573
HLA ANTIGENS IN NORTH AMERICAN PATIENTS WITH TAKAYASU ARTERITIS MAJED M. KHRAISHI, DAFNA D. GLADMAN, PIERRE DAGENAIS, ADEL G. FAM, and EDWARD C. KEYSTONE Objective. To determine the frequency of HLA class I and I1 antigens in Caucasian North American patients with Takayasu arteritis (TA). Methods. Seventy-three class I antigens and 13 class I1 antigens were examined in 21 Caucasian North American patients with TA, and their frequencies were compared with findings in 243 healthy, untreated controls. HLA typing was performed by microlymphocytotoxicity assay. Results. We found no statistically significant positive association of TA with DR2, DR4, DQw3, or any of the other class I or class I1 antigens studied. A negative association between TA and DR1 was noted. There was no significant association between any of the HLA antigens and the severity of the disease or the presence of complications. Conclusion. The negative association between TA and the DRl antigen suggests that this antigen may be protective against the development of the disease. From the Department of Medicine, University of Toronto, The Wellesley Hospital, and the Sunnybrook Medical Centre, Toronto, Ontario, Canada. Majed M. Khraishi, MD, FRCPC: Rheumatology Fellow, Department of Medicine, University of Toronto; Dafna D. Gladman, MD, FRCPC: Associate Professor of Medicine, Rheumatic Disease Unit, University of Toronto, and Rheumatologist, The Wellesley Hospital; Pierre Dagenais, MD, FRCPC: Rheumatology Fellow, Department of Medicine, University of Toronto; Adel G. Fam, MD, FRCPC: Professor of Medicine, Rheumatic Disease Unit, University of Toronto, and Rheumatologist, Sunnybrook Medical Centre; Edward C. Keystone, MD, FRCPC: Associate Professor of Medicine, Rheumatic Disease Unit, University of Toronto, and Rheumatologist, The Wellesley Hospital. Address reprint requests to Edward C. Keystone, MD, FRCPC, The Wellesley Hospital, 160 Wellesley Street East, Room 655, Toronto, Ontario, M4Y 153 Canada. Submitted for publication March 21. 1991; accepted in revised form December 16. 1991. Arthritis and Rheumatism, Vol. 35, No. 5 (May 1992)
Takayasu arteritis (TA) is a rare form of vasculitis involving the large arteries. Most patients with the disease are young females (1-3). The etiology of TA is not known. It has been suggested that there is a genetic predisposition for the disease: An association with HLA Bw52/DRw12 was demonstrated in one series of Japanese patients (4), and a DR2/DQw1 association was shown in another ( 5 ) . It has also been suggested that, in patients with Bw52/DRw 12, the arteritis has a rapid progression (6). Volkman et al, in the only previously published study of a series of North American patients, found an association with DR4/MB3 (DQw3) in 10 patients, 2 of whom were of oriental origin and 1 of whom had 1 Caucasian and 1 black parent (7). The purpose of the present study was to examine the association of HLA class I and class I1 antigens with TA in a large group of North American patients of Caucasian origin and to correlate the presence of HLA antigens with the severity and complications of the disease.
PATIENTS AND METHODS Twenty-one unrelated Caucasian patients with TA were studied. All were seen in the Vasculitis Clinic at the Wellesley Hospital. A complete clinical and laboratory assessment of each patient was performed according to a standard protocol. All patients met the American College of Rheumatology criteria for the diagnosis of TA (8). Angiographic studies were performed in all patients, and in each case the results were consistent with TA. All patients except 1 were age 540 at the time of diagnosis. This latter patient was diagnosed at age 43, but met all of the other criteria for TA. HLA typing was performed by the microlymphocytotoxicity test using One Lambda (Los Angeles, CA) tissue typing trays (9). A total of 73 class I antigens were studied in all 21 patients, and 13 class I1 antigens were tested in 20
KHRAISHI ET AL
574
patients. Two hundred forty-three healthy, unrelated white volunteers from the Toronto area served as controls. Statistical analysis. Statistical analysis was performed using the SAS software package. The frequencies of HLA antigens in patients and controls were compared using the chi-square test or Fisher’s exact test.
