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Current status of thromboangiitis obliterans (Buerger’s disease) in Japan
International Journal of Cardiology 75 (2000) S175–S181 www.elsevier.com / locate / ijcard
Current status of thromboangiitis obliterans (Buerger’s disease) in Japan Shigeyuki Sasaki MD, PhD*, Makoto Sakuma MD, PhD, Keishu Yasuda MD, PhD Department of Cardiovascular Surgery, Hokkaido University School of Medicine, N-14, W-5, Kita-ku, Sapporo 0608648, Japan
Abstract We analysed clinical features and outcome in 850 patients with thromboangiitis obliterans (TAO), based on the 1993 Nationwide Survey of Vasculitis database collected from 3722 clinical sites in Japan. The survey was designed to assess clinical manifestation categorized by Fontaine’s classification, distribution of lesions (arterial involvement and migratory superficial phlebitis), response to medical and surgical treatment, and outcome. There were 771 males (90.7%) and 79 females (9.3%), with a mean age of 50.860.4 (range: 17–81) years. Clinical manifestations at the first consultation were Fontaine I in 8.0%, Fontaine II in 29.6%, Fontaine III in 23.9%, and Fontaine IV in 38.1%. These symptoms had been significantly improved by the time of survey. Ulcer formation in the past history had occurred in 45.2%, which was the most common in toes (85.9%). Failure of smoking cessation significantly affected the risk of ulcer formation (odds ratio51.71, 95%CI51.19–2.47; P50.004) and amputation (odds ratio52.73, 95%CI51.86–4.01; P,0.0001). Clinical features in female patients with TAO were equal to those in male patients, except for the fact that non-smokers were more common in female patients. Abstinence from tobacco significantly reduces the risk of ulcer formation and amputation, and thus improves the quality of life in patients with TAO. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Thromboangiitis obliterans; Buerger’s disease; Peripheral ischemia; Smoking; Epidemiology
1. Introduction Thromboangiitis obliterans (TAO or Buerger’s disease) is a segmental, occlusive inflammatory disease of the small and medium-sized distal arteries and superficial veins of unknown cause, occurring predominantly in young male habitual tobacco users [1]. The current concept of the pathogenetic mechanism for TAO is considered to be an interaction between the coagulation system, its control proteins, and the vascular endothelium [2]. The overall incidence of TAO seems to be decreasing with a relative changing of clinical spectrum, as the smoking habit in general population has significantly decreased [3,4]. TAO is more prevalent in some geographic areas than in North America and there is a probable ethnic pre*Corresponding author. Tel. / fax: 181-11-747-0476. E-mail address: [email protected] (S. Sasaki).
disposition [5]. In Japan, TAO is a common disorder among the chronic arterial occlusive diseases [6]. To clarify the current clinical presentation and outcome of intractable vasculitis, The Intractable Vasculitis Syndromes Research Group in Japan carried out the Nationwide Survey of Intractable Vasculitis in 1993, including TAO, Behc¸et’s disease, Takayasu’s aortitis, and inflammatory abdominal aortic aneurysm. We analysed clinical features and outcome in patients with TAO based on the Nationwide Survey database, and report the current clinical status of TAO in Japan.
2. Subjects and methods This is a retrospective clinical study on adult patients treated for TAO in Japan. The Intractable Vasculitis Syndromes Research Group in Japan de-
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00190-X
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S. Sasaki et al. / International Journal of Cardiology 75 (2000) S175 –S181
signed and performed the Nationwide Survey of TAO to assess clinical manifestation categorized by Fontaine’s classification, distribution of arterial and venous lesions, concomitantly associated disease, response to medical and surgical treatment, and outcome and complications. At the first survey, the questionnaire regarding the number of patients with TAO and other vasculopathy was mailed to 6209 clinical sites in Japan. Only patients aged 16 or older, who were treated or followed up for TAO between January 1 and December 31 in 1993, were considered eligible. The response to the questionnaire was obtained from 3722 clinical sites, and 3446 patients were diagnosed as having TAO. The definitive diagnosis of TAO was made according to the strict criteria which had been determined by the Ministry of Health and Welfare in Japan as shown in Table 1. From the results of the
first survey, the annual number of patients with TAO who visited hospital was estimated as approximately 10 000 (95% CIs (confidence intervals) 8400 to 12 000) in Japan. The second survey was performed on the 3722 clinical sites which responded to the first survey. The questionnaire regarding detailed clinical conditions was mailed to the clinical sites and the record with complete clinical information was collected for 850 patients. There were 771 males (90.7%) and 79 females (9.3%), with the mean age of 50.860.4 (range: 17–81) at the time of survey. The following studies were performed based on their records: 1. Comparison of clinical manifestations categorized by Fontaine’s classification between those at the first consultation in the past history and those at the time of survey.
Table 1 Diagnostic criteria for TAO in Japan a,b 1.
Clinical manifestations (mandatory; at least one or two of following) 1) Coldness, paresthesia, Raynaud’s symptoms in the distal upper or lower extremities 2) Intermittent claudi cation 3) Rest pain in the feet or hands 4) Painful digital ulceration or gangrene 5) Migratory superficial phlebitis
2.
Physical tests (mandatory; at least one or two of following) 1) Decrease in the skin temperature in the upper or lower extremities, or in the tips of the toes or fingers. 2) Absent distal pulses associated with preserved proximal pulses 3) Decrease in the Ankle Pressure Index with measurements of arterial Doppler pressure.
3.
Laboratory tests In patients with TAO, routine laboratory tests are usually normal.
4.
