Heart Vessels (1992) Suppl. 7: 133-137
Heart andVess~] S © Springer-Verlag1992
Medical treatment of Takayasu arteritis Iwao Ito* 1-1-13-207 Fujisaki, Tsuchiura, Ibaraki 300, Japan
Summary. The guidelines for medical treatment of Takayasu arteritis established in 1987 by the Systemic Vascular Disorders Research Committee, Ministry of Health and Welfare of Japan are presented. The first part of the guidelines concerns treatment with adrenocorticosteroids and the second part concerns other medical treatment. A review of the literature referring to steroid therapy and other medical treatment of Takayasu arteritis is also included.
subcommittee members, and the original draft was corrected or modified when considered reasonable. After the above process, the committee confirmed and recommended the following guidelines in 1987.
Guidelines for medical treatment of Takayasu arteritis [1]
Key words: Takayasu arteritis - Aortitis syndrome -
Treatment with adrenocorticosteroids
Hypertension - Adrenocorticosteroids - Immunosuppressives
Indication Patients are treated with adrenocorticosteroids, when they reveal evidence of active arteritis such as fever, pain, accelerated erythrocyte sedimentation rate and increased C-reactive protein.
Standard policy in Japan In an attempt to establish a standardized policy for medical treatment of Takayasu arteritis, the Systemic Vascular Disorders Research Committee, Ministry of Health and Welfare of Japan (Y. Mishima, Chairman) organized a subcommittee headed by I. Ito for this purpose in 1986. As the first step, the subcommittee prepared draft guidelines consisting of 7 items referring to treatment with adrenocorticosteroids and 11 items referring to other modes of medical treatment. The draft was then distributed to 123 university and other hospitals, where the staff was well experienced with Takayasu arteritis, with the request to give their opinion in regard to each item of the guidelines. Responses were obtained from 95 of the 123 hospitals (77%). Subsequently, the comments in these responses were investigated and discussed in detail among the
Address correspondence to: I. Ito * Former vice-president, University of Tsukuba
Initial dose As the initial dose of steroids for adult patients, 30 mg of prednisolone per day is recommended, though it may be modified according to age, severity of symptoms and other conditions. Continuation of the initial dose Administration of the initial dose is continued until the maximum effects of steroids to subjective symptoms and laboratory data are maintained for 2 weeks. Tapering of the dosage Initially, the daily dose of prednisolone is reduced by 5mg every 2 weeks until it is decreased to 10mg. Thereafter, it is reduced by 2.5 mg every 2 weeks to reach 'withdrawal. Maintenance of m i n i m u m required dose When required, a minimal dose of steroids is maintained in order to prevent relapse of subjective symptoms or to eliminate evidences of progressive vascular lesions such as lowering of visual acuity or advancing abnormalities of pulses and blood pressure. Attempt to withdraw from steroids should then be repeated.
134 Strategy against deterioration of laboratory findings Deterioration of erythrocyte sedimentation rate and C-reactive protein without relapse of symptoms or evidences of progressive vascular lesions does not require immediate increase of dosage of steroids, though the patient should be observed carefully. Consideration for side effects Patients receiving steroids should be explained the importance of early diagnosis and early treatment of infections such as a common cold. In children, steroids should not be given in the evening so as not to inhibit secretion of growth hormone during the night.
Other medical treatment Use of anti-inflammatory drugs The effects of anti-inflammatory drugs other than steroids are uncertain, but they may be used as a supplement to steroids. Use of immunosuppressive drugs Since immunosuppressive drugs such as azathioprine, cyclophosphamide and 6-mercaptopurine frequently cause untoward side effects, they are to be used carefully only when withdrawal from steroids is difficult. M a n a g e m e n t of hypertension Patients with hypertension which can be corrected surgically should be so treated as far as possible. However, when surgical treatment is difficult for some reasons, they may be treated with antihypertensive drugs as in essential hypertension, but while considering their influence upon blood flow to the organs perfused by stenosed arteries. U s e of angiotensin converting enzyme inhibitors and [3-blockers Angiotensin converting enzyme inhibitor or 13-blocker is the drug of choice in patients with renovascular hypertension, though the former should be used carefully in patients with bilateral renal artery stenosis or advanced renal failure. M a n a g e m e n t of heart failure Heart failure is treated with digitalis, diuretics, and other drugs as in other diseases. M a n a g e m e n t of angina pectoris Angina pectoris is treated with anti-anginal drugs, as in atherosclerotic coronary artery disease. U s e of vasodilators Vasodilators may be used for treatment of hypertension or heart failure, but no beneficial effect on stenotic changes of diseased arteries can be expected. U s e of platelet inhibitors Platelet inhibitors are to be used in patients with risk
I. Ito: Medical treatment of Takayasu arteritis of cerebral infarction or ischemic changes of other organs due to occlusive arterial lesions. Use of anticoagulants Anticoagulants are to be used in patients with evidence of increased blood coagulability. Value of fibrinolytic therapy Effects of fibrinolytic therapy are questionable. Use of antituberculous drugs Antituberculous drugs are used when there is coexisting tuberculosis or when there is a possibility that steroid therapy may result in an exacerbation of old tuberculosis.