RESULTS The clinical features at presentation in the 21 patients are summarized in Table 1. Notably, all 21 patients were female; their mean age was 29 years. The median duration of followup was 7.5 years (range 1-16 years). The majority of the patients were taking systemic steroids at the time of the study, but only 4 were receiving immunosuppressive/cytotoxic medications. The results of HLA typing revealed that the distribution of class I antigens in the patients did not differ significantly from that in the control group. Of note is the fact that none of our patients had HLABw52. As can be seen in Table 2, the frequencies of HLA-DR2, DR4, and DQw3 were not significantly different from those in the controls. The presence or absence of these antigens in the patients was not associated with the use of cytotoxic medications. The frequency of HLA-DR1 was significantly reduced in our patients (0%) compared with the healthy controls (23%) (uncorrected P = 0.02). No association was found between any HLA antigen and
Table 1. Clinical features at presentation in the 21 patients with Tdkayasu artentis*
No. femaleslno. males Age, mean (range) Years of followup, median (range) Arm claudication Leg claudication Fever Weight loss Headache Localized pain Arthralgidarthritis Vascular bruits Carotid Aortic Subclavian Absent or decreased brachial pulses Blood pressure > 150/95 mm Hg Blood pressure difference between 2 arms >I0 mm Hg Aortic incompetence Focal neurologic symptoms or signs Taking corticosteroids Taking immunosuppressivekytotoxic drugst
* Unless otherwise indicated, values t Azathioprine, cyclophosphamide.
2110 29.25 (18-43) 7.5 (1-16) 65 39 21 33 55
39 37 65 47 65 79 10 70 30 33 90 20
are the percent of patients.
Table 2. Frequencies (%) of selected HLA class 11 antigens in Caucasian patients with Takayasu arteritis (TA) versus controls Antigen DR I DR2 DR3 DR4 DR5 DR6 DR7 DRS DRw52 DRw53 DQwl DQw2 DQw3
Controls (n = 243) 23 30 24 30 16 20 30 5
61 52 63 36 44
TA patients (n = 20) O*
25 30 40 30 15 20 10 70 50
40 25 55
* Uncorrected P = 0.02 (P not significant for all other antigens tested). the radiologic extent of the disease, the requirement for cytotoxic medications, or the presence of complications. There was a higher frequency of HLA-DR4 in patients with accompanying arthritis than in those without joint involvement, but the difference was not statistically significant.
DISCUSSION Immunogenetic factors are thought to play an important role in the pathogenesis of Takayasu arteritis. This concept has arisen from studies in Japanese patients, demonstrating an association between TA and the HLA Bw52 and DRwl2 antigens. Several case reports of familial occurrence have also been published (l(L12). The data on HLA antigen associations with TA in North American patients are sparse. In the only previously reported North American study of Caucasian patients with the disease, Volkman et al (7) demonstrated an association with DR4/MB3 (DQw3). Only I of their patients had DRI, whereas DRl was found in 22% of the North American control population (7). Hall et a1 have cited unpublished observations of a lack of HLA class I or class I1 antigen association in North American patients with TA (13). Our study did not show an association of TA with either DR4 or DQw3. Pooling of the findings in Volkman’s 7 Caucasian patients in whom HLA class 11 antigens were typed with the findings in our patients reveals that 11 patients, or 41%, had DR4, compared with 30% of controls. Thus, there may be a trend toward an increased frequency of HLA-DR4 in Caucasian patients with Takayasu arteritis; however, the
HLA ASSOCIATIONS IN TA
numbers are too small to achieve statistical significance. Moreover, among our patients, this antigen was present more often in those who presented with arthralgia or arthritis. The frequency of HLA-DR4 is known to be increased among patients with rheumatoid arthritis (14). DR4 has also been found to be significantly increased among patients with polymyalgia rheumatica and giant cell arteritis (15). In contrast, the frequency of the HLA-DRl antigen was reduced in our patients with TA. Although the statistical significance of this decrease is lost after correction for the number of antigens tested, a reduction in the frequency of DRl among patients with TA has been noted before. In Volkman’s patients (7) and in one Japanese series (16), its frequency in TA patients was also shown to be decreased. Of interest, we have demonstrated a reduced frequency of HLADRl in patients with giant cell arteritis (15). The significance of a negative association between HLA-DRl and Takayasu arteritis is not clear, particularly because of the small number of patients examined. Nonetheless, DRl may have a protective role against the development of the disease. Further studies with larger numbers of patients are required to confirm this negative association.