Arteriogram (mandatory; at least one or two of following) 1) Multiple, segmental occlusion in the distal artery (beyond the knee or elbow). 2) Chronic arterial occlusion secondary to the extension of thrombus. 3) No evidence for arteriosclerosis such as calcification of the arterial wall. 4) Tapering, abrupt occlusions, tortuosity of affected vessels. 5) The collateral arteries like a ‘corkscrew’ or ‘tree root’ appearance.
5.
No other vasculopathy (mandatory) Vascular disease to be ruled out: 1) Arteriosclerosis obliterans 2) Traumatic arterial thrombosis 3) Popliteal arterial entrapping syndrome 4) Occlusive vasculopathy due to systemic lupus erythematosus or scleroderma diffusum 5) Vasculo-Behcet’s disease a
Patients with distal limb ischemia exhibiting clinical manifestations, physical tests, angiographic findings described above, and without other vasculopathy can be diagnosed as having TAO. b Female patients, non-smokers, patients with risk factors for atherosclerosis such as diabetes mellitus or hyperlipidemia, or patients aged 50 or older should undergo differential diagnosis of other vasculopathy as accurately as possible.
S. Sasaki et al. / International Journal of Cardiology 75 (2000) S175 –S181
2. The incidence of ulcer formation and amputation. 3. The incidence of concomitantly associated disease. 4. Comparison of clinical profile and outcome between smokers and non-smokers to determine whether cessation of smoking affected clinical outcome of TAO.
2.1. Statistical analysis All continuous variables are presented as the mean6standard error (SEM). Univariate analysis was conducted with Student’s t-test for comparisons of continuous variables, the chi-square test for dichotomous variables. Wilcoxon signed-ranks test or Mann–Whitney’s U-test was employed for nonparametric comparisons of the categorized clinical score. Differences were considered significant at P, 0.05. All analyses were performed with SPSS software (SPSS Inc., Chicago, IL).
3. Results Demographic data are summarized in Table 2. The gender ratio was approximately 10:1, thus the incidence of female TAO in this study was 5–10 times as high as that reported previously. The mean age of patients at the time of diagnosis was 40.460.4 (range: 14–74). The most common age at diagnosis was in the 40s (n5331, 38.9%), second most common was in the 30s (n5269, 31.7%). Elderly patients aged 60 or older comprised 2.7% at the time of diagnosis. At the time of survey, the most common age was in the 40s (n5283, 33.3%), second most common in the 50s (n5269, 31.7%). Elderly patients aged 60 or older comprised 22.6% of patients at the time of survey. The majority of patients (93.2%) had a past history of smoking but 6.8% of patients developed TAO in the absence of the smoking history. Among patients with the smoking history, 79.8% of patients were able to stop smoking whereas 20.2% of patients failed to stop during the period of survey. Patient conditions during the period of survey were in-hospital in 3.5%, outpatient in 87.9%, and both in 8.1%. The majority of patients were thus treated as
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outpatient, however, approximately 10% of patients required admission during the period of survey. Four patients died of malignant neoplasm (n53) and cerebrovascular disorder (n51) during the period of survey. By the time of survey, nearly 90% of patients had experienced admission for treatment. The most common treatment was medical treatment, which was applied to 94% of patients (n5802). The frequently used medications were antiplatelet agents (n5611) and prostaglandins (n5460). Because of the distribution of distal arterial involvement, only 15% of patients had undergone surgical treatment. Clinical manifestations are summarized in Table 3. Clinical symptoms at the first consultation were Fontaine I in 8.0%, Fontaine II in 29.6%, Fontaine III in 23.9%, and Fontaine IV in 38.1%. At the time of survey, the severity of disease was significantly attenuated. Clinical manifestations categorized by Fontaine’s classification at the time of survey were symptom-free in 5.4%, Fontaine I in 44.2%, Fontaine II in 38.4%, Fontaine III in 6.2%, and Fontaine IV in 5.8% (P,0.0001 vs. first consultation; by Wilcoxon signed-ranks test). The most commonly affected lesion was the distal peripheral artery in the lower extremities, but approximately 25% of patients suffered upper extremity involvement. The ischemic ulcer has been present in 45.2% of patients in the past history, which was the most common in toes. The migratory superficial phlebitis was present in 16.0%. Major or minor amputation was undertaken for 25.2% of patients. To exclude effects of amputation from improved results of ischemic symptoms, Fontaine’s classification in a subgroup of patients without a history of amputation (n5636) was compared between that at the first consultation and at the time of survey. Clinical symptoms categorized by Fontaine’s classification at the time of survey in these patients were significantly improved when compared to those at the first consultation (P,0.0001 by Wilcoxon signed-ranks test). Findings were thus similar to those obtained in all patients. Table 4 summarizes comparisons of clinical profile and outcome between patients who succeeded in cessation of smoking (ex-smokers) and those unable to stop smoking (smokers). Demographic data and clinical symptoms at the first consultation were not significantly different between the two groups. However, clinical symptoms at the time of survey were
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Table 2 Demographic data No. of patients Male / Female
850 771 (90.7%) / 79 (9.3%)
Age distribution (year) ,20 20–29 30–39 40–49 50–59 60– Mean
At diagnosis 12 (1.4%) 107 (12.6%) 269 (3 1.7%) 331 (38.9%) 108 (12.7%) 23 (2.7%) 40.460.4 (range: 14–74)
Smoking in the past history Yes / No
792 (93.2%) / 58 (6.8%)
Cessation of smoking in smokers a Yes / No
582 (79.8%) / 147 (20.2%)
Patient conditions during the period of survey In-hospital Out-patient In- and out-hospital Deceased (cause of deaths) Malignant neoplasm Cerebrovascular disorder
29 727 67 4
(3.5%) (87.9%) (8.1%) (0.5%)
3 1
The number of admission in the past history None 1 2 3 4 .5
86 388 137 83 36 58
Arteriography (Yes / No)
850 / 0
Medical treatment (Yes / No) Type of medications Antiplatelet Prostaglandins Vasodilators Anticoagulant Others
802 / 48
Surgical treatment (Yes / No) Type of bypass surgery Aortofemoral Femoropopliteal Femorotibial Others a
At survey 2 (0.2%) 23 (2.7%) 81 (9.5%) 283 (33.3%) 269 (3 1.7%) 192 (22.6%) 50.860.4 (range: 17–81)
(10.9%) (49.2%) (17.4%) (10.5%) (4.6%) (7.4%)
611 460 272 119 64 132 / 718 11 52 42 27
Missing data for 63 patients.
