A comprehensive review of the epidemiology and clinical features of 91 cases with Buerger’s disease

Abstract

Background

Thromboangiitis Obliterans (TAO) is a disease of small and medium-sized arteries with an unclear natural course. This study aims to establish a national registry of the disease to gain a better understanding of its epidemiology and clinical course.

Method

This study was a cohort study of 242 patients with a high probability of TAO admitted to Mashhad University of Medical Sciences (MUMS) hospitals from 2000 to 2015. Of these, 91 patients with a confirmed diagnosis were included in the study (90 males and 1 female) with a mean age of 35 ± 7.8 years.

Results

The most common symptom upon onset of the disease was paresthesia (29.7%), followed by cold sensitivity and paresthesia (93.4%) during the progression of the disease and Raynaud syndrome or vasospasm (93.9%) in the active phase. The right lower limb was the most commonly affected limb (46.2%), and presenting ischemic symptoms in 48.4%.

Statistics indicated a positive correlation between the duration of Burger’s disease and the number of affected limbs (p = 0.001). There was no effect of disease duration on the likelihood of amputations (p = 0.28).

Conclusion

Some patients may experience mild, subtle symptoms for years before the initial signs and symptoms appear, which can be severe and rapidly progress to the point of requiring amputation.

We suggest that the diagnostic criteria for Buerger’s disease should be revised in light of the presence of atherosclerosis and its associated risk factors, which present a challenge in terms of diagnosis and treatment. Clinical experience will be of great importance in this regard.

Keywords

Thromboangiitis obliterans epidemiology clinical feature

Introduction

Thromboangiitis Obliterans (TAO), otherwise known as Buerger’s disease, is a non-atherosclerotic, segmental obliterative inflammatory disease of small and medium-sized arteries, primarily impacting the infrapopliteal and infra brachial arteries.^1–4 It can be distinguished from other arterial necrotizing pathologies by its perivascular inflammation and preservation of the arterial internal elastic layer.⁵ Although Buerger’s is a global phenomenon, it is more prevalent in Asia and Eastern Europe than in North America and Western Europe.^6,7 Estimates of TAO’s contribution to arterial occlusive diseases range from 0.5 to 5.6% in western Europe, 45 to 63% in India, and 80% in Ashkenazi Jews.⁸ In North East Iran, the prevalence of TAO is 3 out of 100,000 in the general population,⁹ and 5 out of each 100,000 in Japan in 1985.⁸ The disease is particularly common among young male smokers of low socioeconomic status.^9,10 However, due to the rise in female smokers,^11,12 the incidence of TAO among females is increasing. The strong association between smoking and TAO is a defining characteristic of the disease.¹³

Although the clinical features and diagnosis criteria of TAO have been largely established,¹⁴ the etiology of the disease remains unclear. Additionally, the natural clinical course of the disease has remained unclear due to the interference of therapeutic interventions.

Various sequences of symptoms have been identified, but not comprehensively described.^15,16 This has resulted in the formulation of various diagnostic criteria, such as those proposed by Shionoya, Porter, Miles, Papa, and Olin.^10,17–21

This study was conducted at Mashhad University of Medical Sciences with the aim of establishing a registry system for Buerger’s disease. This registry would include symptoms, the sequence of them, and its clinical course, which would lead to a better understanding and tracking of the disease in Iran.

Methods and material

In this cohort study conducted by the Mashhad Vascular and Endovascular Research Center (MVASRC), 242 patients with a probable diagnosis of TAO admitted to Mashhad University of Medical Sciences (MUMS) hospitals from 2000 to 2015 were studied. According to the diagnostic criteria of Shionoya (Figure 1) and the expert opinion,²² 17 were excluded. The remaining 225 patients were contacted and invited to the clinic for re-evaluation.⁹ This was done to double-check the diagnosis and obtain informed consent. Ultimately, 91 patients with a confirmed diagnosis of Buerger’s disease were enrolled in the study. (Figure 2) The study was approved by the MUMS ethical committee and all participants provided informed consent. Each participant was assigned a unique code, and registry fields were completed in five sections.

A. Personal information including demographic information, past medical history, drug history, social history (i.e., substance abuse and smoking).

B. Clinical and Paraclinical information including symptoms, signs, and presentation of disease, as well as evaluations of disease activity and severity. Lab tests and consultations were also conducted.

C. Clinical course of the disease was noted as course of the disease, record of exacerbation and remission episodes, trigger and alleviating factors and drawing the diagram of turning points (Figure 3).