REFERENCES 1. Stachan RW: Natural history of Takayasu’s arteriopa-
thy. Q J Med 3357-69, 1964 2. Ishikawa K: Diagnostic approach and proposed criteria for the clinical diagnosis of Takayasu’s arteriopathy. J Am Coll Cardiol 12:964, 1988 3. Lupi-Herrera E, Torres GS, Marchushamer J, Mispireta J, Horwitz S, Espino Vera J: Takayasu’s arteritis: clinical study of 107 cases. Am Heart J 93:94-108, 1977 4. Isohisa I, Numano F, Maezawa H, Sasazuki T: HLABw52 in Takayasu disease. Tissue Antigens 12:246248, 1978
575
5. Monuchi J, Wakisaka A, Aizawa M, Yasuda K, Yokata A, Tanabe T, Itakura K: HLA-linked susceptibility gene of Takayasu disease. Hum Immunol 4:87-91, 1982 6. Numano F, Ohta N, Sasazuki T: HLA and clinical manifestations in Takayasu’s disease. Jpn Circ J 46: 184189, 1982 7. Volkman DJ, Mann DL, Fauci AS: Association between Takayasu’s arteritis and a B-cell alloantigen in North Americans. N Engl J Med 306:464465, 1982 8. Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, Fauci AS, Leavitt RY, Lie JT, Lightfoot RW Jr, Masi AT, McShane DJ, Mills JA, Stevens MB, Wallace SL, Zvaifler NJ: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33311291134, 1990 9. Gladman DD, Anhorn KAB: HLA antigens in rheumatoid arthritis: a Canadian experience. J Rheumatol 13: 274-276, 1986 10. Numano F, Isohisa I, Kishi U, Arita M, Maezawa H: Takayasu’s disease in twin sisters: possible genetic factors. Circulation 58:173-177, 1978 1 1. Makino N, Senda Y, Yamaguchi Y: Takayasu’s disease in two brothers: analysis of HLA types. Br Heart J 46:446-448, 1981 12. Enomoto S, Iwasaki Y, Bannai S, Nara Y, Matsuoka A, Aizawa Y, Shibata A: Takayasu’s disease in twin sisters. Jpn Heart J 25:147-152, 1984 13. Hall S, Buchbinder R: Takayasu’s arteritis. Rheum Dis Clin North Am 16:411422, 1990 14. Stastny P, Bau EJ, Khan MA, Olsen NJ, Pincus T, Gao X: HLA-DR4 and other genetic markers in rheumatoid arthritis. Br J Rheumatol 27 (suppl 2): 132-138, 1988 15. Richardson JE, Gladman DD, Fam A, Keystone EC: HLA-DR4 in giant cell arteritis: association with polymyalgia rheumatica syndrome. Arthritis Rheum 30: 1293-1297, 1987 16. Numano F, Isohisa I, Egami M, Ohta N, Sasazuki T: HLA-DR MT and MB antigens in Takayasu’s disease. Tissue Antigens 21:208-212, 1983
HLA ANTIGENS IN NORTH AMERICAN PATIENTS WITH TAKAYASU ARTERITIS MAJED M. KHRAISHI, DAFNA D. GLADMAN, PIERRE DAGENAIS, ADEL G. FAM, and EDWARD C. KEYSTONE Objective. To determine the frequency of HLA class I and I1 antigens in Caucasian North American patients with Takayasu arteritis (TA). Methods. Seventy-three class I antigens and 13 class I1 antigens were examined in 21 Caucasian North American patients with TA, and their frequencies were compared with findings in 243 healthy, untreated controls. HLA typing was performed by microlymphocytotoxicity assay. Results. We found no statistically significant positive association of TA with DR2, DR4, DQw3, or any of the other class I or class I1 antigens studied. A negative association between TA and DR1 was noted. There was no significant association between any of the HLA antigens and the severity of the disease or the presence of complications. Conclusion. The negative association between TA and the DRl antigen suggests that this antigen may be protective against the