areata than in control subjects (3.2% vs 9.7%; OR, 0.30; 95% CI, 0.14 – 0.65; P ⫽ .0019; Pc ⫽ .013) (Supplemental Table 2). The allele frequency of B*54:01 was significantly lower in TRAb-negative patients with alopecia areata (3.2%; OR, 0.23; 95% CI, 0.08 – 0.66; P ⫽ .002; Pc ⫽ .022), but not in TRAb-positive patients (8.5%; OR, 0.65; 95% CI, 0.29 –1.45; NS), than in control subjects
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1980
Noso et al
Thyroid and Islet Autoimmunity in Alopecia Areata
J Clin Endocrinol Metab, May 2015, 100(5):1976 –1983
Table 5. Haplotype Frequencies of HLA-DRB1 and HLA-DQB1 in Healthy Control Subjects and Patients With Alopecia Areata Alopecia Areata, n (%)
n DRB1*01:01-DQB1*05:01 DRB1*04:05-DQB1*04:01 DRB1*08:03-DQB1*06:01 DRB1*09:01-DQB1*03:03 DRB1*13:02-DQB1*06:04 DRB1*15:01-DQB1*06:02 DRB1*15:02-DQB1*06:01 Othersc
TRAbⴙ vs Control
Total vs Control
TRAbⴚ vs Control
Totala
TRAbⴙ
TRAbⴚ
Control, n (%)
OR (95% CI)
P
Pcb
OR (95% CI)
P
Pc
OR (95% CI)
P
Pc
252 21 (8.3) 26 (10.3) 22 (8.7) 27 (10.7) 7 (2.8) 23 (9.1) 25 (9.9) 101 (40.1)
94 9 (9.6) 8 (8.5) 6 (6.4) 10 (10.6) 3 (3.2) 12 (12.8) 13 (13.8) 33 (35.1)
126 10 (7.9) 15 (11.9) 10 (7.9) 14 (11.1) 4 (3.2) 9 (7.1) 10 (7.9) 54 (42.9)
396 35 (8.8) 62 (15.7) 29 (7.3) 56 (14.1) 27 (6.8) 18 (4.5) 43 (10.9) 126 (31.8)
0.94 (0.53–1.65 ) 0.62 (0.38 –1.01 ) 1.21 (0.68 –2.16 ) 0.73 (0.45–1.19 ) 0.39 (0.17– 0.91 ) 2.11 (1.11–3.99 ) 0.90 (0.54 –1.52 )
NS .050 NS NS .029 .030 NS
NS NS NS NS NS NS NS
1.09 (0.51–2.36 ) 0.50 (0.23–1.07 ) 0.86 (0.35–2.14 ) 0.72 (0.35–1.47 ) 0.45 (0.14 –1.48 ) 2.05 (1.01– 4.16 ) 1.32 (0.68 –2.56 )
.82 .075 .30 .37 .24 .0028 .47
NS NS NS NS NS ⬍.02 NS
0.89 (0.43–1.85 ) 0.73 (0.40 –1.33 ) 1.09 (0.52–2.31 ) 0.76 (0.41–1.41 ) 0.45 (0.16 –1.27 ) 1.62 (0.71–3.67 ) 0.71 (0.35–1.45 )
.75 .30 .82 .38 .19 .25 .34
NS NS NS NS NS NS NS
a
Sixteen samples from Yamagata University (n ⫽ 16) are included.
b
Pc values were corrected for number of haplotypes tested (n ⫽ 7).
c
Haplotypes with frequency ⬍5% in both groups, 2 test, or the Fisher exact probability test.
(12.5%) (Supplemental Table 3). The allele frequency of C*01:02 was significantly lower in TRAb-negative patients with alopecia areata (10.3%; OR, 0.37; 95% CI, 0.19 – 0.69; P ⫽ .001; Pc ⫽ .01), but not in TRAb-positive patients (22.3%; OR, 0.91; 95% CI, 0.52–1.59; NS), than in control subjects (23.9%) (Supplemental Table 4).
alopecia areata and AITD is at least in part a genetic factor. A high frequency of AITD in patients with alopecia areata was reported in an epidemiological study in the United States (19). A high prevalence of TPOAb in patients with alopecia areata was also previously reported (14, 20), further supporting a close association of thyroid autoimmunity and alopecia areata. In contrast to the close association with thyroid autoimmunity, no association with type 1 diabetes (Table 2) and no difference in the positivity of Discussion islet-related autoantibodies was observed in patients with The present study demonstrated that thyroid autoimmu- alopecia areata (Table 4). We previously reported that the nity but not islet autoimmunity is closely associated with titer of GAD Ab was significantly higher in GAD-positive alopecia areata, an organ-specific autoimmune disease patients with AITD than in control subjects (7). The presagainst hair follicles. These data suggest common etiology ent study showed that even in patients with alopecia areata and susceptibility shared between AITD and alopecia positive for islet-related autoantibodies, the titer of GAD areata. There was also a strong family history of AITD in Ab was lower than that in AITD (Supplemental Figure 1). patients with alopecia areata (Supplemental Table 1), sug- Together, these observations suggest a strong association gesting that the common susceptibility shared between of thyroid autoimmunity but not islet autoimmunity with alopecia areata. To investigate the genetic basis shared between alopecia areata and other autoimmune diseases, we studied HLA genes as the most prominent susceptibility genes for alopecia areata, as evidenced by a genomewide association study (21). A positive association of DRB1*15:01DQB1*06:02 with alopecia areata was observed only in TRAb-positive patients but not in TRAb-negative patients (Table 5), indicating that this haplotype confers susceptibility to thyroid autoimmunity in patients with alopecia areata. Our previous observation suggested a positive association Figure 1. Haplotype frequencies of DRB1*15:01-DQB1*06:02 (left) and DRB1*04:05-DQB1*04:01 of DRB1*15:01-DQB1*06:02 with (right) in patients with alopecia areata (TRAb-positive and -negative) and type 1 diabetes (T1DM). 1 AITD only in GAD-negative but not in Data for type 1 diabetes are from Kawabata et al (15). Pc, P values corrected for number of GAD-positive patients (7), further comparisons (n ⫽ 6).