D. Therapeutic measurements: Whether they were medical, surgical, or combination.

E. Biobanking: Ten milliliters of blood was collected from the patients for serum separation, DNA extraction, antibody measurement with ELISA, and HLA typing with molecular kits to determine HLA-allele. These samples were stored at −70°C.

According to certainty of diagnosis of the disease, patients were divided in 2 groups:

Group 1 consisted of patients who fulfilled the five diagnostic criteria of Shionoya and whose diagnosis was further confirmed by the authors based on their clinical and paraclinical characteristics.

In Group 2, patients had been affirmed as having Burger’s disease by the expert group, but only met four Shionoya criteria. To be included in the study, these patients had to show no signs of atherosclerosis on imaging or any rheumatologic condition. An expert rheumatologist was consulted to rule out any rheumatologic conditions.

Furthermore, according to the activity phase of the disease, 91 cases were divided into three categories.

A. Active; patients presenting with new symptoms in the past 3 months, such as superficial thrombophlebitis, burning discomforting pain, new ulceration, or progression of existing ulcers, or gangrene.

B. Remission; patients with static cold sensitivity or paresthesia, a stable chronic ulcer, and claudication without a discomforting burning pain or any progression of symptoms in the last 3 months.

C. Clinical cure; patients with no symptom of the disease.

This paper focuses exclusively on the epidemiology, demographic, and clinical symptoms of Burger’s Disease. Other aspects of the disease, such as clinical course, exacerbation and remission factors, and paraclinical tests, are addressed in other publications.^23–27

All data was processed using SPSS Version 24. To compare between groups, appropriate tests were employed for quantitative data (T-test and Mann–Whitney test, Kruskal–Wallis, etc.) and qualitative variables (chi-squared test). Correlation analysis was used to investigate the relationship between affected limbs and the duration of the disease. Regression analysis was conducted to assess the impact of disease duration on the likelihood of limb amputation.

Ethical considerations

This study was approved by the Institutional Review Board of Mashhad University of Medical Sciences, and written informed consent was obtained from all participants in accordance with the principles outlined in the Declaration of Helsinki.

Results

Ninety-nine percent (90 out of 91) of the patients were male, with an average age at the onset of the disease of 35 ± 7.8 years. Two patients were older than 50 years (54 and 52), but possessed other criteria of Shionoya.

The certainty categorization yielded 64 patients in group 1 and 27 in group 2. When comparing the two groups, no statistically significant differences were observed in the average age at which the disease began (34.3 ± 7.3 vs 37.7 ± 8.4, p = 0.083), average disease duration until re-evaluation (7.82 ± 5.45 vs 5.96 ± 6.15, p = 0.054), the most common symptom in the course of the disease (Table 2), first involved limb, frequency of limb ischemic symptoms (Table 5), or tobacco consumption.

Seven patients had a history of other atherosclerotic risk factors in addition to smoking; one had hypertension and hyperlipidemia, four had hypertension, two had diabetes mellitus and hyperlipidemia, yet none of them exhibited any radiologic signs of atherosclerosis.

Eighteen of the 91 patients did not exhibit thrombophlebitis migrans or upper limb involvement, although four of them had impaired Allen’s test results. All patients had lower limb involvement.

Of the 91 cases studied, 6 (6.6%) were highly educated, 72 (79.1%) had some level of education, and 13 (14.3%) were illiterate.

Of the 91 patients with Burger’s Disease, 93.4% (85) were married, 4.4%⁴ were single, and 2.2%² were divorced. 74.7% (68/91) of the patients had a job, while 25.3% (23/91) were unemployed. Four cases had a positive family history of Buerger’s disease.

Seventy-one of the 91 patients (78%) had a prior hospitalization related to Buerger’s Disease, with nine of them having been admitted more than five times.

Ten patients (10.9%) reported a major trauma as a triggering event for the onset of Burger’s Disease.

All the patients (100%) reported using tobacco when the initial symptoms emerged. Among them, 87 (95.6%) were cigarette smokers, 81 (89%) were addicted to opium, and 3 (3.3%) were intravenous illicit drug abusers. On average, the patients began using tobacco and/or opium at 21 ± 6.56 years of age, and the average time between starting and the onset of symptoms was 14.19 ± 7.35 years.

Three patients had quit smoking at the time of re-evaluation, and only these patients met the criteria for being categorized as clinically cured. In this study, quitting smoking was defined as cessation for two or more years without restarting.

