Demographic Traits, Clinical Status, and Comorbidities of Patients With Thromboangiitis Obliterans in Japan

Yoshiko Watanabe; Yuuki Shimizu; Takuya Hashimoto; Toru Iwahashi; Kunihiro Shigematsu; Yoshikazu Nakaoka; Masayoshi Harigai; Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS)

doi:10.1253/circj.CJ-23-0211

Abstract

Background: The latest demographics, clinical and living conditions, and comorbidities of patients with thromboangiitis obliterans (TAO) in Japan are unknown.

Methods and Results: We conducted a retrospective cross-sectional survey using the annual database of the Japanese Ministry of Health, Labour and Welfare medical support system for patients with TAO between April 2013 and March 2014. This study included 3,220 patients (87.6% male), with current age ≥60 years in 2,155 patients (66.9%), including 306 (9.5%) patients aged ≥80 years. Overall, 546 (17.0%) had undergone extremity amputation. The median interval from onset to amputation was 3 years. Compared with never smokers (n=400), 2,715 patients with a smoking history had a higher amputation rate (17.7% vs. 13.0%, P=0.02, odds ratio [OR]=1.437, 95% confidence interval [CI]=1.058–1.953). A lower proportion of workers and students was seen among patients after amputation than among amputation-free patients (37.9% vs. 53.0%, P<0.0001, OR=0.542, 95% CI=0.449–0.654). Comorbidities, including arteriosclerosis-related diseases, were found even in patients in their 20–30 s.

Conclusions: This large survey confirmed that TAO is not a life-threatening but an extremity-threatening disease that threatens patients’ professional lives. Smoking history worsens patients’ condition and extremity prognosis. Long-term total health support is required, including care of extremities and arteriosclerosis-related diseases, social life support, and smoking cessation.

Thromboangiitis obliterans (TAO, Buerger’s disease) is an inflammatory segmental thrombotic condition of medium- and small-sized arteries and veins in the distal extremities. It is a rare but intractable disease and mainly affects young smokers.¹^–⁵ Although the use of tobacco products is considered the most significant risk factor for the initiation and progression of TAO,⁶^–¹¹ its exact pathogenesis is obscure, and currently there are no curative treatments.⁷^,⁹^,¹²^–¹⁷ Furthermore, arterial revascularization is often challenging due to the small diameter and poor runoff of the vessels. Hence, many patients suffer from lifelong extremity ischemia and occasionally amputation of digits or limbs. Recent reports have shown that patients with TAO have a long life expectancy,²^,¹⁰^,¹¹^,¹⁸^,¹⁹ but demographic information is limited,⁴^,⁵ including from Japan (published in 1993²⁰ and 2009¹⁸). Moreover, several studies report limb loss outcomes, but little is known about the patients’ clinical and living conditions.¹⁹^,²¹

The Japanese Ministry of Health, Labour and Welfare (JMHLW) holds an official nationwide database of patients with TAO to survey this disease. For registered patients, JMHLW covers part of the medical expenses. Using this database, we performed a cross-sectional analysis of the demographic parameters, clinical status, and living conditions of contemporary patients with TAO in Japan.

Methods

Study Design, Setting, and Participants

This retrospective cross-sectional study was conducted by the Japan Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis (JPVAS) and included patients with TAO who received medical treatment in Japan. To be registered and receive the medical financial support (TAO recipient), a patient needs to annually submit a prescribed case report form (CRF) filled in by a clinician according to the JMHLW diagnostic criteria for medical recipients of TAO.³ The CRFs are collected by local governments and sent to the JMHLW. Until 2015, all registered patients qualified for financial support regardless of disease severity; hence, almost all patients applied for registration. We used the CRF data of TAO recipients for the fiscal year (FY) 2013 registration (from April 1, 2013, to March 31, 2014). The total number of TAO recipients in FY2013 was quoted from the database of the Number of Recipient Certificates Issued for Specific Disease Treatment, Japan Intractable Disease Information Center.²²