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doi: 10.1210/jc.2014-3985
suggesting that DRB1*15:01-DQB1*06:02 is a susceptible haplotype for thyroid autoimmunity, rather than alopecia areata itself. In contrast, the haplotype frequency of DRB1*04:05-DQB1*04:01 was significantly lower in patients with alopecia areata, irrespective of TRAb positivity, than that in patients with type 1 diabetes (Figure 1, right panel). The high frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, together with the low frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, may explain the low prevalence of islet autoimmunity in patients with alopecia areata. In contrast to the low prevalence of islet autoimmunity in patients with alopecia areata in the present study, we previously reported a high prevalence of islet autoimmunity in patients with AITD and a positive association of DRB1*04: 05-DQB1*04:01 with GAD-positive but not with GADnegative AITD (7), suggesting that DRB1*04:05-DQB1* 04:01 is associated with islet autoimmunity but not thyroid autoimmunity. These data, together with the association of DRB1*15:01-DQB1*06:02 with thyroid autoimmunity in the present study, suggest the contribution of class II HLA to organ specificity in autoimmune diseases, with a contribution of DRB1*15:01-DQB1*06:02 to thyroid autoimmunity and DRB1*04:05-DQB1*04:01 to islet autoimmunity. DRB1*04:01 was reported to be associated with alopecia areata (22, 23), as well as type 1 diabetes (24), in the Caucasian population. In the present study, the association of this haplotype with alopecia areata could not be studied because of the very low frequency of DRB1*04:01 (⬍1% of the general population) in Japanese (25). These data suggest that the presence or absence of HLA haplotypes in each ethnic group affects autoimmunity to a second target organ in patients with an organ-specific autoimmune disease, such as thyroid autoimmunity in patients with alopecia areata. In Japanese, the presence of the DRB1*1501-DQB1*0602 haplotype, which confers susceptibility to alopecia areata, but provides protection against type 1 diabetes, and the absence of DRB1*04:01, which confers susceptibility to alopecia areata and type 1 diabetes in the Caucasian population, may contribute to the lack of association between alopecia areata and type 1 diabetes. In contrast, the DRB1*1501-DQB1*0602 haplotype, which confers susceptibility to both alopecia areata and AITD, is present in diverse populations including Japanese and Caucasian populations (23), and therefore a close association of alopecia areata with AITD is observed in both Japanese and other ethnic groups (9, 13). As for class I HLA, A*33:03 was negatively associated with alopecia areata irrespective of TRAb positivity (Supplemental Table 2), suggesting that A*33:03 is protective against alopecia areata. B*54:01 and C*01:02 were neg-
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atively associated with alopecia areata only when TRAb was negative but not when TRAb was positive (Supplemental Tables 3 and 4), suggesting that class I HLA is associated with alopecia areata itself but not with thyroid autoimmunity. In contrast, the significant association of DRB1*15:01-DQB1*06:02 with TRAb-positive but not TRAb-negative alopecia areata suggests that class II HLA is associated with thyroid autoimmunity rather than alopecia areata itself. Accumulating lines of evidence have suggested an association of class I HLA loci with alopecia areata (26 –28). These data, together with the association of class I HLA with alopecia areata but not with thyroid autoimmunity, in the present study suggest the contribution of class I HLA to autoimmunity against hair follicles. None of the class I HLA molecules is expressed in hair follicles under normal conditions, so-called “immune privilege,” so that hair follicles are protected from an immune reaction (10). However, in patients with alopecia areata, class I HLA molecules were reported to be highly expressed in the tissues around hair follicles with hair loss, suggesting a critical role of class I HLA molecules in the pathogenesis of alopecia areata (10). In addition to a common genetic basis, it is also possible that common etiological mechanisms shared between autoimmunity against the 2 different organs explain the close association of alopecia areata with thyroid autoimmunity. Thyroid function test results in TRAb-positive patients without AITD showed a euthyroid state and were comparable to those in TRAb-negative patients (NS; Supplemental Table 5), suggesting neither a blocking nor a stimulating property of the antibodies. TRAb-positive patients who are presently euthyroid with a low titer of TRAb (Supplemental Figure 2), however, might have latency to develop Graves disease in the future, and therefore careful follow-up is desirable. Expression of the TSH receptor in hair follicles has previously been reported by Bodó et al (29), giving an alternative possibility for the association of TRAb positivity with alopecia areata. Autoimmune destruction may cause spreading of antigen, including the TSH receptor, from destroyed hair follicles in alopecia areata, resulting in the production of antibody to the TSH receptor. Vitiligo is one of the most frequent types of autoimmune dermatitis. Although serological studies of other autoantibodies in vitiligo remain to be conducted, an association with other autoimmune diseases was reported in the United States (AITD: 21.4%; psoriasis: 5.3%) (30) and Japan (AITD: 59.3%; alopecia areata: 2.5%) (31). In addition to alopecia areata, it is also plausible that there is a common genetic basis between vitiligo and AITD (32, 33), suggesting a close relation
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Noso et al
Thyroid and Islet Autoimmunity in Alopecia Areata
between the skin and the thyroid gland as target organs in autoimmunity. In conclusion, our observations indicate a close association of alopecia areata, autoimmunity against the hair follicle, with thyroid autoimmunity, but not with islet autoimmunity, and suggest that HLA may explain, at least in part, the genetic basis of this association. These data, together with our previous study showing a close association of thyroid autoimmunity with islet autoimmunity (7), suggest that common etiology and genetic susceptibility shared among different autoimmune diseases vary, depending on the target organs of autoimmunity: autoimmunity against the thyroid gland is shared with autoimmunity against islets and hair follicles, but autoimmunity against islets and hair follicles is distinct. Identification of etiological and genetic factors shared between different autoimmune diseases will contribute to further understanding of the common etiological pathways shared between different autoimmune diseases as well as specific mechanisms determining organ specificity in each autoimmune disease.