27 cases (29.7%) presented with paresthesia, 20 (22%) with claudication, and 18 (19.8%) with thrombophlebitis migrans as the most commonly reported initial symptoms. Severe rest pain, gangrene, and chronic ulcer occurred as the first symptoms in 12 patients (13.1%), as shown in Table 1.

Table 1.

Frequency of first symptom of TAO in patients.

First symptoms of disease	Frequency	% Frequency
Paresthesia	27	29.7
Claudication	20	22
Thrombophlebitis migrans	18	19.8
Rest pain	8	8.8
Reynaud phenomenon	7	7.7
Purple discoloration	3	3.3
Chronic ulcer	3	3.3
Swelling of the extremities	2	2.2
Others symptom	2	2.2
Gangrene	1	1.1
Total	91	100

The most common symptoms reported during the disease by the patients were cold sensitivity and paresthesia (93.4%), claudication (87.9%), rest pain (81.3%), and chronic ulcer (79.1%). These frequencies are presented in Table 2.

Table 2.

Frequency of symptoms experienced during the disease course.

Symptoms experienced during the disease	Frequency	% Frequency
Paresthesia and cold sensitivity	85	93.4
Claudication	80	87.9
Rest pain	74	81.3
Chronic ulcer	72	79.1
Purple discoloration	61	67
Gangrene	52	57.1
Thrombophlebitis migrans	34	37.4
Nail infection	8	8.8
Subungual hemorrhage	2	2.2

p-value between group 1 and 2 > 0.05.

The prevalence of Burger’s Disease is higher during cold seasons (autumn and winter), as demonstrated in Table 3.

Table 3.

Frequency of TAO onset in different seasons.

Season of TAO onset	Frequency	% Frequency
Winter	34	37.4
Autumn	27	29.7
Summer	17	18.7
Spring	8	8.8
Unknown	5	5.5

At the time of re-evaluation and physical examination, 36.3% of patients were found to be in the active phase of the disease, 38.5% in remission, and 3.3% in clinical cure.

In the active phase of Buerger’s Disease, 93.9% of patients presented with Raynaud Syndrome and vasospasm, while 81.7% reported paresthesia. Claudication (75.8%), ulcer (68.8%), and gangrene (30%) were also common symptoms (Table 4).

Table 4.

Frequency of patients’ symptom in acute phase (N = 33).

TAO symptoms in acute phase	Frequency	% Frequency
Raynaud’s or vasospastic symptoms	31	93.3%
Finger burning and paresthesia	27	81.8%
Claudication	25	75.8%
Purple discoloration	24	72.7%
Chronic ulcer	22	66.7%
Rest pain	18	54.4%
Gangrene	10	30.3%
Thrombophlebitis	2	6.1

The right lower limb was the most commonly affected site (46.2%), most often presenting ischemic symptoms (48.4%). In 77 cases, the lower limbs were the first to be affected, while the upper limbs were the first to be affected in 14 cases. The right side was more commonly affected (55%) than the left (45%), as seen in Table 5.

Table 5.

Frequency of extremities involvement and ischemia at the onset of TAO.

InvolvedLimb	First limb involvement		First limb ischemia
InvolvedLimb	Frequency	% Frequency	Frequency	% Frequency
Lower R^a	42	46.2	44	48.4
Lower L^b	34	37.4	32	35.2
Upper R	8	8.8	8	8.8
Upper L	6	6.6	6	6.6
Lower R and L	1	1.1	1	1.1
Total	91	100	91	100

^aRight.

^bLeft.

p-value between group 1 and 2 = 0.24.

In 53 cases (58%), more than one limb was observed to be affected. Table 6 provides further details.

Table 6.

Frequency of number of involved limb in the course of TAO.

Number of involved limb	Frequency	% Frequency	Average time of illness (y) ± SD
1 Limb	38	41.7	5 ± 4.12
2 Limbs	22	24.2	7.95 ± 6.051
3 Limbs	7	7.7	7 ± 3.70
4 Limbs	24	26.4	10.25 ± 6.50
Total	91	100	—

A statistically significant positive correlation was identified between the number of affected limbs and the duration of the disease (Spearman’s p-value: 0.001, r = 0.314).

Kruskal–Wallis test revealed a significant difference in the average disease duration and number of involved limbs (p < 0.01).

Abnormal Allen’s test was detected in 55 patients (60.5%), as indicated in Table 7.

Table 7.

Frequency of abnormal Allen’s test.