development of the disease. From the Department of Medicine, University of Toronto, The Wellesley Hospital, and the Sunnybrook Medical Centre, Toronto, Ontario, Canada. Majed M. Khraishi, MD, FRCPC: Rheumatology Fellow, Department of Medicine, University of Toronto; Dafna D. Gladman, MD, FRCPC: Associate Professor of Medicine, Rheumatic Disease Unit, University of Toronto, and Rheumatologist, The Wellesley Hospital; Pierre Dagenais, MD, FRCPC: Rheumatology Fellow, Department of Medicine, University of Toronto; Adel G. Fam, MD, FRCPC: Professor of Medicine, Rheumatic Disease Unit, University of Toronto, and Rheumatologist, Sunnybrook Medical Centre; Edward C. Keystone, MD, FRCPC: Associate Professor of Medicine, Rheumatic Disease Unit, University of Toronto, and Rheumatologist, The Wellesley Hospital. Address reprint requests to Edward C. Keystone, MD, FRCPC, The Wellesley Hospital, 160 Wellesley Street East, Room 655, Toronto, Ontario, M4Y 153 Canada. Submitted for publication March 21. 1991; accepted in revised form December 16. 1991. Arthritis and Rheumatism, Vol. 35, No. 5 (May 1992)
Takayasu arteritis (TA) is a rare form of vasculitis involving the large arteries. Most patients with the disease are young females (1-3). The etiology of TA is not known. It has been suggested that there is a genetic predisposition for the disease: An association with HLA Bw52/DRw12 was demonstrated in one series of Japanese patients (4), and a DR2/DQw1 association was shown in another ( 5 ) . It has also been suggested that, in patients with Bw52/DRw 12, the arteritis has a rapid progression (6). Volkman et al, in the only previously published study of a series of North American patients, found an association with DR4/MB3 (DQw3) in 10 patients, 2 of whom were of oriental origin and 1 of whom had 1 Caucasian and 1 black parent (7). The purpose of the present study was to examine the association of HLA class I and class I1 antigens with TA in a large group of North American patients of Caucasian origin and to correlate the presence of HLA antigens with the severity and complications of the disease.
PATIENTS AND METHODS Twenty-one unrelated Caucasian patients with TA were studied. All were seen in the Vasculitis Clinic at the Wellesley Hospital. A complete clinical and laboratory assessment of each patient was performed according to a standard protocol. All patients met the American College of Rheumatology criteria for the diagnosis of TA (8). Angiographic studies were performed in all patients, and in each case the results were consistent with TA. All patients except 1 were age 540 at the time of diagnosis. This latter patient was diagnosed at age 43, but met all of the other criteria for TA. HLA typing was performed by the microlymphocytotoxicity test using One Lambda (Los Angeles, CA) tissue typing trays (9). A total of 73 class I antigens were studied in all 21 patients, and 13 class I1 antigens were tested in 20
KHRAISHI ET AL
574
patients. Two hundred forty-three healthy, unrelated white volunteers from the Toronto area served as controls. Statistical analysis. Statistical analysis was performed using the SAS software package. The frequencies of HLA antigens in patients and controls were compared using the chi-square test or Fisher’s exact test.