significantly improved in ex-smokers than in smokers. In addition, failure of abstinence from tobacco significantly affected the risk of ulcer formation (odds
ratio51.71, 95%CI51.19–2.47; P50.004) and amputation (odds ratio52.73, 95%CI51.86–4.01; P,0.0001). Thus cessation of smoking after the
S. Sasaki et al. / International Journal of Cardiology 75 (2000) S175 –S181 Table 3 Clinical manifestations Fontaine’s classification (all patients) at the first consultation Symptom-free 3 (0.4%) I 68 (8.0%) II 252 (29.6%) III 203 (23.9%) IV 324 (38.1%)
at the time of the survey a 46 (5.4%) 376 (44.2%) 326 (38.4%) 53 (6.2%) 49 (5.8%)
Distribution of arterial involvement Upper extremities 42 (5.1%) Upper and lower 167 (20.2%) Lower extremities 616 (74.7%) History of ischemic ulcer formation Yes / No 384 (45.2%) / 466 (54.8%) Toes 330 (85.9%) Fingers 39 (10.2%) Others 15 (3.9%) History of major or minor amputation Yes / No 214 (25.2%) / 636 (74.8%) Fontaine’s classification in patients without history of amputation at the first consultation at the time of survey a Symptom-free 2 (0.3%) 33 (5.2%) I 63 (9.9%) 310 (48.7%) II 228 (35.8%) 240 (37.7%) III 164 (25.8%) 35 (5.5%) IV 179 (28.1%) 18 (2.8%) Migratory superficial phlebitis Yes / No 136 (16.0%) / 714 (84.0%) Associated disease Hypertension Hyperlipidemia Diabetes a
115 (13.5%) 67 (7.9%) 37 (4.4%)
P,0.0001 by Wilcoxon signed-ranks test.
definite diagnosis significantly improved clinical course and quality of life (QOL) in patients with TAO.
4. Discussion Thromboangiitis obliterans is a progressive, often relentless and devastating, vasculitis causing significant loss of digits and limbs predominantly in a youthful population of tobacco users. The age of onset usually ranges from 35 to 50 years, more frequently found in males. Although the cause of TAO is unknown, tobacco use is clearly a trigger for
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what appears to be an autoimmune mechanism in a group of patients [7,8]. In addition to abnormal peripheral microcirculation, some systemic factors (immunological or humoral) and an interaction between the coagulation system, its control proteins, and the vascular endothelium may be involved with development of TAO [2,9,10]. Papa and associates reported that patients with TAO had a significantly higher frequency of HLA-DR4 and a significantly lower frequency of the HLADRW6 antigen than control groups [9]. Eichhorn and associates have recently reported that patients with TAO had a higher titer of antiendothelial cell antibodies (AECA) than normal healthy subjects [10]. It appears that there may be some predisposition or some abnormality in the humoral or cell-mediated response to endothelial cells, collagen, or a tobacco glycoprotein antigen in people who will develop TAO, and these genetic predisposition may account for the development of TAO in non-smokers. Since the smoking habit in general population has significantly decreased, the incidence of TAO appears to be decreasing. According to Lie and associates, the prevalence rate of TAO has declined steadily from 104 / 100 000 in 1947 to 13 / 100 000 in 1986 (an eight-fold decrease) in North America [1]. TAO has a worldwide distribution with greater prevalence in the Orient, India, Southeast Asia than in North America [5,11]. In this series, the estimated prevalence rate of TAO (8400 to 12 000 in Japan, equivalent to 7 to 10 / 100 000) was almost equal to that in North America in 1986. Among the chronic arterial occlusive diseases, TAO is a common disorder in Japan. The present study documented the changes in demographic spectrum in patients with TAO. Until the middle of 1980s, female or elderly patients were thought to comprise less than 2% of the patients with TAO [1,5]. However, the prevalence of TAO in women has been increasing, which is attributable to the increased number of women cigarette smokers in the past few decades [4,5]. The prevalence of female TAO in this study is 9.3%, which is almost consistent with the reported prevalence rate ranging from 11 to 23% [1,4]. In addition, the prevalence of elderly patients was also increasing [4]. In this series, patients with TAO aged 60 or older comprised 22.6% of patients at the time of survey. The onset age of TAO usually ranges from 35 to 50 years, but the
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Table 4 Comparison of clinical profile and outcome between ex-smokers and smokers Factors
Ex-smokers (n5582)
Smokers (n5147)
Age Male / Female
50.460.4 533 / 49
51.160.8 139 / 8
Fontaine’s classification at the first consultation symptom-free 3 (0.5%) I 44 (7.6%) II 181 (31.1%) III 139 (23.9%) IV 215 (36.9%) Chi-Square value (Pearson)55.958 Fontaine’s classification at the time of survey symptom-free I II III IV
Ulcer or gangrene formation Yes No Major or minor limb amputation Yes No
0.483 0.229
0 (0.0%) 15 (10.2%) 37 (25.2%) 29 (19.7%) 66 (44.9%) 0.202
39 (6.7%) 270 (46.4%) 223 (38.3%) 26 (4.5%) 24(4.1%) Chi-Square value (Pearson)525.04
5 (3.4%) 47 (32.0%) 64 (43.5%) 16 (10.9%) 15 (10.2%)