Review of the iiterature
Treatment with adrenocorticosteroids According to Nakao et al. [2], corticosteroids administered to 29 patients with Takayasu arteritis induced remarkable clinical remission in 5 cases and sufficient remission in 13. The radial pulse became palpable in 5, fever disappeared in 2, and local pain subsided in 2. Erythrocyte sedimentation rate and C-reactive protein tended to return to normal in most cases. This treatment, however, had poor effect in 11 patients and could not suppress the inflammatory findings in 2. Of the 22 patients with Takayasu arteritis observed by Fraga et al. in Mexico [3], 12 patients were treated with adrenocorticosteroids. Prednisolone was started at 30mg/day for 9 weeks and tapered down slowly thereafter to a maintenance dose of 5 to 10mg/day (average 7.5 mg/day). Fatigue disappeared in all of 12 patients, headache disappeared in 5 of 11 patients, muscular weakness improved in 7/9, paresthesia in 3/9, upper extremity claudication in 2/7, lower extremity claudication in 3/6, dizziness in 2/7, blurred vision in 2/5, nausea in 2/3, Raynaud's phenomenon in 2/2, exertional dyspnea in 1/2, and weight loss in 1/1. Pulse reappeared in 7 arteries after an average period of 24.5 months, while 15 arteries with decreased pulsation remained unchanged. There were no deaths nor evidence of vascular deterioration in patients receiving a maintenance dose of prednisolone. Kulkarni et al. [4] reported reversal of renovascular hypertension caused by nonspecific aortitis after corticosteroid therapy in a 17-year-old female. In this patient, aortography demonstrated constriction of the abdominal aorta below the level of the renal arteries and narrowing of bilateral renal arteries at and near their origin. Prednisolone was administered in a daily dose of 20 mg during the 1st month, 15 mg during the 2nd month and 10 mg during the subsequent 6 months. Aortography performed after the treatment revealed regression of the stenosis of the abdominal aorta
I. Ito: Medical treatment of Takayasu arteritis as weil as that of the renal arteries. Blood pressure measured directly in the aorta proximal to the stenosis, which was 180/115 mmHg before the treatment, was lowered to 130/80 mmHg after the treatment. During my own experiences, 45 out of 85 patients with aortitis syndrome (Takayasu arteritis) were treated with adrenocorticosteroids [5]. In most cases, the initial daily dose of prednisolone was 20-30mg, and the maintenance dose was 5-10mg. Erythrocyte sedimentation rate was improved most frequently (42/45), followed by fever (14/15), CRP (29/33), dizziness (13/18), headache (12/17), pain (12/17), numbness (5/10), palpitation (3/6), shoulder stiffness (2/4), and visual disturbance (3/7). Occasionally, improvement was noted in arterial pulsation (8/38) and blood pressure (9/45). Although long-term steroid therapy was offen necessary, steroids could be successfully withdrawn in 12 cases after an average period of 618 days. Case records of 150 patients with aortitis syndrome treated with adrenocorticosteroids were collected and analyzed by the Aortitis Syndrome Research Committee, Ministry of Health and Welfare of Japan [6]. The initial daily dose and maintenance dose of prednisolone averaged 27.4 + l l . 6 m g and 11.2 + 7.7mg, respectively. Fever was improved in 98.3% (59/60), pain in 97.1% (34/35), headache in 64.7% (33/51), fatigue in 62.1% (41/66), dizziness in 47.8% (32/67), numbness of the arm in 36.2% (21/58), visual disturbance in 34.5% (10/29), palpitation in 31.6% (18/57), abnormalities of pulses in 25.4% (31/122), abnormalities of blood pressure in 23.0% (28/122), dyspnea in 15.9% (7/44), coldness of the arm in 14.3% (5/35), and syncope in 8.3% (1/12). Erythrocyte sedimentation rate, which was 21mm/h or higher in 95.5% before the treatment, became 20 mm/h or lower in 77.4% after the treatment. The quality of life of the patients after the treatment was evaluated as "improved" in 51.3%, "unchanged" in 37.2%, and "deteriorated" in 11.5%. "Deterioration" included visual disturbance in 8 cases, loss of arterial pulsation in 7, cerebrovascular accidents in 3, angina pectoris in 3, aortic regurgitation in 3, heart failure in 2, and death in 4. As for the side effects of steroid therapy, moon face was noted in 60.7%, increased body weight in 30.0%, acne in 25.3%, polytrichosis in 22.7%, flushed face in 4.0%, gastrointestinal disturbance in 4.0%, mental disturbance in 4.0%, peptic ulcer in 3.3%, striae of the skin in 3.3%, and osteal lesions in 3.3%. In the follow-up of 81 patients reported by Ishikawa [7], corticosteroid therapy was given to 41 patients. The initial daily dose of corticosteroids was usually 30-50mg prednisolone, and was gradually reduced to 10-20mg. Favorable responses were obtained in patients with accelerated erythrocyte sedimentation
