Current Status of Patients with Buerger Disease in Japan

Abstract

The prevalence and clinical characteristics of Japanese patients with Buerger disease (thromboangiitis obliterans: TAO) were analyzed based on the Ministry of Health, Labour and Welfare (MHLW) database in 2009. A total of 129 new patients and 3639 patients in follow-up were selected according to the clinical criteria of TAO. The current number of patients with TAO in Japan is estimated at about 4000. The clinical course is relatively favorable, and the rates of limb morbidity and mortality were not completely discouraging.

Introduction

Buerger disease (TAO) is characterized by segmental lesions in arteries and veins of the extremities, and is observed in young and middle aged male smokers. Although smoking, nutritional disorder, autoimmunity, activation of vascular endothelial cells, and infection including chronic anaerobic periodontitis^1–5) have been proposed as factors influencing the onset of TAO, the true cause of TAO is still unknown.

TAO has been defined as one of the ‘Specified Rare and Intractable Diseases’ since 1972 in Japan. Due to the lack of information and statistics on patients with TAO, a nationwide research project was started in 1973 in Japan. At the same time, an official application system for patients with ‘Specified Rare and Intractable Diseases’ to aid with medical costs was established. Based on the data on TAO cases published by the Japan Intractable Diseases information Center (JIDIC) with the support of the Ministry of Health, Labour and Welfare (MHLW), the number of patients with TAO who received aid with medical costs has rapidly decreased over the last 10 years in Japan. In 2009, 7591 patients with TAO were certified as having a Specific Disease (Fig. 1).⁶⁾

Fig. 1.

The number of patients with a claimant certification for medical care of Buerger disease.

With permission for the use of clinical research registration forms in 2009 directly obtained from the MHLW, the current status regarding the epidemiological and clinical aspects of TAO was analyzed.

Patients and Methods

In new patients, who were initially registered in 2009, factors such as gender, age, age at disease onset, age at diagnosis, clinical criteria (definite or probable), smoking habit, severity of symptoms, site of ischemic limbs, clinical symptoms, angiographic findings, differential diagnosis from other peripheral arterial diseases, treatments, present social activity, and present lifestyle were reviewed. Patients who fulfilled all the diagnostic criteria for TAO were defined as “definite” and those who did not fulfill all the diagnostic criteria but were strongly suspected to have TAO from clinical symptoms and imaging findings were defined as “probable”.

In patients in follow-up, factors such as gender, age, age at disease onset, age at diagnosis, clinical criteria (definite or probable), smoking habit, severity of symptoms and clinical symptoms both at the time of being first diagnosed and at present, treatments, the clinical state over the last year, present social activity, and present lifestyle were reviewed.

A detailed description of the registration system is as follows: once clinical questionnaires are completed by the doctors who examine and treat the patients, and patients submit these to the local health department. After the contents of questionnaires are confirmed by a prefecture review committee, they are reported to the MHLW. The diagnosis of TAO is based on the criteria for published by the Intractable Vasculitis Study Group of the MHLW (Table 1),⁷⁾ which were originally proposed by Shionoya.⁸⁾

According to the clinical criteria for TAO, in both new and follow-up patients, those with an onset age more than 50 were excluded. Only new patients with DM were excluded. However, in follow-up patients, those with DM were not excluded because there is a possibility of them suffering from DM in the clinical course after the onset of Buerger disease. Of the 239 new patients (male: 201; female: 38), 110 (male: 91; female: 19) were excluded, and of the 5990 patients undergoing follow-up (male: 5222; female: 768), 2351 patients (male: 2028; female: 323) were excluded.

The severity classification of TAO was categorized into 5 stages in the questionnaire, is shown in Table 2.

Statistical Analysis

Rates of the clinical symptoms were analyzed with a 2-sided Fisher exact test. A p-value <0.05 was defined as being significant.

Results

Characteristics of the new patients and patients in follow-up are shown in Table 3.

New patients

Overall, 129 patients (male: 110; female: 19) were enrolled in this study.

Clinical symptoms at the first diagnosis compared with at new registration are shown in Table 4. Some symptoms except for claudication, gangrene, and skin ulcer had significantly improved at new registration.

Social functioning of the new patients is shown in Table 5. Seventy-seven percent of patients could lead a daily life despite ischemic symptoms.