243 (41.8%) 339 (58.2%) Odds Ratio51.71 (95% CIs51.19 to 2.47)
81 (55.1%) 66 (44.9%)
120 (20.6%) 462 (79.4%) Odds Ratio52.73 (95% CIs51.86 to 4.01)
61(41.5%) 86 (58.5%)
mean age of patients may become higher as they grow older. The additional demographic change in the distribution of arterial involvement is the increasing prevalence of upper-extremity involvement. The peripheral distal arteries in the lower extremities were affected in nearly all patients (94.9%), but approximately 25% of patients suffered upper extremity involvement in this series. The reported incidence of upper extremity involvement ranges 28–50% [1,4], thus this report is also consistent with the increased incidence of upper extremity involvement [4]. Major or minor amputation was still required in 25.2% of patients in this series, the relatively high rate of amputation documented the virulence of TAO [7]. Medical treatment has been undertaken for nearly all patients (94.4%) whereas surgical treatment has been employed for only 15.5% of patients, because of the distribution of arterial involvement and the lack of distal anastomotic sites available for outflow vessels. The majority of patients (88.5%) were treated as outpatient during the period of survey, but approximately 90% of patients had undergone in-
P-value
,0.0001
0.004
,0.0001
hospital treatment in the past history. They needed admission in the hospital most likely due to amputation surgery, arterial reconstruction surgery, treatment for ischemic ulcers, or angiography for a definitive diagnosis. Concomitantly associated disease was not characteristic and rare complications, such as ischemia of the small bowel or central nervous system involvement [12–14], were not observed in this series. Antiplatelet drugs, prostaglandins, and vasodilators were commonly used in many clinical sites in Japan, although there has been no reliable evidence that they might interrupt progression of disease. Fiessinger and associates have demonstrated the efficacy of iloprost [15] compared with an ordinary regimen, but the current study could not identify the regimen which would be the most likely to be effective. Anyway, the severity of disease at the time of survey was significantly improved when compared with that at the first consultation, probably in response to treatment or cessation of smoking. In general, cessation of smoking is the most important factor in the treatment of TAO. Smokers
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account for almost all patients with TAO [16]. Disease progression and major limb loss usually depend upon whether the patient stops smoking or not [17]. Medical and surgical therapy palliate accrued damage, but only complete abstinence from tobacco use allows stabilization of the process. The overall incidence of smoking has declined especially among educated people, but the rate of decline of smoking among women has not been as great as that among men due in part to the high rate of smoking among young women [16]. As far as smokers account for nearly all patients with TAO, the male-to-female ratio of TAO will continue to be decreasing. In the current series, clinical symptoms at the first consultation were not significantly different between patients who stopped smoking and those who continued smoking. However, clinical symptoms at the time of survey were significantly improved in patients who stopped smoking. In addition, failure of smoking cessation significantly affected the risk of ulcer formation and amputation. Thus this paper also documented that cessation of smoking after having diagnosis of TAO significantly improved the clinical course and QOL. Although this survey included comparison of clinical manifestations categorized by Fontaine’s classification, the use of Fontaine’s classification may not be the best way to categorize clinical manifestations in TAO. The pathophysiology of ischemia in TAO is different from that in atherosclerosis, and the earliest complaints of patients with TAO are usually rest pain in the feet or hands, painful digital ulcerations or gangrene. Unfortunately, there has not been an appropriate, worldwide-accepted clinical staging that corresponds to ischemic symptoms in TAO. This may be a reason that Fontaine’s classification has been employed for the clinical staging of peripheral occlusive disease other than atherosclerosis in the past literature [18]. It should be noted that Fontaine’s classification for TAO is used only as a simple expedient to indicate ischemic clinical manifestations. As this study is one of the largest series of surveillance for TAO in the last decade, the obtained results will help us understand current clinical status in TAO. We conclude that TAO is a treatable disease
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when diagnosed early and if strict cessation of smoking is observed. Abstinence from tobacco significantly reduces the risk of ulcer formation and amputation, and thus improves the quality of life in patients with TAO.