135 rate, resulting in an improvement of their complaints and prevention of progression of arterial involvement during the active period of the disease. However, 11 out of 41 patients required the drug for more than 4 years. According to Waern et al. [8], 7 out of 15 cases of Takayasu arteritis seen in the Uppsala Hospital region of Sweden were treated with corticosteroids. The initial dose was equivalent to 30 mg prednisolone daily and the maintenance dose was 5mg daily. Azathioprine was added in 4 cases, at a maintenance dose of 100mg/day. The results of treatment judged from medical records were good improvement in 2 cases, fair improvement in 2, improvement in 2, and no notable effects in 1. The mean duration of treatment was 8 years. The effects of steroid therapy in 14 patients with Takayasu arteritis of active stage were reported by Fujioka et al. [9]. Improvement of subjective symptoms was obtäined in five patients, and in four of them radial arterial pulsation became palpable. In seven patients, steroid was successfully withdrawn after an average period of 5.3 +_ 3.7 years, but maintenance therapy with steroid was necessary in the other seven patients. The initial daily dose of prednisolone was 32.1 _ 11.5mg and the maintenance dose was 8.2 ± 5.3 mg. In the study of 32 North American patients by Hall et al. [10], 29 patients were treated with corticosteroids, with initial doses ranging between 30 and 100mg daily. Thirteen of them discontinued corticosteroids after a median period of 22 months, while eleven were still taking corticosteroids after periods ranging between 9 and 108 months, and daily dose of prednisolone at last follow-up being 15 mg or less in most cases. Three patients were also treated with immunosuppressives in addition to corticosteroids. In all patients, systemic inflammatory symptoms were dramatically improved within days to weeks of beginning the treatment with corticosteroids. In 8 out of 16 patients absent pulses returned although this was usually delayed several months. When steroid therapy was titrated against the erythrocyte sedimentation rate to keep it in the normal fange, there was no progression of vasculitis over 8 years of observation. In the prospective study of 20 patients by Shelhamer et al. [11], 16 patients with active inflammatory Takayasu arteritis were treated with corticosteroids. Eight patients responded to therapy, but six had clinical or angiographic progression of their vasculitis. The latter patients were then given cyclophosphamide together with prednisolone on alternate days. Four of these six patients had no progression of vascular lesions while receiving cyclophosphamide, but two had progression of vascular lesions even after 30 and 48 months of therapy, respectively. Vascular recon-
136 structive surgery was successfully performed in seven patients. Although in the study by Shelhamer et al. [11], the response to corticosteroid treatment was considered to be unsatisfactory if there was angiographic progression of arterial lesions, Hall and Hunder [12] pointed out the possibility that progression of stenoses may occur due to noninflammatory fibrosis as sequela to previous inflammatory changes that have been resolved. They also point out the great significance of oligomenorrhea commonly caused by cyclophosphamide treatment, since it is usually associated with reduction in estrogen production and therefore withdrawal of the major single protective factor against corticosteroid-induced osteoporosis. Hayashi et al. [13] reported a 17-year-old female with Takayasu arteritis of acute phase, in whom aortography demonstrated marked narrowing of the descending aorta at 2 sites and marked thickening of the aortic wall. This patient was treated with 30mg prednisolone per day for 10 days and 20 mg/day thereafter. A follow-up CT scan performed 7 months after the beginning of steroid therapy revealed reduction in the degree of aortic wall thickening, though blood pressure of her upper extremity remained elevated. In a case of Takayasu disease reported by Ishikawa and Yonekawa [14], considerable regression of bilateral common carotid stenoses was confirmed by aortography after 32 months of treatment with prednisolone gradually reduced from 50 to 3.75mg daily. All five patients with Takayasu arteritis observed by Sise et al. [15] were maintained on corticosteroid therapy. One of them underwent a trial of cyclophosphamide because of disease progression despite corticosteroid therapy. This patient had renovascular hypertension and was subjected to percutaneous transluminal angioplasty followed by aortorenal bypass. Aortic valve replacement was performed in two other patients. They concluded that corticosteroid therapy is the key to successful management of Takayasu arteritis and that surgical reconstruction has a selective role and produces acceptable long-term relief of symptoms. Other medical treatment
Case records of 28 patients with aortitis syndrome treated with immunosuppressive drugs were collected and analyzed by the Aortitis Syndrome Research Committee, Ministry of Health and Welfare of Japan [16]. Nine cases were treated with azathioprine, 7 with cyclophosphamide, 9 with 6-mercaptopurine, and the remaining 3 cases were treated initially with cyclophosphamide but subsequently with azathioprine. The daily dose was 100 mg or less for each of these drugs. The period of treatment was 20-710 (average 184)