RESULTS The clinical features at presentation in the 21 patients are summarized in Table 1. Notably, all 21 patients were female; their mean age was 29 years. The median duration of followup was 7.5 years (range 1-16 years). The majority of the patients were taking systemic steroids at the time of the study, but only 4 were receiving immunosuppressive/cytotoxic medications. The results of HLA typing revealed that the distribution of class I antigens in the patients did not differ significantly from that in the control group. Of note is the fact that none of our patients had HLABw52. As can be seen in Table 2, the frequencies of HLA-DR2, DR4, and DQw3 were not significantly different from those in the controls. The presence or absence of these antigens in the patients was not associated with the use of cytotoxic medications. The frequency of HLA-DR1 was significantly reduced in our patients (0%) compared with the healthy controls (23%) (uncorrected P = 0.02). No association was found between any HLA antigen and
Table 1. Clinical features at presentation in the 21 patients with Tdkayasu artentis*
No. femaleslno. males Age, mean (range) Years of followup, median (range) Arm claudication Leg claudication Fever Weight loss Headache Localized pain Arthralgidarthritis Vascular bruits Carotid Aortic Subclavian Absent or decreased brachial pulses Blood pressure > 150/95 mm Hg Blood pressure difference between 2 arms >I0 mm Hg Aortic incompetence Focal neurologic symptoms or signs Taking corticosteroids Taking immunosuppressivekytotoxic drugst
* Unless otherwise indicated, values t Azathioprine, cyclophosphamide.
2110 29.25 (18-43) 7.5 (1-16) 65 39 21 33 55
39 37 65 47 65 79 10 70 30 33 90 20
are the percent of patients.
Table 2. Frequencies (%) of selected HLA class 11 antigens in Caucasian patients with Takayasu arteritis (TA) versus controls Antigen DR I DR2 DR3 DR4 DR5 DR6 DR7 DRS DRw52 DRw53 DQwl DQw2 DQw3
Controls (n = 243) 23 30 24 30 16 20 30 5
61 52 63 36 44
TA patients (n = 20) O*
25 30 40 30 15 20 10 70 50
40 25 55
* Uncorrected P = 0.02 (P not significant for all other antigens tested). the radiologic extent of the disease, the requirement for cytotoxic medications, or the presence of complications. There was a higher frequency of HLA-DR4 in patients with accompanying arthritis than in those without joint involvement, but the difference was not statistically significant.
DISCUSSION Immunogenetic factors are thought to play an important role in the pathogenesis of Takayasu arteritis. This concept has arisen from studies in Japanese patients, demonstrating an association between TA and the HLA Bw52 and DRwl2 antigens. Several case reports of familial occurrence have also been published (l(L12). The data on HLA antigen associations with TA in North American patients are sparse. In the only previously reported North American study of Caucasian patients with the disease, Volkman et al (7) demonstrated an association with DR4/MB3 (DQw3). Only I of their patients had DRI, whereas DRl was found in 22% of the North American control population (7). Hall et a1 have cited unpublished observations of a lack of HLA class I or class I1 antigen association in North American patients with TA (13). Our study did not show an association of TA with either DR4 or DQw3. Pooling of the findings in Volkman’s 7 Caucasian patients in whom HLA class 11 antigens were typed with the findings in our patients reveals that 11 patients, or 41%, had DR4, compared with 30% of controls. Thus, there may be a trend toward an increased frequency of HLA-DR4 in Caucasian patients with Takayasu arteritis; however, the
HLA ASSOCIATIONS IN TA
numbers are too small to achieve statistical significance. Moreover, among our patients, this antigen was present more often in those who presented with arthralgia or arthritis. The frequency of HLA-DR4 is known to be increased among patients with rheumatoid arthritis (14). DR4 has also been found to be significantly increased among patients with polymyalgia rheumatica and giant cell arteritis (15). In contrast, the frequency of the HLA-DRl antigen was reduced in our patients with TA. Although the statistical significance of this decrease is lost after correction for the number of antigens tested, a reduction in the frequency of DRl among patients with TA has been noted before. In Volkman’s patients (7) and in one Japanese series (16), its frequency in TA patients was also shown to be decreased. Of interest, we have demonstrated a reduced frequency of HLADRl in patients with giant cell arteritis (15). The significance of a negative association between HLA-DRl and Takayasu arteritis is not clear, particularly because of the small number of patients examined. Nonetheless, DRl may have a protective role against the development of the disease. Further studies with larger numbers of patients are required to confirm this negative association.