References [1] Lie JT. The rise and fall and resurgence of thromboangiitis obliterans (Buerger’s disease). Acta Pathol Japan 1989;39:153–8. [2] Lie JT. Visceral intestinal Buerger’s disease. Int J Cardiol 1998;66(Suppl 1):S249–56. [3] Mills JL, Taylor LJ, Porter JM. Buerger’s disease in the modern era. Am J Surg 1987;154:123–9. [4] Olin JW, Young JR, Graor RA, Ruschhaupt WF, Bartholomew JR. The changing clinical spectrum of thromboangiitis obliterans (Buerger’s disease). Circulation 1990;82(Suppl IV):3–8. [5] Lie JT. Thromboangiitis obliterans (Buerger’s disease) in women. Medicine 1987;66:65–72. [6] Nakajima N. The change in concept and surgical treatment on Buerger’s disease – personal experience and review. Int J Cardiol 1998;66(Suppl 1):S273–80. [7] Joyce JW. Buerger’s disease (thromboangiitis obliterans). Rheum Dis Clin North Am 1990;16:463–70. [8] Olin JW. Thromboangiitis obliterans. Curr Opin Rheum 1994;6:44– 9. [9] Papa M, Bass A, Adar R et al. Autoimmune mechanisms in thromboangiitis obliterans (Buerger’s disease): the role of tobacco antigen and the major histocompatibility complex. Surgery 1992;111:527–31. [10] Eichhorn J, Sima D, Lindschau C et al. Antiendothelial cell antibodies in thromboangiitis obliterans. Am J Med Sci 1998;315:17–23. [11] Lie JT. Thromboangiitis obliterans (Buerger’s disease) revisited. Pathol Annu 1988;23:257–91. [12] Broide E, Scapa E, Peer A, Witz E, Abramowich D, Eshchar J. Buerger’s disease presenting as acute small bowel ischemia. Gastroenterology 1993;104:1192–5. [13] Molaie M, Collins GH. Systemic noninflammatory vasculopathy with prominent CNS involvement – a case report. Angiology 1987;38:686–95. [14] Schellong SM, Bernhards J, Ensslen F, Schafers HJ, Alexander K. Intestinal type of thromboangiitis obliterans (Buerger’s disease). J Intern Med 1994;235:69–73. [15] Fiessinger JN, Schafer M. Trial of iloprost versus aspirin treatment for critical limb ischaemia of thromboangiitis obliterans. The TAO Study. The TAO Study. Lancet 1990;335:555–7. [16] Lakier JB. Smoking and cardiovascular disease. Am J Med 1992;93(suppl 1A):8S–12S. [17] Ohta T, Shionoya S. Fate of the ischaemic limb in Buerger’s disease. Br J Surg 1988;75:259–62. [18] Mandalam KR, Rao VR, Sandhyamani S et al. Focal occlusive disease of the common femoral artery: a report of 20 cases. Cardiovasc Surg 1994;2:498–502.
Current status of thromboangiitis obliterans (Buerger’s disease) in Japan Shigeyuki Sasaki MD, PhD*, Makoto Sakuma MD, PhD, Keishu Yasuda MD, PhD Department of Cardiovascular Surgery, Hokkaido University School of Medicine, N-14, W-5, Kita-ku, Sapporo 0608648, Japan
Abstract We analysed clinical features and outcome in 850 patients with thromboangiitis obliterans (TAO), based on the 1993 Nationwide Survey of Vasculitis database collected from 3722 clinical sites in Japan. The survey was designed to assess clinical manifestation categorized by Fontaine’s classification, distribution of lesions (arterial involvement and migratory superficial phlebitis), response to medical and surgical treatment, and outcome. There were 771 males (90.7%) and 79 females (9.3%), with a mean age of 50.860.4 (range: 17–81) years. Clinical manifestations at the first consultation were Fontaine I in 8.0%, Fontaine II in 29.6%, Fontaine III in 23.9%, and Fontaine IV in 38.1%. These symptoms had been significantly improved by the time of survey. Ulcer formation in the past history had occurred in 45.2%, which was the most common in toes (85.9%). Failure of smoking cessation significantly affected the risk of ulcer formation (odds ratio51.71, 95%CI51.19–2.47; P50.004) and amputation (odds ratio52.73, 95%CI51.86–4.01; P,0.0001). Clinical features in female patients with TAO were equal to those in male patients, except for the fact that non-smokers were more common in female patients. Abstinence from tobacco significantly reduces the risk of ulcer formation and amputation, and thus improves the quality of life in patients with TAO. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Thromboangiitis obliterans; Buerger’s disease; Peripheral ischemia; Smoking; Epidemiology
1. Introduction Thromboangiitis obliterans (TAO or Buerger’s disease) is a segmental, occlusive inflammatory disease of the small and medium-sized distal arteries and superficial veins of unknown cause, occurring predominantly in young male habitual tobacco users [1]. The current concept of the pathogenetic mechanism for TAO is considered to be an interaction between the coagulation system, its control proteins, and the vascular endothelium [2]. The overall incidence of TAO seems to be decreasing with a relative changing of clinical spectrum, as the smoking habit in general population has significantly decreased [3,4]. TAO is more prevalent in some geographic areas than in North America and there is a probable ethnic pre*Corresponding author. Tel. / fax: 181-11-747-0476. E-mail address: [email protected] (S. Sasaki).
disposition [5]. In Japan, TAO is a common disorder among the chronic arterial occlusive diseases [6]. To clarify the current clinical presentation and outcome of intractable vasculitis, The Intractable Vasculitis Syndromes Research Group in Japan carried out the Nationwide Survey of Intractable Vasculitis in 1993, including TAO, Behc¸et’s disease, Takayasu’s aortitis, and inflammatory abdominal aortic aneurysm. We analysed clinical features and outcome in patients with TAO based on the Nationwide Survey database, and report the current clinical status of TAO in Japan.
2. Subjects and methods This is a retrospective clinical study on adult patients treated for TAO in Japan. The Intractable Vasculitis Syndromes Research Group in Japan de-
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00190-X
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S. Sasaki et al. / International Journal of Cardiology 75 (2000) S175 –S181
signed and performed the Nationwide Survey of TAO to assess clinical manifestation categorized by Fontaine’s classification, distribution of arterial and venous lesions, concomitantly associated disease, response to medical and surgical treatment, and outcome and complications. At the first survey, the questionnaire regarding the number of patients with TAO and other vasculopathy was mailed to 6209 clinical sites in Japan. Only patients aged 16 or older, who were treated or followed up for TAO between January 1 and December 31 in 1993, were considered eligible. The response to the questionnaire was obtained from 3722 clinical sites, and 3446 patients were diagnosed as having TAO. The definitive diagnosis of TAO was made according to the strict criteria which had been determined by the Ministry of Health and Welfare in Japan as shown in Table 1. From the results of the
first survey, the annual number of patients with TAO who visited hospital was estimated as approximately 10 000 (95% CIs (confidence intervals) 8400 to 12 000) in Japan. The second survey was performed on the 3722 clinical sites which responded to the first survey. The questionnaire regarding detailed clinical conditions was mailed to the clinical sites and the record with complete clinical information was collected for 850 patients. There were 771 males (90.7%) and 79 females (9.3%), with the mean age of 50.860.4 (range: 17–81) at the time of survey. The following studies were performed based on their records: 1. Comparison of clinical manifestations categorized by Fontaine’s classification between those at the first consultation in the past history and those at the time of survey.