I. Ito: Medical treatment of Takayasu arteritis days for azathioprine, 23-1,116 (average 185) days for cyclophosphamide, and 12-1,037 (average 275) days for 6-mercaptopurine. The total dose administered was 1.6-26.5 (average 11.3) gm for azathioprine, 1.0-60.0 (average 10.6) gm for cyclophosphamide, and 0.6-40.2 (average 10.8) gm for 6-mercaptopurine. Erythrocyte Sedimentation rate was improved in 55%, subjective symptoms in 29%, abnormalities of pulses in 16%, and abnormalities of blood pressure in 13%. Azathioprine caused side effects in 42% (5/12), cyclophosphamide in 90% (9/10) and 6-mercaptopurine in 44% (4/9). The most frequent side effect was gastrointestinal disturbance (42%), followed by leukopenia (13%), and loss of hair (10%). The dosage of adrenocorticosteroids could be reduced in 48% and was successfully withdrawn in 26%. Overall results of immunosuppressive therapy were evaluated to be excellent in none, good in 29%, fair in 33%, and ineffective in 29%. Use of immunosuppressive drugs in combination with steroid therapy is described in several other investigations [8, 10, 11, 15]. On the basis of the results obtained by clinical use of captopril in 3 patients with Takayasu disease, Grossman et al. [17] recommend it for treatment of renovascular hypertension when surgical correction is impossible. Two children with Takayasu arteritis and bilateral renal artery stenosis were also treated with captopril by Eke and Balfe [18]. From the experiences with their first case, they recommend a low initial dose (0.25mg/kg) for the first 2h of administration, since such patients may be sensitive to the first dose because of high plasma renin levels. Fukumoto et al. [19] reported a 7-year-old female with aortitis syndrome, who had intractable hypertension due to renal artery stenosis and developed repeated episodes of heart failure and hypertensive encephalopathy. Although hypertension in this patient was resistant to the conventional antihypertensive therapy, use of captopril resulted in a successful long-term control of blood pressure. Uyama et al. [20] reported that the peripheral venous plasma levels of 6-keto-prostaglandin FI« determined by radioimmunoassay were significantly lower in patients with Takayasu arteritis than in control subjects. According to Numano et al. [21], plasma thromboxane B2 levels were statistically higher and cyclic AMP levels were statistically lower in patients with Takayasu disease than in age-matched healthy controls. Numano et al. [22] suggest that long-term treatment with aspirin is effective in preventing thrombus formation in surface-damaged blood vessels. In their study of 20 patients with segmental arterial lesions of unilateral upper extremity, plasma thromboxane B2 level and ADP-induced platelet aggregability of antecubital venous blood were significantly higher on the affected side than on the nonaffected side.
I. Ito: Medical treatment of Takayasu arteritis Administration of 80mg aspirin daily for 1 month resulted in a significant decrease in both of these parameters. Effects of 40mg aspirin daily were not significant. Pantell and G o o d m a n [23] reported on a 12-year-old female who developed Takayasu arteritis within 1 month of the appearance of tuberculous cervical adenitis. Anti-tuberculous therapy in this patient resulted in complete symptomatic remission as well as return of pulses. Fujishita et al. [24] described a probable case of so-called cryptic miliary tuberculosis which was considered to have been provoked by acute Takayasu arteritis. Although liver dysfunction, infiltrative pulmonary lesion, and pleuropericardial effusion in this case were improved by anti-tuberculous therapy, low-grade fever, accelerated erythrocyte sedimentation rate, and increased CRP persisted until they were normalized by prednisolone.
137
10. 11. 12. 13.
14.
15. 16.
References 1. Tanabe T (1987) Guidelines for medical treatment of aortitis syndrome. Annual Report of the Systemic Vascular Disorders Research Committee of the Ministry of Health and Welfare of Japan (in Japanese). p 15 2. Nakao K, Ikeda M, Kimata S, Niitani H, Miyahara M, Ishimi Z, Hashiba K, Takeda Y, Ozawa T, Matsushita S, Kuramochi M (1967) Takayasu's arteritis: Clinical report of eighty-four cases and immunological studies of seven cases. Circulation 35:1141-1155 3. Fraga A, Mintz G, Valle L, Flores-Izquierdo G (1972) Takayasu's arteritis: Frequency of systemic manifestations (study of 22 patients) and favorable response to maintenance steroid therapy with adrenocorticosteroids (12 patients). Arthritis Rheum 15:617-624 4. Kulkarni TP, D'Cruz IA, Gandhi MJ, Dadhich DS (1974) Reversal of renovascular hypertension caused by nonspecific aortitis after corticosteroid therapy. Br Heart J 36:114-116 5. Ito I (1974) Clinical observations of 85 patients with aortitis syndrome (in Japanese). Nippon Iji Shinpo (Jpn Med J) 2612:3-9 6. Inada K, Ito I (1976) Steroid therapy of aortitis syndrome. Annual Report of the Aortitis Syndrome Research Committee of the Ministry of Health and Welfare of Japan (in Japanese). pp 174-178 7. Ishikawa K (1981) Survival and morbidity after diagnosis of occlusive thromboaortopathy (Takayasu's disease). Am J Cardiol 47:1026-1032 8. Waern AU, Andersson P, Hemmingsson A (1983) Takayasu's arteritis: A hospital-region based study on occurrence, treatment and prognosis. Angiology 34: 311-320 9. Fujioka T, Takahashi S, Sekiguchi M, Kimata S, Kondo M, Hirosawa K (1985) The effectiveness of steroid
17. 18. 19.
20.
21.