Abnormal Allen’s test	Frequency	% Frequency
Right	10	11.0
Left	6	6.6
Right and left	39	42.9
Normal	36	39.5
Total	91	100

Thirty-three patients underwent a minor amputation, with 30 cases (33.7%) involving the lower limb and 9 (10%) involving the upper limb. Major amputation of the lower limb occurred in 13 cases (14.2%), while one patient experienced major amputation of the upper limb.

Regression analysis was applied to assess the effect of disease duration on major, minor, and number of limb amputations. The results revealed that disease duration did not have a significant effect on the likelihood of amputations (p = 0.28).

All 91 patients received basic oral medical treatment, including anti-platelet, calcium channel blocker, and folic acid as a three-drug regimen. 25 patients were treated solely with this trio of medications, while two patients additionally received Iloprost (PGI2) and 12 Prostavasin (PGE1). The most common surgical intervention was sympathectomy, with 73 cases (8 thoracic and 65 lumbar) in total. Angioplasty and bypass surgery were also employed in 16 and 6 cases, respectively. Stem cell treatment was attempted in one instance, but it was unsuccessful (Table 8).

Table 8.

Frequency of treatment.

Treatment	Frequency
Open lumbar sympathectomy	42
Laparoscopic lumbar sympathectomy	23
Thoracoscopic sympathectomy	8
Angioplasty	16
Prostavasin (PGE1)	12
Iloprost (PGI2)	2
Bypass surgery	6
CDT	2
Stem cell therapy	1
Only oral medical treatment	25

Discussion

Despite its introduction over a century ago, the pathogenesis, diagnosis, and treatment of TAO remain poorly understood.

Since there is no definitive diagnostic test, the diagnosis of Burger’s Disease is often unclear and controversial. As it is impossible to obtain a specimen for vascular pathology in an ischemic limb, clinicians rely on clinical criteria for diagnosis. Usually, these criteria are established in a timely manner. However, nonspecific symptoms such as cold sensitivity or superficial migratory thrombophlebitis can make diagnosis difficult. Severe symptoms such as gangrene and severe resting pain may initially occur without the presence of other symptoms necessary for completion of clinical criteria.^28–31 This suggests that the clinical criteria is not always efficient in clinical practice.¹⁷ For instance, in the current study, 12 patients presented with severe symptoms such as severe rest pain, gangrene, and chronic ulcer, while only 6 of them completed the criteria. Clinicians’ awareness of milder presentations of Burger’s Disease in the early stages may lead to earlier diagnosis and thus prevent the occurrence of more serious symptoms. Additionally, in this study, 14 patients experienced symptoms beginning in the upper limbs and later extending to the lower extremities. Ultimately, the key to diagnosis was the high clinical suspicion and experience of the physicians.²²

The mean time from symptom onset to first visit was 7.35 ± 5.66 years, indicating a long delay in definitive diagnosis. Among our 91 patients, 27 met only four of Shionoya’s criteria. There was no significant difference in characteristics between these patients and those who met all five criteria. This suggests that clinical expertise is more important than classic criteria for diagnosing thromboangiitis obliterans.²²

Additionally, the sole etiology of TAO due to cigarette smoking has been questioned.^32,33 In some studies, symptoms similar to TAO have been reported in association with opium, cocaine, amphetamines, and cannabis.^13–15,34 Although all patients in this study used tobacco, Modaghegh et al.9⁹ reported that 4.8% of patients had only opium usage in a previous study. Moreover, in some patients of this study, recurrence of symptoms occurred with opium alone, suggesting that the patient criteria of smoking may be uncertain and warranting further investigation.

We also know that the majority of smokers do not develop Burger’s Disease.³² Thus, other factors, such as genetics,^1–3 hormones, immunological factors,^12,35 or hypercoagulation disorders1^1,36 may be involved. Furthermore, the authors have conducted an unpublished study which found that the prevalence of protein c and s deficiency, as well as other hypercoagulation factors, was significantly higher in patients with a definitive diagnosis of Burger’s Disease than in the general population.

As reported in this study and other studies, the majority of patients are from low socioeconomic and illiterate groups. Currently, the disease is gradually disappearing from high socioeconomic and industrial societies.⁹ Consequently, it can be concluded that economic factors may influence the incidence of BD, and should thus be taken into consideration when examining the pathophysiology of the disease.

Concomitant atherosclerosis risk factors in patients with Burger’s Disease (BD) are not uncommon.²² Evidence suggests that when the diagnosis of BD is made years after the onset of the disease, other risk factors of atherosclerosis may be present.^10,18 In addition, Kröger3³⁷ found that atherosclerosis in individuals as young as 30 years old is not uncommon, indicating that BD and atherosclerosis can co-occur at a young age. In the present study, 7 patients (7.69%) had risk factors for atherosclerosis such as diabetes mellitus, hypertension, or hyperlipidemia; however, imaging and angiography findings were consistent with BD.