Table 1 Diagnostic criteria for TAO in Japan a,b 1.
Clinical manifestations (mandatory; at least one or two of following) 1) Coldness, paresthesia, Raynaud’s symptoms in the distal upper or lower extremities 2) Intermittent claudi cation 3) Rest pain in the feet or hands 4) Painful digital ulceration or gangrene 5) Migratory superficial phlebitis
2.
Physical tests (mandatory; at least one or two of following) 1) Decrease in the skin temperature in the upper or lower extremities, or in the tips of the toes or fingers. 2) Absent distal pulses associated with preserved proximal pulses 3) Decrease in the Ankle Pressure Index with measurements of arterial Doppler pressure.
3.
Laboratory tests In patients with TAO, routine laboratory tests are usually normal.
4.
Arteriogram (mandatory; at least one or two of following) 1) Multiple, segmental occlusion in the distal artery (beyond the knee or elbow). 2) Chronic arterial occlusion secondary to the extension of thrombus. 3) No evidence for arteriosclerosis such as calcification of the arterial wall. 4) Tapering, abrupt occlusions, tortuosity of affected vessels. 5) The collateral arteries like a ‘corkscrew’ or ‘tree root’ appearance.
5.
No other vasculopathy (mandatory) Vascular disease to be ruled out: 1) Arteriosclerosis obliterans 2) Traumatic arterial thrombosis 3) Popliteal arterial entrapping syndrome 4) Occlusive vasculopathy due to systemic lupus erythematosus or scleroderma diffusum 5) Vasculo-Behcet’s disease a
Patients with distal limb ischemia exhibiting clinical manifestations, physical tests, angiographic findings described above, and without other vasculopathy can be diagnosed as having TAO. b Female patients, non-smokers, patients with risk factors for atherosclerosis such as diabetes mellitus or hyperlipidemia, or patients aged 50 or older should undergo differential diagnosis of other vasculopathy as accurately as possible.
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2. The incidence of ulcer formation and amputation. 3. The incidence of concomitantly associated disease. 4. Comparison of clinical profile and outcome between smokers and non-smokers to determine whether cessation of smoking affected clinical outcome of TAO.
2.1. Statistical analysis All continuous variables are presented as the mean6standard error (SEM). Univariate analysis was conducted with Student’s t-test for comparisons of continuous variables, the chi-square test for dichotomous variables. Wilcoxon signed-ranks test or Mann–Whitney’s U-test was employed for nonparametric comparisons of the categorized clinical score. Differences were considered significant at P, 0.05. All analyses were performed with SPSS software (SPSS Inc., Chicago, IL).
3. Results Demographic data are summarized in Table 2. The gender ratio was approximately 10:1, thus the incidence of female TAO in this study was 5–10 times as high as that reported previously. The mean age of patients at the time of diagnosis was 40.460.4 (range: 14–74). The most common age at diagnosis was in the 40s (n5331, 38.9%), second most common was in the 30s (n5269, 31.7%). Elderly patients aged 60 or older comprised 2.7% at the time of diagnosis. At the time of survey, the most common age was in the 40s (n5283, 33.3%), second most common in the 50s (n5269, 31.7%). Elderly patients aged 60 or older comprised 22.6% of patients at the time of survey. The majority of patients (93.2%) had a past history of smoking but 6.8% of patients developed TAO in the absence of the smoking history. Among patients with the smoking history, 79.8% of patients were able to stop smoking whereas 20.2% of patients failed to stop during the period of survey. Patient conditions during the period of survey were in-hospital in 3.5%, outpatient in 87.9%, and both in 8.1%. The majority of patients were thus treated as
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outpatient, however, approximately 10% of patients required admission during the period of survey. Four patients died of malignant neoplasm (n53) and cerebrovascular disorder (n51) during the period of survey. By the time of survey, nearly 90% of patients had experienced admission for treatment. The most common treatment was medical treatment, which was applied to 94% of patients (n5802). The frequently used medications were antiplatelet agents (n5611) and prostaglandins (n5460). Because of the distribution of distal arterial involvement, only 15% of patients had undergone surgical treatment. Clinical manifestations are summarized in Table 3. Clinical symptoms at the first consultation were Fontaine I in 8.0%, Fontaine II in 29.6%, Fontaine III in 23.9%, and Fontaine IV in 38.1%. At the time of survey, the severity of disease was significantly attenuated. Clinical manifestations categorized by Fontaine’s classification at the time of survey were symptom-free in 5.4%, Fontaine I in 44.2%, Fontaine II in 38.4%, Fontaine III in 6.2%, and Fontaine IV in 5.8% (P,0.0001 vs. first consultation; by Wilcoxon signed-ranks test). The most commonly affected lesion was the distal peripheral artery in the lower extremities, but approximately 25% of patients suffered upper extremity involvement. The ischemic ulcer has been present in 45.2% of patients in the past history, which was the most common in toes. The migratory superficial phlebitis was present in 16.0%. Major or minor amputation was undertaken for 25.2% of patients. To exclude effects of amputation from improved results of ischemic symptoms, Fontaine’s classification in a subgroup of patients without a history of amputation (n5636) was compared between that at the first consultation and at the time of survey. Clinical symptoms categorized by Fontaine’s classification at the time of survey in these patients were significantly improved when compared to those at the first consultation (P,0.0001 by Wilcoxon signed-ranks test). Findings were thus similar to those obtained in all patients. Table 4 summarizes comparisons of clinical profile and outcome between patients who succeeded in cessation of smoking (ex-smokers) and those unable to stop smoking (smokers). Demographic data and clinical symptoms at the first consultation were not significantly different between the two groups. However, clinical symptoms at the time of survey were