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7.
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10. 11.
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Acknowledgments We thank Shie Hayase for her skillful technical assistance. Address all correspondence and requests for reprints to: Hiroshi Ikegami, MD, PhD, Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan. E-mail: [email protected]. This work was supported in part by the Ministry of Education, Science, Sports, Culture, and Technology of Japan [Grantsin-Aid for Scientific Research (C) 26461349, 24591347, 23591328, 25461368, and 24591346] and the Ministry of Health, Labor, and Welfare of Japan (Health and Labor Sciences Research Grant for the Research Committee of Intractable Pancreatic Disease; principle investigator: Yoshifumi Takeyama). Disclosure Summary: The authors have nothing to disclose.
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References 1. Mimura G, Kida K, Matsuura N, et al. Immunogenetics of earlyonset insulin-dependent diabetes mellitus among the Japanese: HLA, Gm, BF, GLO, and organ-specific autoantibodies—the J.D.S. study. Diabetes Res Clin Pract. 1990;8:253–262. 2. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med. 2009;360:1646 –1654. 3. Vaidya B, Kendall-Taylor P, Pearce SH. The genetics of autoimmune thyroid disease. J Clin Endocrinol Metab. 2002;87:5385–5397. 4. Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358:221–229. 5. Kawasaki E, Takino H, Yano M, et al. Autoantibodies to glutamic acid decarboxylase in patients with IDDM and autoimmune thyroid disease. Diabetes. 1994;43:80 – 86. 6. Kordonouri O, Klinghammer A, Lang EB, Grüters-Kieslich A, Gra-
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27. Haida Y, Ikeda S, Takagi A, et al. Association analysis of the HLA-C gene in Japanese alopecia areata. Immunogenetics. 2013;65:553– 557. 28. Xiao FL, Yang S, Yan KL, et al. Association of HLA class I alleles with alopecia areata in Chinese Hans. J Dermatol Sci. 2006;41: 109 –119. 29. Bodó E, Kromminga A, Biró T, et al. Human female hair follicles are a direct, nonclassical target for thyroid-stimulating hormone. J Invest Dermatol. 2009;129:1126 –1139. 30. Laberge G, Mailloux CM, Gowan K, et al. Early disease onset and
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increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res. 2005;18:300 –305. 31. Narita T, Oiso N, Fukai K, Kabashima K, Kawada A, Suzuki T. Generalized vitiligo and associated autoimmune diseases in Japanese patients and their families. Allergol Int. 2011;60:505–508. 32. Spritz RA. Shared genetic relationships underlying generalized vitiligo and autoimmune thyroid disease. Thyroid. 2010;20:745–754. 33. Kasumagic-Halilovic E, Prohic A, Begovic B, Ovcina-Kurtovic N. Association between vitiligo and thyroid autoimmunity. J Thyroid Res. 2011;2011:938257.
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ARTICLE
Organ Specificity in Autoimmune Diseases: Thyroid and Islet Autoimmunity in Alopecia Areata Shinsuke Noso,* Choongyong Park,* Naru Babaya, Yoshihisa Hiromine, Takeshi Harada, Hiroyuki Ito, Yasunori Taketomo, Kousei Kanto, Naoki Oiso, Akira Kawada, Tamio Suzuki, Yumiko Kawabata, and Hiroshi Ikegami Department of Endocrinology, Metabolism and Diabetes (S.N., C.P., N.B., Y.H., T.H., H.I., Y.T., K.K., Y.K., H.I.), Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan; Department of Dermatology (N.O., A.K.), Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan; and Department of Dermatology (T.S.), Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
Context: Multiple autoimmune diseases, such as autoimmunity against the thyroid gland and pancreatic islets, are often observed in a single patient. Although alopecia areata (AA) is one of the most frequent organ-specific autoimmune diseases, the association of AA with other autoimmune diseases and the genetic basis of the association remain to be analyzed. Objective: The aim of this study was to clarify the similarities and differences in HLA and clinical characteristics of thyroid and islet autoimmunity in patients with AA. Participants: A total of 126 patients with AA were newly recruited. Anti-islet and antithyroid autoantibodies were tested, and genotypes of HLA genes were determined. Results: Among the autoimmune diseases associated with AA, autoimmune thyroid disease was most frequent (10.0%), followed by vitiligo (2.7%) and rheumatoid arthritis (0.9%) but not type 1 diabetes (0.0%). The prevalence of thyroid-related autoantibodies in patients with AA was significantly higher than that in controls (TSH receptor antibody [TRAb]: 42.7% vs 1.2%, P ⫽ 1.6 ⫻ 10⫺46; thyroid peroxidase antibody: 29.1% vs 11.6%; P ⫽ 1.7 ⫻ 10⫺6), whereas the prevalence of islet-related autoantibodies was comparable between patients with AA and control subjects. The frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, was significantly higher in TRAb-positive (12.8%, P ⫽ .0028, corrected P value [Pc] ⫽ .02) but not TRAbnegative (7.1%, not significant) patients with AA than in control subjects (4.5%). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, was significantly lower in patients with AA (TRAb-positive: 8.5%; TRAb-negative: 11.9%) than in those with type 1 diabetes (29.5%, Pc ⬍ .0003 and Pc ⬍ .0008, respectively). Conclusion: AA was associated with thyroid autoimmunity but not islet autoimmunity, which correlated with class II HLA haplotypes susceptible or resistant to each autoimmune disease. (J Clin Endocrinol Metab 100: 1976 –1983, 2015)
rgan-specific autoimmune diseases against multiple target organs, such as type 1 diabetes and autoimmune thyroid disease (AITD), are often observed in a single patient (1), suggesting common etiology and genetic
O
susceptibility shared among different autoimmune diseases. Both type 1 diabetes (2) and AITD (Graves disease, and Hashimoto thyroiditis) (3) are multifactorial diseases, caused by exposure to environmental factors in genetically
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received November 3, 2014. Accepted February 26, 2015. First Published Online March 3, 2015
* S.N. and C.P. contributed equally to the study. Abbreviations: AITD, autoimmune thyroid disease; CI, confidence interval; GAD, glutamic acid decarboxylase; GAD Ab, glutamic acid decarboxylase antibody; IA-2 Ab, insulinomaassociated antigen 2 autoantibody; IAA, insulin autoantibody; NS, not significant; OR, odds ratio; RA, rheumatoid arthritis; rh, recombinant human; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TRAb, TSH (thyrotropin) receptor antibody.