22. 23. 24.
therapy in active stage aortitis syndrome (in Japanese). Kokyu To Junkan (Respiration and Circulation) 33: 1459-1464 Hall S, Barr W, Lie JT, Stanson AW, Kazmier FJ, Hunder GG (1985) Takayasu arteritis: A study of 32 North American patients. Medicine 64:89-99 Shelhamer JH, Volkman DJ, Parrillo JE, Lawley TJ, Johnston MR, Fauci AS (1985) Takayasu's arteritis and its therapy. Ann Intern Med 103:121-126 Hall S, Hunder GG (1986) Treatment of Takayasu's arteritis. Ann Intern Med 104:288 Hayashi K, Fukushima T, Matsunaga N, Hombo Z (1986) Takayasu's arteritis: Decrease in aortic wall thickening following steroid therapy documented by CT. Br J Radiol 59:281-283 Ishikawa K, Yonekawa Y (1987) Regression of carotid stenoses after corticosteroid therapy in occlusive thromboaortopathy (Takayasu's disease). Stroke 18: 677-679 Sise MJ, Counihan CM, Shackford SR, Rowley WR (1988) The clinical spectrum of Takayasu's arteritis. Surgery 104:905-910 Inada K, Ito I, Abe K (1976) Immunosuppressive therapy of aortitis syndrome. Annual Report of the Aortitis Syndrome Research Committee of the Ministry of Health and Welfare of Japan (in Japanese). pp 179185 Grossman E, Morag B, Nussinovitch N, Boichis H, Knecht A, Rosenthal T (1984) Clinical use of captopril in Takayasu's disease. Arch Intern Med 144:95-96 Eke F, Balle JW (1984) Captopril in Takayasu's disease in children. Arch Intern Med 144:2283-2284 Fukumoto N, Miyake T, Kawamori J, Yoshida T (1987) Successful treatment with captopril for long-term control of hypertension in a child with aortitis syndrome (in Japanese). Shonika Rinsho (Jpn J Pediat) 40:353-356 Uyama O, Nagatsuka K, Nakamura M, Matsumoto M, Fujisawa A, Yoneda S, Kimura K, Abe H (1982) Plasma concentrations of 6-keto-prostaglandin FI~ in patients with hypertension, cerebrovascular disease or Takayasu's arteritis. Thrombosis Res 25:71-79 Numano F, Shimokado K, Kishi Y, Nishiyama K, Türkoglu C, Yajima M, Numano F, Maezawa H (1982) Changes in plasma levels of thromboxane B2 and cyclic nucleotides in patients with Takayasu disease. J p n Circulat J 46:16-20 Numano F, Maruyama Y, Koyama T, Numano F (1986) Antiaggregative aspirin dosage at the affected vessel wall. Angiology 37:695-701 Pantell RH, Goodman BW Jr (1981) Takayasu's arteritis: The relationship with tuberculosis. Pediatrics 67:84-88 Fujishita M, Imamura J, Kitagawa T, Kobayashi M, Taguchi H, Matsumoto T, Miyoshi I (1986) A case of aortic arch syndrome associated with liver dysfunction, pulmonary lesion and pleuropericardial effusion which were responsive to anti-tuberculous treatment (in Japanese). Nippon Kyobu Shikkan Gakkai Zasshi (Jpn J Thorac Dis) 24:1146-1150
Heart andVess~] S © Springer-Verlag1992
Medical treatment of Takayasu arteritis Iwao Ito* 1-1-13-207 Fujisaki, Tsuchiura, Ibaraki 300, Japan
Summary. The guidelines for medical treatment of Takayasu arteritis established in 1987 by the Systemic Vascular Disorders Research Committee, Ministry of Health and Welfare of Japan are presented. The first part of the guidelines concerns treatment with adrenocorticosteroids and the second part concerns other medical treatment. A review of the literature referring to steroid therapy and other medical treatment of Takayasu arteritis is also included.
subcommittee members, and the original draft was corrected or modified when considered reasonable. After the above process, the committee confirmed and recommended the following guidelines in 1987.
Guidelines for medical treatment of Takayasu arteritis [1]
Key words: Takayasu arteritis - Aortitis syndrome -
Treatment with adrenocorticosteroids
Hypertension - Adrenocorticosteroids - Immunosuppressives
Indication Patients are treated with adrenocorticosteroids, when they reveal evidence of active arteritis such as fever, pain, accelerated erythrocyte sedimentation rate and increased C-reactive protein.
Standard policy in Japan In an attempt to establish a standardized policy for medical treatment of Takayasu arteritis, the Systemic Vascular Disorders Research Committee, Ministry of Health and Welfare of Japan (Y. Mishima, Chairman) organized a subcommittee headed by I. Ito for this purpose in 1986. As the first step, the subcommittee prepared draft guidelines consisting of 7 items referring to treatment with adrenocorticosteroids and 11 items referring to other modes of medical treatment. The draft was then distributed to 123 university and other hospitals, where the staff was well experienced with Takayasu arteritis, with the request to give their opinion in regard to each item of the guidelines. Responses were obtained from 95 of the 123 hospitals (77%). Subsequently, the comments in these responses were investigated and discussed in detail among the
Address correspondence to: I. Ito * Former vice-president, University of Tsukuba
Initial dose As the initial dose of steroids for adult patients, 30 mg of prednisolone per day is recommended, though it may be modified according to age, severity of symptoms and other conditions. Continuation of the initial dose Administration of the initial dose is continued until the maximum effects of steroids to subjective symptoms and laboratory data are maintained for 2 weeks. Tapering of the dosage Initially, the daily dose of prednisolone is reduced by 5mg every 2 weeks until it is decreased to 10mg. Thereafter, it is reduced by 2.5 mg every 2 weeks to reach 'withdrawal. Maintenance of m i n i m u m required dose When required, a minimal dose of steroids is maintained in order to prevent relapse of subjective symptoms or to eliminate evidences of progressive vascular lesions such as lowering of visual acuity or advancing abnormalities of pulses and blood pressure. Attempt to withdraw from steroids should then be repeated.