Measures

We reviewed the patients’ sex, age, probable age at onset, smoking history, current smoking status, clinical symptoms at initial hospital visit (digit coldness, numbness, Raynaud’s phenomenon, intermittent claudication, digit pain at rest, digit ulcer, gangrene, and phlebitis), disease severity grade at initial registration, medical history of surgical extremity amputation, current daily activity (worker/student, house worker, cared patient [home care patient, hospitalized, residential care patient], or other), and current comorbidities (arteriosclerosis, diabetes mellitus, heart disease, kidney disease, cerebrovascular disease, hepatic disease, visceral artery occlusive disease, or other). Details of the amputation were not surveyed. Among patients who had continued their registration (previously registered patients [PrePt]), data on the current status of clinical symptoms and disease severity grade were also obtained. Disease severity grade was classified according to the most severe condition within 6 months before the current registration using the JMHLW grading system (Table 1).³ Surgical extremity amputation, the highest level amputation per patient, was classified into major (above the ankle) and minor (digits or distal to the ankle). In addition to summarizing the overall data, we also compared the clinical features of patients at initial visit between newly registered patients in FY2013 (NewPt) and PrePt. In PrePt, clinical signs and symptoms and disease severity grade at the initial hospital visit were compared with those at the current registration. Patients with and without ulcer/gangrene at the initial visit were compared in terms of amputation history. Patients with and without smoking history were compared in terms of disease severity grade at initial registration and amputation history. Furthermore, the current daily activities and comorbidities were assessed by dividing patients into 10-year age groups (from 10–19 to 90–99 years). In addition, the distribution of daily activities was compared between patients with and without extremity amputation.

Table 1. Diagnostic Criteria for TAO From the Japanese Ministry of Health, Labour and Welfare³

Diagnostic criteria

1. Signs and symptoms

　1) Coldness, paresthesia, Raynaud’s symptoms in the distal upper or lower extremities

　2) Intermittent claudication

　3) Rest pain in digits

　4) Digital ulceration or gangrene

　5) Migratory superficial phlebitis

2. Physical examination findings

　1) Decrease in skin temperature in the upper or lower extremities or in the digits

　2) Absent distal pulses in the upper or lower extremities

　3) Decrease in ankle pressure

3. Arteriography findings

　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 of arteriosclerosis, such as calcification of the arterial wall

　4) Abrupt or tapering occlusion of the affected vessels

　5) Collateral arteries with bridging or corkscrew appearance

4. No other vasculopathy

　1) Arteriosclerosis obliterans

　2) Traumatic arterial thrombus

　3) Popliteal entrapment syndrome

　4) Cystic adventitial disease of the popliteal artery

　5) Occlusive vasculopathy due to systemic lupus erythematosus or scleroderma diffusum

　6) Vascular involvement in Behcet’s disease

Patients with distal limb ischemia exhibiting clinical manifestations (1), physical test findings (2), and arteriography findings (3) described
above (mandatory; at least one item from each section) and without other vasculopathy (4) can be diagnosed with TAO. Patients are smokers
and usually have neither arteriosclerosis nor risk factors for arteriosclerosis, such as diabetes mellitus. Female patients, non-smokers, or
patients aged ≥50 years should undergo differential diagnosis of other vasculopathy as accurately as possible.

The arteriography images or the report must be submitted for evaluation.

Disease severity

　Grade 1: The patient has coldness, numbness, or skin color change but can carry out daily and social life activities without difficulty with
conservative treatment only.

　Grade 2: The patient has intermittent claudication and Grade 1 symptoms, but the disabilities do not significantly affect performance of daily
and social life activities with conservative treatment only.

　Grade 3: The patient has localized ulcer/gangrene or severe intermittent claudication, difficulty in performing daily and social life activities,
and sometimes needs surgical care.

　Grade 4: The patient cannot carry out daily and social life activities due to severe pain or ulcer/gangrene, and sometimes needs
hospitalization.

　Grade 5: The patient has an intolerable pain and an advanced ulcer/gangrene and requires intensive treatment in a hospital.

TAO, thromboangiitis obliterans. Adapted from Watanabe et al³ with permission.

Statistical Analysis

Categorical and continuous variables are presented as numbers (percentages) and medians (interquartile range [IQR]), respectively. Categorical variables were compared using Fisher’s exact test (2-sided) for 2 categories and Pearson’s chi-squared test for ≥2 categories. Continuous values were compared using Wilcoxon rank-sum test. Statistical significance was defined as P<0.05. All statistical analyses were performed using JMP statistical software (version 14.3.0; SAS Institute, Cary, NC, USA).