1976
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doi: 10.1210/jc.2014-3985
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doi: 10.1210/jc.2014-3985
susceptible individuals. Type 1 diabetes is caused by “islet autoimmunity” characterized by specific infiltration of lymphocytes into pancreatic islets (4). Patients with type 1 diabetes frequently develop other organ-specific autoimmune diseases, of which AITD is the most frequent disorder (5, 6). We previously reported a high prevalence of islet autoimmunity in patients with AITD, as indicated by high positivity of glutamic acid decarboxylase antibody (GAD Ab) and high frequencies of type 1 diabetes-susceptible HLA haplotypes (7). All of these observations suggest a common etiology and genetic basis for islet and thyroid autoimmunity. Identification of the mechanisms and genes shared among different autoimmune diseases will provide important information on the common etiological pathways of autoimmune diseases, leading to effective methods for prevention and intervention in autoimmune diseases. Alopecia areata, which is characterized by specific infiltration of lymphocytes into the hair follicles, leading to hair loss, is one of the most frequent organ-specific autoimmune diseases. The overall incidence of alopecia areata is 20.2 per 100 000 person-years, and the lifetime risk was estimated to be 1.7% (1,700 per 100 000) as reported in a survey of hospital- and nonhospital-based data in the United States (8, 9). The autoimmune mechanisms as the basis for alopecia areata have emerged from accumulating lines of evidence. Hair follicles are protected from immune reaction due to lack of expression of HLA class I molecules under normal conditions (10). Despite this “immune privilege” around hair follicles, patients with alopecia areata show infiltration of lymphocytes, including T cells and natural killer cells, into hair follicles (11). Melanocytes were considered to be one of the candidates for target cells in alopecia areata (12), but specific autoantibodies have not been identified thus far. Patients with alopecia areata are also known to develop other autoimmune diseases, such as autoimmune thyroiditis, rheumatoid arthritis (RA), and vitiligo (9, 13, 14). However, the clinical and genetic characteristics of autoimmunity associated with alopecia areata are largely unknown. As a part of an ongoing project to clarify common etiology and genetic susceptibility shared among different autoimmune diseases, we studied the clinical and genetic characteristics of thyroid and islet autoimmunity in patients with alopecia areata.
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tients with alopecia areata, for 110 patients data on detailed clinical characteristics, such as age, age at onset, duration of disease, other autoimmune diseases, and thyroid- and islet-related autoantibodies were available. A genetic association study of HLA genes with susceptibility to alopecia areata itself was performed in 126 patients with alopecia areata, and subanalysis using data of positivity for thyroid-related autoantibodies was performed in 110 patients. This study was approved by the appropriate ethics committees, and informed consent was obtained from all participants. Subjects were questioned about the age at onset, duration of the disease, and personal and familial medical history of AITD (Graves disease and Hashimoto thyroiditis), RA, type 1 diabetes mellitus, vitiligo, psoriasis, pernicious anemia, systemic lupus erythematosus, Addison disease, and other autoimmune diseases. To compare genotypes of HLA in alopecia areata with those of other autoimmune diseases, genotypic data of patients with type 1 diabetes (15) from our previous report were used.
Autoantibody assay TSH (thyrotropin) receptor antibody (TRAb) was measured with a commercially available radioreceptor assay kit using 125Ilabeled recombinant human (rh) TSH (DYNOtest TRAb human kit; Yamasa). Samples were defined as positive when the titer of antibody was higher than 1.0 IU/L. Thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) were measured with commercially available RIA kits using 125I-labeled rh thyroglobulin and thyroid peroxidase as tracer reagents, respectively (Cosmic). Samples were defined as positive when the titer of antibody was higher than the threshold of 0.3 U/mL. GAD Ab was measured with a commercially available RIA kit using 125Ilabeled rh GAD65 as a tracer reagent (Cosmic). Samples were defined as positive when the titer of antibody was higher than 1.5 U/mL, as recommended by the manufacturer. Autoantibody to insulinoma-associated antigen 2 (IA-2 Ab) was measured by an immunoprecipitation assay using 125I-labeled IA-2. Samples were defined as positive when the titer of antibody was higher than 1.0 U/mL. Insulin autoantibody (IAA) was measured with a commercially available RIA kit using 125I-labeled rh insulin as a tracer reagent (Yamasa). Samples were defined as positive when the titer of antibody was higher than 125 nU/mL.
Genotyping of HLA (DRB1, DQB1, A, B, and C) Class II HLA-DRB1 and -DQB1, and class I A, B, and C alleles were genotyped in 126 patients with alopecia areata and 198 healthy control participants. HLA genotyping was performed by PCR-restriction fragment length polymorphism and PCR sequence-specific oligonucleotide and/or sequence-based typing methods as described previously (15). The most probable DRB1-DQB1 haplotypes were deduced according to known linkage disequilibria in the Japanese population.
Statistics Subjects and Methods Participants We studied 126 Japanese patients with alopecia areata and 198 healthy control participants. Patients were diagnosed with alopecia areata by board-certified dermatologists of Kinki University Hospital or Yamagata University Hospital. Of 126 pa-
2 and Fisher exact probability tests were used to determine the significance of differences in the distribution of the number of subjects and alleles. Corrected P values (Pc) were calculated by multiplying the nominal P value with the number of alleles or haplotypes studied. Student t test was used to compare clinical parameters. Statistical significance was defined as a P value of ⬍.05.