The lifestyle of the new patients is shown in Table 6. The majority of patients could lead an independent life.

118 of the 129 patients (male: 104; female: 14) (91.4%) had undergone arteriography. The details of arteriographic findings are shown in Table 7.

The possibility of the differentiation of TAO from other peripheral arterial diseases is shown in Table 8.

The use of oral medicine in 129 patients was as follows: platelet aggregation inhibitor, 110 (85.3%); vasodilator, 74 (57.4%); and anticoagulant, 23 (17.8%).

Forty-one of the 129 patients (31.8%) had a history of surgery. Eighteen (14.0%) had undergone arterial reconstruction, 18 (14.0%) limb amputation (major amputation, 6; minor amputation, 11; unknown, 1), and 19 (14.7%) lumbar or thoracic sympathectomy.

Patients undergoing follow-up

Overall, 3639 patients (male, 3194; female, 445) were enrolled in this study.

The use of oral medicine in 3639 patients was as follows: platelet aggregation inhibitor, 2816 (77.4%); vasodilator, 1950 (53.6%); and anticoagulant, 691 (19.0%).

There were 1453 patients (39.9%) that had a history of surgical intervention, 1969 (14.0%) with no surgical intervention, and 217 (14.7%) with no records.

Among 3639 patients, 1453 patients (39.9%) had a history of surgical intervention, 1969 (14.0%) had no surgical intervention, and 217 (14.7%) had no records. Among patients with surgical intervention, 480 (13.2%) had a history of arterial reconstruction, 644 (17.7%) had undergone limb amputation (major amputation, 227; minor amputation, 341; unknown, 76), and 946 (14.7%) had received lumbar or thoracic sympathectomy. Among the 3639 patients, 227 (6.2%) underwent major amputation. Many patients received a variety of medical treatments and sympathectomy, and the outcome of arterial reconstruction was not described in the registration form. Therefore, it was difficult to clarify what kind of treatment was effective for limb salvage in this study.

The severity of ischemia at the first diagnosis was compared with those at the follow-up registration (Table 9). The percentages of patients with Stage I/II increased, and those with Stage III/IV/V significantly decreased.

Clinical symptoms at the first diagnosis were compared with those at the follow-up registration (Table 10). The percentages of patients significantly decreased for every symptom.

Social functioning of the follow-up patients is shown in Table 11.

The high frequency of patients requiring home care might be because of the inclusion of patients over the age of 70.

Physical functioning is shown in Table 12. The majority of patients could lead an independent daily life without help.

Results regarding the medical condition over the past year were as follows: 226 (6.2%), improved; 2995 (82.3%), stable; 258 (7.1%), gradually deteriorated; 26 (0.7%), rapidly deteriorated. In 1870 patients over the age of 60 (51.4%), enlargement of an ischemic ulcer occurred in only one patient with an age of 76 (0.005). The occurrence or recurrence of ischemic ulcers seemed to be rare in those with TAO.

Discussion

On analyzing the clinical research forms of TAO patients in 2009 directly obtained from the MHLW, several limitations were revealed.

First, comparing the total registered patients in this database (n = 6529) in 2009 with the number of patients officially applying for aid with medical costs (n = 7591) reported by the JIDIC in 2009,⁶⁾ the input rate of patients was low (86.0%). This is because several prefectures failed to submit annual reports of TAO registration in 2009.

Second, the diagnosis of TAO should be confirmed based on 5 clinical criteria.^7,8) Of the 6529 patients directly obtained from the MHLW in 2009, 110 of the 239 new patients and 3281 of the 6290 patients who underwent follow-up should be excluded because their ages at disease onset were over 50 or they were diabetic. The true number of patients with TAO may be smaller than that reported by the JIDIC.