The age of onset for Burger’s Disease cannot be confined to a single number. While it is true that the probability of BD, like other autoimmune diseases, decreases with age due to weakened immune activity,^10,21 its occurrence cannot be ruled out. Among the 91 patients in the present study, two were over the age of 50 when their condition began; however, no other clinical diagnosis could explain their symptoms. This result is in line with findings from other studies, such as the one conducted in Taiwan.³⁸

The clinical course of Burger’s Disease has been found to vary greatly between individuals. In many cases, the disease begins abruptly and progresses rapidly to the point of requiring major amputation. Conversely, it can also be mild for many years without necessitating amputation. As has been observed in other studies, the lower limbs are usually the first to be affected.³⁹ Involvement of other extremities typically begins after about 5 years from the onset of the disease; however, the duration of the disease does not appear to be associated with the rate of amputation. This suggests that the aggressiveness of the disease is unpredictable, despite its progressive nature. Further research is needed to understand the basis of the differences in clinical course among patients, which may lead to the development of better treatment strategies.

The most recommended strategy in treating Burger’s Disease is complete cessation of tobacco use. Significant improvement can be observed when tobacco use is discontinued and medical treatment is administered.^{5,8,12,38,40,41} In this study, only three patients were able to fully quit smoking and opium, and only these individuals entered the complete remission phase, indicating the crucial role of smoking in the development and maintenance of this disease.

In addition to quitting tobacco use, anti-platelet medications (such as aspirin and ticlopidine), calcium channel blockers, folic acid, antibiotics (if necessary), analgesics, sympathectomy,^5,12,40 and intravenous prostaglandins are commonly prescribed. Other interventions, including stem cell therapy,^42,43 spinal cord stimulation,⁴⁴ omental transfer,^45,46 vascular bypass surgery,⁴⁷ angioplasty in extremities with critical ischemia,⁴⁸ and thrombolytic therapy,³⁹ have been reported with varying levels of success in reducing Burger’s disease symptoms.

Sympathectomy has traditionally been the most common surgical procedure for Burger’s Disease; however, recent studies have shown that intravenous prostaglandins and angioplasty are more preferable alternatives.

Sixteen of the patients underwent angioplasty. Compared to bypass surgery, angioplasty can be an effective treatment for Buerger’s patients with critical ischemia, especially when other treatments have failed. However, reintervention may be necessary if smoking is continued.⁴⁸

Although six patients underwent bypass surgery, it has been found to be of little importance in the treatment of TAO due to the fact that the disease mainly affects distal vessels with inadequate runoff.⁴⁹ The high success rate of revascularization surgery in TAO reported in some studies may be attributed to misdiagnosis of conditions such as hypercoagulation, connective tissue disease, or large vessel vasculitis, where proximal vascular involvement is more common.^9,39

Conclusion

Diagnosing a patient with Buerger’s disease is based solely on clinical criteria, as no pathognomonic test has been identified for this condition. As the symptoms may appear asynchronously, the diagnosis is often delayed until all the criteria are exhibited. Furthermore, the initial signs and symptoms, such as cold intolerance and thrombophlebitis migrans, are often uncharacteristic. Additionally, the presence of atherosclerosis and its associated risk factors have been increasingly observed in patients with Buerger’s disease, making diagnosis more difficult.

The authors strongly recommend that young smokers with related signs and symptoms be notified of the potential for developing the disease in a timely manner. Quitting smoking is the only definitive treatment option and should be strongly advised. The clinical course of TAO is highly variable; some patients may experience years of mild, subtle symptoms without any serious complications, while others may have an aggressive onset of symptoms that culminate in limb amputation.

Despite a lack of comprehensive research into the natural course of Buerger’s Disease, such research would be immensely beneficial in furthering our understanding of the disease.

Angioplasty has demonstrated promising outcomes in addressing critical ischemia in the acute phase of Burger’s Disease; however, TAO is typically managed medically and not surgically.

Footnotes

Acknowledgements

We would like to thank research vice presidency of Mashhad university of Medical Sciences for approving the proposal of this study. This study has been extracted from the result of a subspecialty thesis, conducted in Vascular and Endovascular Surgery Research Center of Mashhad University of Medical Sciences, Mashhad, Iran.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Mohammad Hadi Saeed Modaghegh

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