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Noso et al
Thyroid and Islet Autoimmunity in Alopecia Areata
Table 1. Clinical Characteristics of Patients With Alopecia Areata
n Age ⬍10 y 10 –19 y 20 –29 y 30 –39 y 40 – 49 y 50 –59 y 60 – 69 y 70 –79 y ⱖ80 y Mean ⫾ SD Range Median Age at onset ⬍10 y 10 –19 y 20 –29 y 30 –39 y 40 – 49 y 50 –59 y 60 – 69 y 70 –79 y ⱖ80 y Mean ⫾ SD Range Median Duration of disease, y Mean ⫾ SD Range Median
Total, n (%)
Female, n (%)
Male, n (%)
110
76
34
8 (7.3) 14 (12.7) 15 (13.6) 30 (27.3) 14 (12.7) 11 (10.0) 11 (10.0) 6 (5.5) 1 (0.9) 37.5 ⫾ 19.4 5– 89 36
6 (7.9) 10 (13.2) 11 (14.5) 14 (18.4) 11 (14.5) 10 (13.2) 8 (10.5) 5 (6.6) 1 (1.3) 38.8 ⫾ 20.3 5– 89 36
2 (5.9) 4 (11.8) 4 (11.8) 16 (47.1) 3 (8.8) 1 (2.9) 3 (8.8) 1 (2.9) 0 (0.0) 34.6 ⫾ 16.7 5–79 35
22 (20.0) 11 (10.0) 15 (13.6) 26 (23.6) 13 (11.8) 8 (7.3) 9 (8.2) 5 (4.5) 1 (0.9) 34.3 ⫾ 20.4 0 – 88 35
16 (21.1) 9 (11.8) 11 (14.5) 12 (15.8) 10 (13.2) 6 (7.9) 7 (9.2) 4 (5.3) 1 (1.3) 35.3 ⫾ 21.3 0 – 88 35
6 (17.6) 2 (5.9) 4 (11.8) 14 (41.2) 3 (8.8) 2 (5.9) 2 (5.9) 1 (2.9) 0 (0.0) 32.2 ⫾ 18.0 2–79 32.5
3.1 ⫾ 6.6 0 –34 1
3.5 ⫾ 7.2 0 –34 1
2.5 ⫾ 4.8 0 –27 1
Results Clinical characteristics and family history of patients with alopecia areata A total of 110 patients with alopecia areata, including 34 men and 76 women, were newly recruited in the western part of Japan (Table 1). The mean age at onset was 34.3 ⫾ 20.4 years. The largest number of patients were aged 30 to 39 years, and the second largest number of patients were aged less than 10 years. Similar tendencies in the age and age at onset were observed between women and men. Autoimmune diseases and allergic diseases in patients with alopecia areata are shown in Table 2. Among these, AITD was observed in 10.0% of patients with alopecia areata (6.4% with Graves disease and 3.6% with Hashimoto thyroiditis), vitiligo was present in 2.7% and RA in 0.9%, and no patient had type 1 diabetes. Atopic dermatitis was observed in 30.9% of patients with alopecia areata, bronchial asthma in 12.7%, allergic rhinitis in 34.5%, and allergic conjunctivitis in 14.5%. The family history of patients with alopecia areata is shown in Supplemental Table 1. Thirty-eight subjects
J Clin Endocrinol Metab, May 2015, 100(5):1976 –1983
Table 2. Autoimmune Diseases and Allergic Diseases in Patients With Alopecia Areata
n Autoimmune disease AITD Graves disease Hashimoto thyroiditis Vitiligo RA Type 1 diabetes SLE Addison disease Pernicious anemia Psoriasis Allergic disease Atopic dermatitis Bronchial asthma Allergic rhinitis Allergic conjunctivitis
Total, n (%)
Female, n (%)
Male, n (%)
110
76
34
11 (10.0) 7 (6.4) 4 (3.6) 3 (2.7) 1 (0.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
10 (13.2) 7 (9.2) 3 (3.9) 3 (3.9) 1 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
1 (2.9) 0 (0.0) 1 (2.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
34 (30.9) 14 (12.7) 38 (34.5) 16 (14.5)
21 (27.6) 9 (11.8) 29 (38.2) 15 (19.7)
13 (38.2) 5 (14.7) 9 (26.5) 1 (2.9)
Abbreviation: SLE, systemic lupus erythematosus.
(34.9%) had a family history of alopecia areata, 7 (6.4%) had a family history of AITD (4.6% with Graves disease and 1.8% with Hashimoto thyroiditis), and 2 (1.8%) had a family history of RA. Regarding allergic diseases, a family history of atopic dermatitis was observed in 21.1% of patients with alopecia areata, bronchial asthma in 25.7%, allergic rhinitis in 18.3%, and allergic conjunctivitis in 1.8%. Organ-specific autoantibodies in patients with alopecia areata Regarding thyroid autoimmunity, the prevalence of positivity for TRAb in patients with alopecia areata was significantly higher than that in control subjects (42.7% vs 1.2%; odds ratio [OR], 60.9; 95% confidence interval [CI], 34.6 –107.2; P ⫽ 1.58 ⫻ 10⫺46) (Table 3). The prevalence of TPO Ab in patients with alopecia areata was also significantly higher than that in control subjects (29.1% vs 11.6%; OR, 3.1; 95% CI, 2.0 – 4.9; P ⫽ 1.68 ⫻ 10⫺6). No significant difference in the prevalence of TgAb was observed between patients with alopecia areata and control subjects (29.1% vs 22.2%; OR, 1.4; 95% CI, 0.9 –2.2; not significant [NS]). The positivity of islet-related autoantibodies (GAD Ab, IA-2 Ab, and IAA) in patients with alopecia areata was comparable to that in control subjects (Table 4). The titer of GAD Ab in antibody-positive patients with alopecia areata was significantly lower than that in GAD Ab–positive patients with AITD (2.4 vs 3176.8 U/mL; P ⫽ .008, Mann-Whitney U test) and comparable to that in control subjects (6.6 U/mL, NS) (Supplemental Figure 1).
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doi: 10.1210/jc.2014-3985
Table 3.