134 Strategy against deterioration of laboratory findings Deterioration of erythrocyte sedimentation rate and C-reactive protein without relapse of symptoms or evidences of progressive vascular lesions does not require immediate increase of dosage of steroids, though the patient should be observed carefully. Consideration for side effects Patients receiving steroids should be explained the importance of early diagnosis and early treatment of infections such as a common cold. In children, steroids should not be given in the evening so as not to inhibit secretion of growth hormone during the night.
Other medical treatment Use of anti-inflammatory drugs The effects of anti-inflammatory drugs other than steroids are uncertain, but they may be used as a supplement to steroids. Use of immunosuppressive drugs Since immunosuppressive drugs such as azathioprine, cyclophosphamide and 6-mercaptopurine frequently cause untoward side effects, they are to be used carefully only when withdrawal from steroids is difficult. M a n a g e m e n t of hypertension Patients with hypertension which can be corrected surgically should be so treated as far as possible. However, when surgical treatment is difficult for some reasons, they may be treated with antihypertensive drugs as in essential hypertension, but while considering their influence upon blood flow to the organs perfused by stenosed arteries. U s e of angiotensin converting enzyme inhibitors and [3-blockers Angiotensin converting enzyme inhibitor or 13-blocker is the drug of choice in patients with renovascular hypertension, though the former should be used carefully in patients with bilateral renal artery stenosis or advanced renal failure. M a n a g e m e n t of heart failure Heart failure is treated with digitalis, diuretics, and other drugs as in other diseases. M a n a g e m e n t of angina pectoris Angina pectoris is treated with anti-anginal drugs, as in atherosclerotic coronary artery disease. U s e of vasodilators Vasodilators may be used for treatment of hypertension or heart failure, but no beneficial effect on stenotic changes of diseased arteries can be expected. U s e of platelet inhibitors Platelet inhibitors are to be used in patients with risk
I. Ito: Medical treatment of Takayasu arteritis of cerebral infarction or ischemic changes of other organs due to occlusive arterial lesions. Use of anticoagulants Anticoagulants are to be used in patients with evidence of increased blood coagulability. Value of fibrinolytic therapy Effects of fibrinolytic therapy are questionable. Use of antituberculous drugs Antituberculous drugs are used when there is coexisting tuberculosis or when there is a possibility that steroid therapy may result in an exacerbation of old tuberculosis.
Review of the iiterature
Treatment with adrenocorticosteroids According to Nakao et al. [2], corticosteroids administered to 29 patients with Takayasu arteritis induced remarkable clinical remission in 5 cases and sufficient remission in 13. The radial pulse became palpable in 5, fever disappeared in 2, and local pain subsided in 2. Erythrocyte sedimentation rate and C-reactive protein tended to return to normal in most cases. This treatment, however, had poor effect in 11 patients and could not suppress the inflammatory findings in 2. Of the 22 patients with Takayasu arteritis observed by Fraga et al. in Mexico [3], 12 patients were treated with adrenocorticosteroids. Prednisolone was started at 30mg/day for 9 weeks and tapered down slowly thereafter to a maintenance dose of 5 to 10mg/day (average 7.5 mg/day). Fatigue disappeared in all of 12 patients, headache disappeared in 5 of 11 patients, muscular weakness improved in 7/9, paresthesia in 3/9, upper extremity claudication in 2/7, lower extremity claudication in 3/6, dizziness in 2/7, blurred vision in 2/5, nausea in 2/3, Raynaud's phenomenon in 2/2, exertional dyspnea in 1/2, and weight loss in 1/1. Pulse reappeared in 7 arteries after an average period of 24.5 months, while 15 arteries with decreased pulsation remained unchanged. There were no deaths nor evidence of vascular deterioration in patients receiving a maintenance dose of prednisolone. Kulkarni et al. [4] reported reversal of renovascular hypertension caused by nonspecific aortitis after corticosteroid therapy in a 17-year-old female. In this patient, aortography demonstrated constriction of the abdominal aorta below the level of the renal arteries and narrowing of bilateral renal arteries at and near their origin. Prednisolone was administered in a daily dose of 20 mg during the 1st month, 15 mg during the 2nd month and 10 mg during the subsequent 6 months. Aortography performed after the treatment revealed regression of the stenosis of the abdominal aorta
I. Ito: Medical treatment of Takayasu arteritis as weil as that of the renal arteries. Blood pressure measured directly in the aorta proximal to the stenosis, which was 180/115 mmHg before the treatment, was lowered to 130/80 mmHg after the treatment. During my own experiences, 45 out of 85 patients with aortitis syndrome (Takayasu arteritis) were treated with adrenocorticosteroids [5]. In most cases, the initial daily dose of prednisolone was 20-30mg, and the maintenance dose was 5-10mg. Erythrocyte sedimentation rate was improved most frequently (42/45), followed by fever (14/15), CRP (29/33), dizziness (13/18), headache (12/17), pain (12/17), numbness (5/10), palpitation (3/6), shoulder stiffness (2/4), and visual disturbance (3/7). Occasionally, improvement was noted in arterial pulsation (8/38) and blood pressure (9/45). Although long-term steroid therapy was offen necessary, steroids could be successfully withdrawn in 12 cases after an average period of 618 days. Case records of 150 patients with aortitis syndrome treated with adrenocorticosteroids were collected and analyzed by the Aortitis Syndrome Research Committee, Ministry of Health and Welfare of Japan [6]. The initial daily dose and maintenance dose of prednisolone averaged 27.4 + l l . 