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Table 2 Demographic data No. of patients Male / Female
850 771 (90.7%) / 79 (9.3%)
Age distribution (year) ,20 20–29 30–39 40–49 50–59 60– Mean
At diagnosis 12 (1.4%) 107 (12.6%) 269 (3 1.7%) 331 (38.9%) 108 (12.7%) 23 (2.7%) 40.460.4 (range: 14–74)
Smoking in the past history Yes / No
792 (93.2%) / 58 (6.8%)
Cessation of smoking in smokers a Yes / No
582 (79.8%) / 147 (20.2%)
Patient conditions during the period of survey In-hospital Out-patient In- and out-hospital Deceased (cause of deaths) Malignant neoplasm Cerebrovascular disorder
29 727 67 4
(3.5%) (87.9%) (8.1%) (0.5%)
3 1
The number of admission in the past history None 1 2 3 4 .5
86 388 137 83 36 58
Arteriography (Yes / No)
850 / 0
Medical treatment (Yes / No) Type of medications Antiplatelet Prostaglandins Vasodilators Anticoagulant Others
802 / 48
Surgical treatment (Yes / No) Type of bypass surgery Aortofemoral Femoropopliteal Femorotibial Others a
At survey 2 (0.2%) 23 (2.7%) 81 (9.5%) 283 (33.3%) 269 (3 1.7%) 192 (22.6%) 50.860.4 (range: 17–81)
(10.9%) (49.2%) (17.4%) (10.5%) (4.6%) (7.4%)
611 460 272 119 64 132 / 718 11 52 42 27
Missing data for 63 patients.
significantly improved in ex-smokers than in smokers. In addition, failure of abstinence from tobacco significantly affected the risk of ulcer formation (odds
ratio51.71, 95%CI51.19–2.47; P50.004) and amputation (odds ratio52.73, 95%CI51.86–4.01; P,0.0001). Thus cessation of smoking after the
S. Sasaki et al. / International Journal of Cardiology 75 (2000) S175 –S181 Table 3 Clinical manifestations Fontaine’s classification (all patients) at the first consultation Symptom-free 3 (0.4%) I 68 (8.0%) II 252 (29.6%) III 203 (23.9%) IV 324 (38.1%)
at the time of the survey a 46 (5.4%) 376 (44.2%) 326 (38.4%) 53 (6.2%) 49 (5.8%)
Distribution of arterial involvement Upper extremities 42 (5.1%) Upper and lower 167 (20.2%) Lower extremities 616 (74.7%) History of ischemic ulcer formation Yes / No 384 (45.2%) / 466 (54.8%) Toes 330 (85.9%) Fingers 39 (10.2%) Others 15 (3.9%) History of major or minor amputation Yes / No 214 (25.2%) / 636 (74.8%) Fontaine’s classification in patients without history of amputation at the first consultation at the time of survey a Symptom-free 2 (0.3%) 33 (5.2%) I 63 (9.9%) 310 (48.7%) II 228 (35.8%) 240 (37.7%) III 164 (25.8%) 35 (5.5%) IV 179 (28.1%) 18 (2.8%) Migratory superficial phlebitis Yes / No 136 (16.0%) / 714 (84.0%) Associated disease Hypertension Hyperlipidemia Diabetes a
115 (13.5%) 67 (7.9%) 37 (4.4%)
P,0.0001 by Wilcoxon signed-ranks test.
definite diagnosis significantly improved clinical course and quality of life (QOL) in patients with TAO.
4. Discussion Thromboangiitis obliterans is a progressive, often relentless and devastating, vasculitis causing significant loss of digits and limbs predominantly in a youthful population of tobacco users. The age of onset usually ranges from 35 to 50 years, more frequently found in males. Although the cause of TAO is unknown, tobacco use is clearly a trigger for
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what appears to be an autoimmune mechanism in a group of patients [7,8]. In addition to abnormal peripheral microcirculation, some systemic factors (immunological or humoral) and an interaction between the coagulation system, its control proteins, and the vascular endothelium may be involved with development of TAO [2,9,10]. Papa and associates reported that patients with TAO had a significantly higher frequency of HLA-DR4 and a significantly lower frequency of the HLADRW6 antigen than control groups [9]. Eichhorn and associates have recently reported that patients with TAO had a higher titer of antiendothelial cell antibodies (AECA) than normal healthy subjects [10]. It appears that there may be some predisposition or some abnormality in the humoral or cell-mediated response to endothelial cells, collagen, or a tobacco glycoprotein antigen in people who will develop TAO, and these genetic predisposition may account for the development of TAO in non-smokers. Since the smoking habit in general population has significantly decreased, the incidence of TAO appears to be decreasing. According to Lie and associates, the prevalence rate of TAO has declined steadily from 104 / 100 000 in 1947 to 13 / 100 000 in 1986 (an eight-fold decrease) in North America [1]. TAO has a worldwide distribution with greater prevalence in the Orient, India, Southeast Asia than in North America [5,11]. In this series, the estimated prevalence rate of TAO (8400 to 12 000 in Japan, equivalent to 7 to 10 / 100 000) was almost equal to that in North America in 1986. Among the chronic arterial occlusive diseases, TAO is a common disorder in Japan. The present study documented the changes in demographic spectrum in patients with TAO. Until the middle of 1980s, female or elderly patients were thought to comprise less than 2% of the patients with TAO [1,5]. However, the prevalence of TAO in women has been increasing, which is attributable to the increased number of women cigarette smokers in the past few decades [4,5]. The prevalence of female TAO in this study is 9.3%, which is almost consistent with the reported prevalence rate ranging from 11 to 23% [1,4]. In addition, the prevalence of elderly patients was also increasing [4]. In this series, patients with TAO aged 60 or older comprised 22.6% of patients at the time of survey. The onset age of TAO usually ranges from 35 to 50 years, but the