REFERENCES 1. Stachan RW: Natural history of Takayasu’s arteriopa-
thy. Q J Med 3357-69, 1964 2. Ishikawa K: Diagnostic approach and proposed criteria for the clinical diagnosis of Takayasu’s arteriopathy. J Am Coll Cardiol 12:964, 1988 3. Lupi-Herrera E, Torres GS, Marchushamer J, Mispireta J, Horwitz S, Espino Vera J: Takayasu’s arteritis: clinical study of 107 cases. Am Heart J 93:94-108, 1977 4. Isohisa I, Numano F, Maezawa H, Sasazuki T: HLABw52 in Takayasu disease. Tissue Antigens 12:246248, 1978
575
5. Monuchi J, Wakisaka A, Aizawa M, Yasuda K, Yokata A, Tanabe T, Itakura K: HLA-linked susceptibility gene of Takayasu disease. Hum Immunol 4:87-91, 1982 6. Numano F, Ohta N, Sasazuki T: HLA and clinical manifestations in Takayasu’s disease. Jpn Circ J 46: 184189, 1982 7. Volkman DJ, Mann DL, Fauci AS: Association between Takayasu’s arteritis and a B-cell alloantigen in North Americans. N Engl J Med 306:464465, 1982 8. Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, Fauci AS, Leavitt RY, Lie JT, Lightfoot RW Jr, Masi AT, McShane DJ, Mills JA, Stevens MB, Wallace SL, Zvaifler NJ: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33311291134, 1990 9. Gladman DD, Anhorn KAB: HLA antigens in rheumatoid arthritis: a Canadian experience. J Rheumatol 13: 274-276, 1986 10. Numano F, Isohisa I, Kishi U, Arita M, Maezawa H: Takayasu’s disease in twin sisters: possible genetic factors. Circulation 58:173-177, 1978 1 1. Makino N, Senda Y, Yamaguchi Y: Takayasu’s disease in two brothers: analysis of HLA types. Br Heart J 46:446-448, 1981 12. Enomoto S, Iwasaki Y, Bannai S, Nara Y, Matsuoka A, Aizawa Y, Shibata A: Takayasu’s disease in twin sisters. Jpn Heart J 25:147-152, 1984 13. Hall S, Buchbinder R: Takayasu’s arteritis. Rheum Dis Clin North Am 16:411422, 1990 14. Stastny P, Bau EJ, Khan MA, Olsen NJ, Pincus T, Gao X: HLA-DR4 and other genetic markers in rheumatoid arthritis. Br J Rheumatol 27 (suppl 2): 132-138, 1988 15. Richardson JE, Gladman DD, Fam A, Keystone EC: HLA-DR4 in giant cell arteritis: association with polymyalgia rheumatica syndrome. Arthritis Rheum 30: 1293-1297, 1987 16. Numano F, Isohisa I, Egami M, Ohta N, Sasazuki T: HLA-DR MT and MB antigens in Takayasu’s disease. Tissue Antigens 21:208-212, 1983