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Positivity of Antithyroid Antibodies in Healthy Control Subjects and Patients With Alopecia Areata
TRAb Total Male Female TPOAb Total Male Female TgAb Total Male Female
Alopecia Areata, n (%)
Control, n (%)a
OR (95% CI)
P
47/110 (42.7) 10/34 (29.4) 37/804 (48.7)
22/1818 (1.2) 7/804 (0.9) 15/1014 (1.5)
60.9 (34.6 –107.2) 47.4 (16.6 –135.3) 63.2 (32.0 –124.7)
1.58 ⫻ 10⫺46b 4.74 ⫻ 10⫺11 1.82 ⫻ 10⫺35b
32/110 (29.1) 6/34 (17.6) 26/76 (34.2)
210/1818 (11.6) 58/804 (7.2) 152/1014 (15.0)
3.1 (2.0 – 4.9) 2.8 (1.1– 6.9) 2.9 (1.8 – 4.9)
1.68 ⫻ 10⫺6 .039 3.98 ⫻ 10⫺5
32/110 (29.1) 8/34 (23.5) 24/76 (31.6)
403/1818 (22.2) 105/804 (13.1) 298/1014 (29.4)
1.4 (0.9 –2.2) 2.0 (0.9 – 4.6) 1.1 (0.7–1.8)
NS NS NS
a
Data from Kasagi et al (16).
b
One-tailed Fisher’s exact probability test; P ⬍ .0001 for two-tailed test.
Genetic analysis in patients with alopecia areata Regarding HLA class II genes, the haplotype frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes (15), tended to be higher in patients with alopecia areata than in control subjects (9.1% vs 4.5%; OR, 2.11; 95% CI, 1.11–3.99; P ⫽ .03) (Table 5). When the patients with alopecia areata were stratified by the presence or absence of TRAb, a positive association with DRB1*15:01-DQB1*06:02 was observed in TRAbpositive but not TRAb-negative patients with alopecia areata (Table 5). The frequency of the DRB1*15:01DQB1*06:02 haplotype in TRAb-positive patients with alopecia areata was significantly higher than that in control subjects (12.8% vs 4.5%; OR, 2.05; 95% CI, 1.01– 4.16; P ⫽ .0028, Pc ⬍ .02) (Table 5). To compare haplotype frequencies with those in other autoimmune diseases, the frequency of the DRB1*15:01-DQB1*06:02 haplotype in alopecia areata was compared with that in type 1 Table 4. Positivity of Anti-Islet Antibodies in Healthy Control Subjects and Patients With Alopecia Areata
GAD Ab Total Male Female IA-2 Ab Total Male Female IAA Total Male Female
1979
Alopecia Areata, n (%)
Control, n (%)a
4/110 (3.6) 1/34 (2.9) 3/76 (3.9)
OR (95% CI)
P
6/282 (2.1) 0/80 (0.0) 6/202 (3.0)
1.74 (0.5– 6.3) 1.34 (0.3–5.5)
NS NS NS
2/110 (1.8) 0/34 (0.0) 2/76 (2.6)
1/78 (1.3) ND ND
1.43 (0.1–16.0)
NS
1/110 (0.9) 0/34 (0.0) 1/76 (1.3)
2/150 (1.3) ND ND
0.68 (0.1–7.6)
NS
Abbreviation: ND, no data. a Data for GAD Ab were from Moriguchi (7), data for IA-2Ab were from Kasuga et al (17), and data for IAA were from Murayama et al. (18).
diabetes in our previous study (Figure 1, left panel). As reported previously, the frequency of DRB1*15:01DQB1*06:02 was significantly lower in patients with type 1 diabetes than in control participants (15), indicating that this haplotype is protective against type 1 diabetes (Figure 1, left panel). Even in TRAb-negative patients with alopecia areata, the haplotype frequency was significantly higher than that in patients with type 1 diabetes (7.1% vs 0.4%; Pc ⫽ .002) (Figure 1, left panel). The haplotype frequency of DRB1*08:03-DQB1*06:01, another susceptible haplotype for AITD as reported in our previous study (7), showed no difference between TRAb-positive patients with alopecia areata and control subjects (6.4% vs 7.3%; OR, 0.86; 95% CI, 0.35–2.14; NS) (Table 5). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes (15), was significantly higher in patients with type 1 diabetes than in control subjects (29.5% vs 15.7%; Pc ⫽ .0001) (Figure 1, right panel). The frequency of DRB1*04:05-DQB1*04:01 in patients with alopecia areata tended to be lower than that in control subjects (10.3% vs 15.7%; OR, 0.62; 95% CI, 0.38 –1.01; P ⫽ .05) (Table 5). In comparison with persons with type 1 diabetes (29.5%), the haplotype frequency was significantly lower in patients with alopecia areata, regardless of TRAb positivity (TRAb-positive patients with alopecia areata: 8.5%, Pc ⬍ .0003; TRAbnegative patients with alopecia areata:11.9%, Pc ⬍ .0008) (Figure 1, right panel). As for HLA class I genes, the allele frequency of A*33:03 was significantly lower in patients with alopecia areata than in control subjects (3.2% vs 9.7%; OR, 0.30; 95% CI, 0.14 – 0.65; P ⫽ .0019; Pc ⫽ .013) (Supplemental Table 2). The allele frequency of B*54:01 was significantly lower in TRAb-negative patients with alopecia areata (3.2%; OR, 0.23; 95% CI, 0.08 – 0.66; P ⫽ .002; Pc ⫽ .022), but not in TRAb-positive patients (8.5%; OR, 0.65; 95% CI, 0.29 –1.45; NS), than in control subjects
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1980