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Table 4 Comparison of clinical profile and outcome between ex-smokers and smokers Factors
Ex-smokers (n5582)
Smokers (n5147)
Age Male / Female
50.460.4 533 / 49
51.160.8 139 / 8
Fontaine’s classification at the first consultation symptom-free 3 (0.5%) I 44 (7.6%) II 181 (31.1%) III 139 (23.9%) IV 215 (36.9%) Chi-Square value (Pearson)55.958 Fontaine’s classification at the time of survey symptom-free I II III IV
Ulcer or gangrene formation Yes No Major or minor limb amputation Yes No
0.483 0.229
0 (0.0%) 15 (10.2%) 37 (25.2%) 29 (19.7%) 66 (44.9%) 0.202
39 (6.7%) 270 (46.4%) 223 (38.3%) 26 (4.5%) 24(4.1%) Chi-Square value (Pearson)525.04
5 (3.4%) 47 (32.0%) 64 (43.5%) 16 (10.9%) 15 (10.2%)
243 (41.8%) 339 (58.2%) Odds Ratio51.71 (95% CIs51.19 to 2.47)
81 (55.1%) 66 (44.9%)
120 (20.6%) 462 (79.4%) Odds Ratio52.73 (95% CIs51.86 to 4.01)
61(41.5%) 86 (58.5%)
mean age of patients may become higher as they grow older. The additional demographic change in the distribution of arterial involvement is the increasing prevalence of upper-extremity involvement. The peripheral distal arteries in the lower extremities were affected in nearly all patients (94.9%), but approximately 25% of patients suffered upper extremity involvement in this series. The reported incidence of upper extremity involvement ranges 28–50% [1,4], thus this report is also consistent with the increased incidence of upper extremity involvement [4]. Major or minor amputation was still required in 25.2% of patients in this series, the relatively high rate of amputation documented the virulence of TAO [7]. Medical treatment has been undertaken for nearly all patients (94.4%) whereas surgical treatment has been employed for only 15.5% of patients, because of the distribution of arterial involvement and the lack of distal anastomotic sites available for outflow vessels. The majority of patients (88.5%) were treated as outpatient during the period of survey, but approximately 90% of patients had undergone in-
P-value
,0.0001
0.004
,0.0001
hospital treatment in the past history. They needed admission in the hospital most likely due to amputation surgery, arterial reconstruction surgery, treatment for ischemic ulcers, or angiography for a definitive diagnosis. Concomitantly associated disease was not characteristic and rare complications, such as ischemia of the small bowel or central nervous system involvement [12–14], were not observed in this series. Antiplatelet drugs, prostaglandins, and vasodilators were commonly used in many clinical sites in Japan, although there has been no reliable evidence that they might interrupt progression of disease. Fiessinger and associates have demonstrated the efficacy of iloprost [15] compared with an ordinary regimen, but the current study could not identify the regimen which would be the most likely to be effective. Anyway, the severity of disease at the time of survey was significantly improved when compared with that at the first consultation, probably in response to treatment or cessation of smoking. In general, cessation of smoking is the most important factor in the treatment of TAO. Smokers
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account for almost all patients with TAO [16]. Disease progression and major limb loss usually depend upon whether the patient stops smoking or not [17]. Medical and surgical therapy palliate accrued damage, but only complete abstinence from tobacco use allows stabilization of the process. The overall incidence of smoking has declined especially among educated people, but the rate of decline of smoking among women has not been as great as that among men due in part to the high rate of smoking among young women [16]. As far as smokers account for nearly all patients with TAO, the male-to-female ratio of TAO will continue to be decreasing. In the current series, clinical symptoms at the first consultation were not significantly different between patients who stopped smoking and those who continued smoking. However, clinical symptoms at the time of survey were significantly improved in patients who stopped smoking. In addition, failure of smoking cessation significantly affected the risk of ulcer formation and amputation. Thus this paper also documented that cessation of smoking after having diagnosis of TAO significantly improved the clinical course and QOL. Although this survey included comparison of clinical manifestations categorized by Fontaine’s classification, the use of Fontaine’s classification may not be the best way to categorize clinical manifestations in TAO. The pathophysiology of ischemia in TAO is different from that in atherosclerosis, and the earliest complaints of patients with TAO are usually rest pain in the feet or hands, painful digital ulcerations or gangrene. Unfortunately, there has not been an appropriate, worldwide-accepted clinical staging that corresponds to ischemic symptoms in TAO. This may be a reason that Fontaine’s classification has been employed for the clinical staging of peripheral occlusive disease other than atherosclerosis in the past literature [18]. It should be noted that Fontaine’s classification for TAO is used only as a simple expedient to indicate ischemic clinical manifestations. As this study is one of the largest series of surveillance for TAO in the last decade, the obtained results will help us understand current clinical status in TAO. We conclude that TAO is a treatable disease
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when diagnosed early and if strict cessation of smoking is observed. Abstinence from tobacco significantly reduces the risk of ulcer formation and amputation, and thus improves the quality of life in patients with TAO.
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