Third, there is no specific diagnostic test and no positive serologic markers for diagnosing TAO. Although we mentioned ‘the diagnosis of TAO should be confirmed based on 5 clinical criteria’ in the previous section, it is sometimes clinically difficult to distinguish between TAO and some types of collagen disease even if employing 5 clinical criteria. Clinical features of collagen disease, including the age at disease onset, symptoms, sites of arterial involvement, and arteriographic findings, are sometimes similar to those of TAO. According to the JIDIC, the prevalence of women in those with Buerger disease is 9%,⁹⁾ but that of those with systemic lupus erythematosus is 90%¹⁰⁾ and scleroderma is 92%.¹¹⁾ In this study, the prevalence of women was 14% in the new patients and 12% in the patients in follow-up. Several authors reported an extremely low prevalence of women with TAO;^12–16) however, others reported a higher prevalence.^17,18) They suggested that the reason for an increase in the prevalence of women with TAO is a rise in cigarette smoking among women. However, it is possible that a certain number of patients, especially women, with other autoimmune vasculitis are included. In order to rule this out, such serologic markers as anti-nuclear antibodies, anti-SS-A and anti-SS-B antibodies, anti-RNP antibodies, anti-ds-DNA antibodies, anti-cardiolipin antibodies, anti-centromere antibodies, anti-topoisomerase antibodies, lupus anticoagulant, and C3, C4, CH50 should be added to the clinical questionnaire.

Forth, patients with TAO can receive the subsidized medical costs according to their income. In order to receive the subsidy, it is necessary to submit both the clinical questionnaire form completed by doctors and the application form for aid with medical costs. Patients with a high income do not usually submit both forms. At the same time, there is a medical payment support system in Japan to aid patients aged over 65, and total medical support for patients receiving public assistance. These patients also do not need to submit both forms. Thus, these patients with TAO may be lost in the database.

The prevalence of TAO has been gradually decreasing in Japan.^19,20) It was difficult to clarify the correct number of patients with TAO in the MHWL database in 2009, because 110 of 239 new patients (46.0%) and 2351 of the 5990 patients in follow-up (39.2%) who did not fulfill the clinical criteria of TAO were excluded. The present prevalence in Japan may be far lower than that previously reported based on the registered questionnaire. Indeed, only a few new patients per year are currently encountered at our outpatient clinic. While the true etiology of this disease remains unknown, we consider that the decrease in the prevalence of TAO might have resulted from the improvement of sanitary conditions of daily life resulting from an improvement of the socioeconomic status.^14,21)

It is well known that smoking is very closely related to the exacerbation and remission of the disease and limb amputation.^12–18) An analysis of 850 patients identified in a national study in Japan showed that the risk of amputation was 2.73 times higher (95% CI: 1.86-4.01) in patients who continued to smoke.¹⁶⁾ In this study, only 233 of 3768 new and follow-up patients (6.2%) underwent major limb amputation. The fate of limbs was not completely discouraging. Further research on the association between continuing smoking and the fate of limbs is necessary.

In our previous study,^12,14) no ischemic ulcers occurred or recurred in patients older than 60 years. In this study, an ischemic ulcer occurred in only one of 1870 patients older than 60 years (0.05%). These findings suggest that the occurrence or recurrence of ischemic ulcers is rare in those over the age of 60 in patients with TAO, perhaps because the progression of arterial occlusion due to TAO might stop over the age of 60, and atherosclerotic changes might be unlikely in the developed collateral arteries.

The mortality demographics in patients with TAO are similar to those in the normal population.^12–14) It is difficult to know the actual situation because of the absence of an item about mortality rates in the questionnaire; however, it can be estimated that the outcome in patients with TAO is relatively favorable from the age distribution of the patients who were followed up shown in Table 3.

In conclusion, this study suggested that the diagnosis of TAO remains difficult due to a lack of specific clinical findings. The current number of patients with TAO in Japan is considered to be about 4000. The decrease in the prevalence of TAO could be mainly related to more precise diagnostic criteria. The clinical course regarding limb morbidity was not discouraging. The progression of symptoms was self-limited and recurrent ulcers occurred less frequently with aging. Further efforts to accurately clarify the prevalence of patients with a correct diagnosis and obtaining more precise information about the clinical course regarding limb morbidity and mortality are necessary to eradicate the disease in the near future.

Acknowledgement

We would like to gratefully acknowledge the enthusiastic supervision and leadership of Professor Hirofumi Makino (Department of Medicine and Clinical Science, Okayama Graduate School of Medicine and Dentistry) who is a team leader of the research project on intractable vasculitis funded with a Health and Labour Sciences Research Grant, and we would like to thank members of the Health Service Bureau in Ministry of Health, Labour and Welfare for the kind cooperation in the use of national data for 2009.

Disclosure Statement

We received a subsidy from the Health and Labour Sciences Research Grant for Research Projects on Intractable Vasculitis in 2009.