6 m g and 11.2 + 7.7mg, respectively. Fever was improved in 98.3% (59/60), pain in 97.1% (34/35), headache in 64.7% (33/51), fatigue in 62.1% (41/66), dizziness in 47.8% (32/67), numbness of the arm in 36.2% (21/58), visual disturbance in 34.5% (10/29), palpitation in 31.6% (18/57), abnormalities of pulses in 25.4% (31/122), abnormalities of blood pressure in 23.0% (28/122), dyspnea in 15.9% (7/44), coldness of the arm in 14.3% (5/35), and syncope in 8.3% (1/12). Erythrocyte sedimentation rate, which was 21mm/h or higher in 95.5% before the treatment, became 20 mm/h or lower in 77.4% after the treatment. The quality of life of the patients after the treatment was evaluated as "improved" in 51.3%, "unchanged" in 37.2%, and "deteriorated" in 11.5%. "Deterioration" included visual disturbance in 8 cases, loss of arterial pulsation in 7, cerebrovascular accidents in 3, angina pectoris in 3, aortic regurgitation in 3, heart failure in 2, and death in 4. As for the side effects of steroid therapy, moon face was noted in 60.7%, increased body weight in 30.0%, acne in 25.3%, polytrichosis in 22.7%, flushed face in 4.0%, gastrointestinal disturbance in 4.0%, mental disturbance in 4.0%, peptic ulcer in 3.3%, striae of the skin in 3.3%, and osteal lesions in 3.3%. In the follow-up of 81 patients reported by Ishikawa [7], corticosteroid therapy was given to 41 patients. The initial daily dose of corticosteroids was usually 30-50mg prednisolone, and was gradually reduced to 10-20mg. Favorable responses were obtained in patients with accelerated erythrocyte sedimentation
135 rate, resulting in an improvement of their complaints and prevention of progression of arterial involvement during the active period of the disease. However, 11 out of 41 patients required the drug for more than 4 years. According to Waern et al. [8], 7 out of 15 cases of Takayasu arteritis seen in the Uppsala Hospital region of Sweden were treated with corticosteroids. The initial dose was equivalent to 30 mg prednisolone daily and the maintenance dose was 5mg daily. Azathioprine was added in 4 cases, at a maintenance dose of 100mg/day. The results of treatment judged from medical records were good improvement in 2 cases, fair improvement in 2, improvement in 2, and no notable effects in 1. The mean duration of treatment was 8 years. The effects of steroid therapy in 14 patients with Takayasu arteritis of active stage were reported by Fujioka et al. [9]. Improvement of subjective symptoms was obtäined in five patients, and in four of them radial arterial pulsation became palpable. In seven patients, steroid was successfully withdrawn after an average period of 5.3 +_ 3.7 years, but maintenance therapy with steroid was necessary in the other seven patients. The initial daily dose of prednisolone was 32.1 _ 11.5mg and the maintenance dose was 8.2 ± 5.3 mg. In the study of 32 North American patients by Hall et al. [10], 29 patients were treated with corticosteroids, with initial doses ranging between 30 and 100mg daily. Thirteen of them discontinued corticosteroids after a median period of 22 months, while eleven were still taking corticosteroids after periods ranging between 9 and 108 months, and daily dose of prednisolone at last follow-up being 15 mg or less in most cases. Three patients were also treated with immunosuppressives in addition to corticosteroids. In all patients, systemic inflammatory symptoms were dramatically improved within days to weeks of beginning the treatment with corticosteroids. In 8 out of 16 patients absent pulses returned although this was usually delayed several months. When steroid therapy was titrated against the erythrocyte sedimentation rate to keep it in the normal fange, there was no progression of vasculitis over 8 years of observation. In the prospective study of 20 patients by Shelhamer et al. [11], 16 patients with active inflammatory Takayasu arteritis were treated with corticosteroids. Eight patients responded to therapy, but six had clinical or angiographic progression of their vasculitis. The latter patients were then given cyclophosphamide together with prednisolone on alternate days. Four of these six patients had no progression of vascular lesions while receiving cyclophosphamide, but two had progression of vascular lesions even after 30 and 48 months of therapy, respectively. Vascular recon-
136 structive surgery was successfully performed in seven patients. Although in the study by Shelhamer et al. [11], the response to corticosteroid treatment was considered to be unsatisfactory if there was angiographic progression of arterial lesions, Hall and Hunder [12] pointed out the possibility that progression of stenoses may occur due to noninflammatory fibrosis as sequela to previous inflammatory changes that have been resolved. They also point out the great significance of oligomenorrhea commonly caused by cyclophosphamide treatment, since it is usually associated with reduction in estrogen production and therefore withdrawal of the major single protective factor against corticosteroid-induced osteoporosis. Hayashi et al. [13] reported a 17-year-old female with Takayasu arteritis of acute phase, in whom aortography demonstrated marked narrowing of the descending aorta at 2 sites and marked thickening of the