Noso et al
Thyroid and Islet Autoimmunity in Alopecia Areata
J Clin Endocrinol Metab, May 2015, 100(5):1976 –1983
Table 5. Haplotype Frequencies of HLA-DRB1 and HLA-DQB1 in Healthy Control Subjects and Patients With Alopecia Areata Alopecia Areata, n (%)
n DRB1*01:01-DQB1*05:01 DRB1*04:05-DQB1*04:01 DRB1*08:03-DQB1*06:01 DRB1*09:01-DQB1*03:03 DRB1*13:02-DQB1*06:04 DRB1*15:01-DQB1*06:02 DRB1*15:02-DQB1*06:01 Othersc
TRAbⴙ vs Control
Total vs Control
TRAbⴚ vs Control
Totala
TRAbⴙ
TRAbⴚ
Control, n (%)
OR (95% CI)
P
Pcb
OR (95% CI)
P
Pc
OR (95% CI)
P
Pc
252 21 (8.3) 26 (10.3) 22 (8.7) 27 (10.7) 7 (2.8) 23 (9.1) 25 (9.9) 101 (40.1)
94 9 (9.6) 8 (8.5) 6 (6.4) 10 (10.6) 3 (3.2) 12 (12.8) 13 (13.8) 33 (35.1)
126 10 (7.9) 15 (11.9) 10 (7.9) 14 (11.1) 4 (3.2) 9 (7.1) 10 (7.9) 54 (42.9)
396 35 (8.8) 62 (15.7) 29 (7.3) 56 (14.1) 27 (6.8) 18 (4.5) 43 (10.9) 126 (31.8)
0.94 (0.53–1.65 ) 0.62 (0.38 –1.01 ) 1.21 (0.68 –2.16 ) 0.73 (0.45–1.19 ) 0.39 (0.17– 0.91 ) 2.11 (1.11–3.99 ) 0.90 (0.54 –1.52 )
NS .050 NS NS .029 .030 NS
NS NS NS NS NS NS NS
1.09 (0.51–2.36 ) 0.50 (0.23–1.07 ) 0.86 (0.35–2.14 ) 0.72 (0.35–1.47 ) 0.45 (0.14 –1.48 ) 2.05 (1.01– 4.16 ) 1.32 (0.68 –2.56 )
.82 .075 .30 .37 .24 .0028 .47
NS NS NS NS NS ⬍.02 NS
0.89 (0.43–1.85 ) 0.73 (0.40 –1.33 ) 1.09 (0.52–2.31 ) 0.76 (0.41–1.41 ) 0.45 (0.16 –1.27 ) 1.62 (0.71–3.67 ) 0.71 (0.35–1.45 )
.75 .30 .82 .38 .19 .25 .34
NS NS NS NS NS NS NS
a
Sixteen samples from Yamagata University (n ⫽ 16) are included.
b
Pc values were corrected for number of haplotypes tested (n ⫽ 7).
c
Haplotypes with frequency ⬍5% in both groups, 2 test, or the Fisher exact probability test.
(12.5%) (Supplemental Table 3). The allele frequency of C*01:02 was significantly lower in TRAb-negative patients with alopecia areata (10.3%; OR, 0.37; 95% CI, 0.19 – 0.69; P ⫽ .001; Pc ⫽ .01), but not in TRAb-positive patients (22.3%; OR, 0.91; 95% CI, 0.52–1.59; NS), than in control subjects (23.9%) (Supplemental Table 4).
alopecia areata and AITD is at least in part a genetic factor. A high frequency of AITD in patients with alopecia areata was reported in an epidemiological study in the United States (19). A high prevalence of TPOAb in patients with alopecia areata was also previously reported (14, 20), further supporting a close association of thyroid autoimmunity and alopecia areata. In contrast to the close association with thyroid autoimmunity, no association with type 1 diabetes (Table 2) and no difference in the positivity of Discussion islet-related autoantibodies was observed in patients with The present study demonstrated that thyroid autoimmu- alopecia areata (Table 4). We previously reported that the nity but not islet autoimmunity is closely associated with titer of GAD Ab was significantly higher in GAD-positive alopecia areata, an organ-specific autoimmune disease patients with AITD than in control subjects (7). The presagainst hair follicles. These data suggest common etiology ent study showed that even in patients with alopecia areata and susceptibility shared between AITD and alopecia positive for islet-related autoantibodies, the titer of GAD areata. There was also a strong family history of AITD in Ab was lower than that in AITD (Supplemental Figure 1). patients with alopecia areata (Supplemental Table 1), sug- Together, these observations suggest a strong association gesting that the common susceptibility shared between of thyroid autoimmunity but not islet autoimmunity with alopecia areata. To investigate the genetic basis shared between alopecia areata and other autoimmune diseases, we studied HLA genes as the most prominent susceptibility genes for alopecia areata, as evidenced by a genomewide association study (21). A positive association of DRB1*15:01DQB1*06:02 with alopecia areata was observed only in TRAb-positive patients but not in TRAb-negative patients (Table 5), indicating that this haplotype confers susceptibility to thyroid autoimmunity in patients with alopecia areata. Our previous observation suggested a positive association Figure 1. Haplotype frequencies of DRB1*15:01-DQB1*06:02 (left) and DRB1*04:05-DQB1*04:01 of DRB1*15:01-DQB1*06:02 with (right) in patients with alopecia areata (TRAb-positive and -negative) and type 1 diabetes (T1DM). 1 AITD only in GAD-negative but not in Data for type 1 diabetes are from Kawabata et al (15). Pc, P values corrected for number of GAD-positive patients (7), further comparisons (n ⫽ 6).
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doi: 10.1210/jc.2014-3985
suggesting that DRB1*15:01-DQB1*06:02 is a susceptible haplotype for thyroid autoimmunity, rather than alopecia areata itself. In contrast, the haplotype frequency of DRB1*04:05-DQB1*04:01 was significantly lower in patients with alopecia areata, irrespective of TRAb positivity, than that in patients with type 1 diabetes (Figure 1, right panel). The high frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, together with the low frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, may explain the low prevalence of islet autoimmunity in patients with alopecia areata. In contrast to the low prevalence of islet autoimmunity in patients with alopecia areata in the present study, we previously reported a high prevalence of islet autoimmunity in patients with AITD and a positive association of DRB1*04: 05-DQB1*04:01 with GAD-positive but not with GADnegative AITD (7), suggesting that DRB1*04:05-DQB1* 04:01 is associated with islet autoimmunity but not thyroid autoimmunity. These data, together with the association of DRB1*15:01-DQB1*06:02 with thyroid autoimmunity in the present study, suggest the contribution of class II HLA to organ specificity in autoimmune diseases, with a contribution of DRB1*15:01-DQB1*06:02 to thyroid autoimmunity and DRB1*04:05-DQB1*04:01 to islet autoimmunity. DRB1*04:01 was reported to be associated with alopecia areata (22, 23), as well as type 1 diabetes (24), in the Caucasian population. In the present study, the association of this haplotype with alopecia areata could not be studied because of the very low frequency of DRB1*04:01 (⬍1% of the general population) in Japanese (25). These data suggest that the presence or absence of HLA haplotypes in each ethnic group affects autoimmunity to a second target organ in patients with an organ-specific autoimmune disease, such as thyroid autoimmunity in patients with alopecia areata. In Japanese, the presence of the DRB1*1501-DQB1*0602 haplotype, which confers susceptibility to alopecia areata, but provides protection against type 1 diabetes, and the absence of DRB1*04:01, which confers susceptibility to alopecia areata and type 1 diabetes in the Caucasian population, may contribute to the lack of association between alopecia areata and type 1 diabetes. In contrast, the DRB1*1501-DQB1*0602 haplotype, which confers susceptibility to both alopecia areata and AITD, is present in diverse populations including Japanese and Caucasian populations (23), and therefore a close association of alopecia areata with AITD is observed in both Japanese and other ethnic groups (9, 13). As for class I HLA, A*33:03 was negatively associated with alopecia areata irrespective of TRAb positivity (Supplemental Table 2), suggesting that A*33:03 is protective against alopecia areata. B*54:01 and C*01:02 were neg-
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atively associated with alopecia areata only when TRAb was negative but not when TRAb was positive (Supplemental Tables 3 and 4), suggesting that class I HLA is associated with alopecia areata itself but not with thyroid autoimmunity. In contrast, the significant association of DRB1*15:01-DQB1*06:02 with TRAb-positive but not TRAb-negative alopecia areata suggests that class II HLA is associated with thyroid autoimmunity rather than alopecia areata itself. Accumulating lines of evidence have suggested an association of class I HLA loci with alopecia areata (26 –28). These data, together with the association of class I HLA with alopecia areata but not with thyroid autoimmunity, in the present study suggest the contribution of class I HLA to autoimmunity against hair follicles. None of the class I HLA molecules is expressed in hair follicles under normal conditions, so-called “immune privilege,” so that hair follicles are protected from an immune reaction (10). However, in patients with alopecia areata, class I HLA molecules were reported to be highly expressed in the tissues around hair follicles with hair loss, suggesting a critical role of class I HLA molecules in the pathogenesis of alopecia areata (10). In addition to a common genetic basis, it is also possible that common etiological mechanisms shared between autoimmunity against the 2 different organs explain the close association of alopecia areata with thyroid autoimmunity. Thyroid function test results in TRAb-positive patients without AITD showed a euthyroid state and were comparable to those in TRAb-negative patients (NS; Supplemental Table 5), suggesting neither a blocking nor a stimulating property of the antibodies. TRAb-positive patients who are presently euthyroid with a low titer of TRAb (Supplemental Figure 2), however, might have latency to develop Graves disease in the future, and therefore careful follow-up is desirable. Expression of the TSH receptor in hair follicles has previously been reported by Bodó et al (29), giving an alternative possibility for the association of TRAb positivity with alopecia areata. Autoimmune destruction may cause spreading of antigen, including the TSH receptor, from destroyed hair follicles in alopecia areata, resulting in the production of antibody to the TSH receptor. Vitiligo is one of the most frequent types of autoimmune dermatitis. Although serological studies of other autoantibodies in vitiligo remain to be conducted, an association with other autoimmune diseases was reported in the United States (AITD: 21.4%; psoriasis: 5.3%) (30) and Japan (AITD: 59.3%; alopecia areata: 2.5%) (31). In addition to alopecia areata, it is also plausible that there is a common genetic basis between vitiligo and AITD (32, 33), suggesting a close relation
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1982
Noso et al
Thyroid and Islet Autoimmunity in Alopecia Areata
between the skin and the thyroid gland as target organs in autoimmunity. In conclusion, our observations indicate a close association of alopecia areata, autoimmunity against the hair follicle, with thyroid autoimmunity, but not with islet autoimmunity, and suggest that HLA may explain, at least in part, the genetic basis of this association. These data, together with our previous study showing a close association of thyroid autoimmunity with islet autoimmunity (7), suggest that common etiology and genetic susceptibility shared among different autoimmune diseases vary, depending on the target organs of autoimmunity: autoimmunity against the thyroid gland is shared with autoimmunity against islets and hair follicles, but autoimmunity against islets and hair follicles is distinct. Identification of etiological and genetic factors shared between different autoimmune diseases will contribute to further understanding of the common etiological pathways shared between different autoimmune diseases as well as specific mechanisms determining organ specificity in each autoimmune disease.
J Clin Endocrinol Metab, May 2015, 100(5):1976 –1983
7.
8.
9.
10. 11.
12.
13.
14.
15.
Acknowledgments We thank Shie Hayase for her skillful technical assistance. Address all correspondence and requests for reprints to: Hiroshi Ikegami, MD, PhD, Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan. E-mail: [email protected]. This work was supported in part by the Ministry of Education, Science, Sports, Culture, and Technology of Japan [Grantsin-Aid for Scientific Research (C) 26461349, 24591347, 23591328, 25461368, and 24591346] and the Ministry of Health, Labor, and Welfare of Japan (Health and Labor Sciences Research Grant for the Research Committee of Intractable Pancreatic Disease; principle investigator: Yoshifumi Takeyama). Disclosure Summary: The authors have nothing to disclose.
16.
17.
18.
19. 20. 21.
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