aortic wall. This patient was treated with 30mg prednisolone per day for 10 days and 20 mg/day thereafter. A follow-up CT scan performed 7 months after the beginning of steroid therapy revealed reduction in the degree of aortic wall thickening, though blood pressure of her upper extremity remained elevated. In a case of Takayasu disease reported by Ishikawa and Yonekawa [14], considerable regression of bilateral common carotid stenoses was confirmed by aortography after 32 months of treatment with prednisolone gradually reduced from 50 to 3.75mg daily. All five patients with Takayasu arteritis observed by Sise et al. [15] were maintained on corticosteroid therapy. One of them underwent a trial of cyclophosphamide because of disease progression despite corticosteroid therapy. This patient had renovascular hypertension and was subjected to percutaneous transluminal angioplasty followed by aortorenal bypass. Aortic valve replacement was performed in two other patients. They concluded that corticosteroid therapy is the key to successful management of Takayasu arteritis and that surgical reconstruction has a selective role and produces acceptable long-term relief of symptoms. Other medical treatment
Case records of 28 patients with aortitis syndrome treated with immunosuppressive drugs were collected and analyzed by the Aortitis Syndrome Research Committee, Ministry of Health and Welfare of Japan [16]. Nine cases were treated with azathioprine, 7 with cyclophosphamide, 9 with 6-mercaptopurine, and the remaining 3 cases were treated initially with cyclophosphamide but subsequently with azathioprine. The daily dose was 100 mg or less for each of these drugs. The period of treatment was 20-710 (average 184)
I. Ito: Medical treatment of Takayasu arteritis days for azathioprine, 23-1,116 (average 185) days for cyclophosphamide, and 12-1,037 (average 275) days for 6-mercaptopurine. The total dose administered was 1.6-26.5 (average 11.3) gm for azathioprine, 1.0-60.0 (average 10.6) gm for cyclophosphamide, and 0.6-40.2 (average 10.8) gm for 6-mercaptopurine. Erythrocyte Sedimentation rate was improved in 55%, subjective symptoms in 29%, abnormalities of pulses in 16%, and abnormalities of blood pressure in 13%. Azathioprine caused side effects in 42% (5/12), cyclophosphamide in 90% (9/10) and 6-mercaptopurine in 44% (4/9). The most frequent side effect was gastrointestinal disturbance (42%), followed by leukopenia (13%), and loss of hair (10%). The dosage of adrenocorticosteroids could be reduced in 48% and was successfully withdrawn in 26%. Overall results of immunosuppressive therapy were evaluated to be excellent in none, good in 29%, fair in 33%, and ineffective in 29%. Use of immunosuppressive drugs in combination with steroid therapy is described in several other investigations [8, 10, 11, 15]. On the basis of the results obtained by clinical use of captopril in 3 patients with Takayasu disease, Grossman et al. [17] recommend it for treatment of renovascular hypertension when surgical correction is impossible. Two children with Takayasu arteritis and bilateral renal artery stenosis were also treated with captopril by Eke and Balfe [18]. From the experiences with their first case, they recommend a low initial dose (0.25mg/kg) for the first 2h of administration, since such patients may be sensitive to the first dose because of high plasma renin levels. Fukumoto et al. [19] reported a 7-year-old female with aortitis syndrome, who had intractable hypertension due to renal artery stenosis and developed repeated episodes of heart failure and hypertensive encephalopathy. Although hypertension in this patient was resistant to the conventional antihypertensive therapy, use of captopril resulted in a successful long-term control of blood pressure. Uyama et al. [20] reported that the peripheral venous plasma levels of 6-keto-prostaglandin FI« determined by radioimmunoassay were significantly lower in patients with Takayasu arteritis than in control subjects. According to Numano et al. [21], plasma thromboxane B2 levels were statistically higher and cyclic AMP levels were statistically lower in patients with Takayasu disease than in age-matched healthy controls. Numano et al. [22] suggest that long-term treatment with aspirin is effective in preventing thrombus formation in surface-damaged blood vessels. In their study of 20 patients with segmental arterial lesions of unilateral upper extremity, plasma thromboxane B2 level and ADP-induced platelet aggregability of antecubital venous blood were significantly higher on the affected side than on the nonaffected side.
I. Ito: Medical treatment of Takayasu arteritis Administration of 80mg aspirin daily for 1 month resulted in a significant decrease in both of these parameters. Effects of 40mg aspirin daily were not significant. Pantell and G o o d m a n [23] reported on a 12-year-old female who developed Takayasu arteritis within 1 month of the appearance of tuberculous cervical adenitis. Anti-tuberculous therapy in this patient resulted in complete symptomatic remission as well as return of pulses. Fujishita et al. [24] described a probable case of so-called cryptic miliary tuberculosis which was considered to have been provoked by acute Takayasu arteritis. Although liver dysfunction, infiltrative pulmonary lesion, and pleuropericardial effusion in this case were improved by anti-tuberculous therapy, low-grade fever, accelerated erythrocyte sedimentation rate, and increased CRP persisted until they were normalized by prednisolone.
137
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14.
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