Results

Demographics of Patients

A total of 6,979 TAO recipients registered in FY2013, but data from some local government units were missing. Therefore, the CRF data of 3,220 recipients (46.1%) were available for analysis and comprised 80 (2.5%) NewPt and 3,140 (97.5%) PrePt (Table 2). Among these, 2,820 (87.6%) were male, and the median probable age at onset was 43 (IQR: 35–50) years. The male/female proportion and the probable age at onset were equal between NewPt and PrePt. Patients ≥60 years of age were the most common (2,155, 66.9%), and 306 patients (9.5%) were ≥80 years (Figure 1). The median estimated disease duration was 20 (IQR: 11–28, range: 0–68) years (Figure 2). Smoking history was found in 2,715 (84.3%) patients, and of them 225 (8.3%) were current smokers.

Table 2. Demographic Characteristics of Patients With TAO

	Registration status			P value^a
	Overall (n=3,220)	Newly registered (NewPt) (n=80)	Previously registered (PrePt) (n=3,140)	P value^a
Sex, n (%)
Male	2,820 (87.6)	69 (86)	2,751 (87.6)	0.74
Female	400 (12.4)	11 (14)	389 (12.4)
Probable age at onset, years, median (IQR)	43 (35–50)	45 (36.25–56.5)	43 (35–50)^b	0.06
Current age, years, median (IQR)	65 (55–72.75)	46.5 (37.25–57.75)	65 (56–73)
Estimated disease duration, years, median (IQR)	20 (11–28)	1 (0–1.75)	20 (12–28)^b
Smoking status at current registration, n (%)
Patients with smoking history	2,715 (84.3)	73 (91)	2,642 (84.2)	0.13
Current smoker	225 (8.3)^c	25 (34)^c	200 (7.5)^c
Former smoker	2,144 (79.0)^c	32 (44)^c	2,112 (80.0)^c
Missing data	346 (12.7)^c	16 (22)^c	330 (12.5)^c
Never smoker	400 (12.5)	7 (9)	393 (12.5)
Missing data of smoking history	105 (3.2)	0	105 (3.3)
Clinical signs and symptoms, n (%)
During initial hospital visit
Digit coldness, numbness, or Raynaud’s phenomenon	2,993 (93.0)	74 (93)	2,919 (93.0)	0.83
Intermittent claudication	2,135 (66.3)	36 (45)	2,099 (66.9)	<0.0001
Rest pain in the digit	2,120 (65.8)	63 (79)	2,057 (65.5)	0.02
Digit ulcer	1,272 (39.5)	39 (49)	1,233 (39.3)	0.11
Gangrene	709 (22.0)	19 (24)	690 (22.0)	0.69
Phlebitis	537 (16.7)	6 (8)	531 (16.9)	0.03
At current registration
Digit coldness, numbness, or Raynaud’s phenomenon	–	–	2,611 (83.2)
Intermittent claudication	–	–	1,581 (50.4)
Rest pain in the digit	–	–	878 (28.0)
Digit ulcer	–	–	229 (7.3)
Gangrene	–	–	1 (0.03)
Phlebitis	–	–	190 (6.1)
Disease severity grade, n (%)
At initial registration
1	462 (14.3)	18 (23)	444 (14.4)	0.09
2	1,009 (31.3)	18 (23)	991 (31.3)
3	682 (21.2)	19 (24)	663 (21.2)
4	418 (13.0)	12 (15)	406 (13.0)
5	520 (16.2)	13 (16)	507 (16.1)
Missing data of grade	129 (4.0)	0	129 (4.0)
Within current 6 months
1	–	–	1,274 (40.6)
2	–	–	1,446 (46.1)
3	–	–	196 (6.2)
4	–	–	90 (2.9)
5	–	–	51 (1.6)
Missing data of grade	–	–	83 (2.6)
Surgical extremity amputation, n (%)	546 (17.0)	4 (5)	542 (17.3)
Major^e	186 (5.8)	0	186 (5.9)
Minor^f	286 (8.9)	3 (4)	283 (9.0)
Missing data of amputation level	74 (2.3)	1 (1)	73 (2.3)

Data are expressed as number of patients (column percentage) or median (interquartile range [IQR]). ^aComparison of percentages between NewPts and PrePts with TAO. ^bProbable age at onset and disease durations were evaluated in 3,119/3,140 patients with data. ^cPercentage among patients with smoking history in each column. ^dAmputation above the ankle. ^eAmputation of the digits or distal to the ankle. TAO, thromboangiitis obliterans.

Figure 1.

Age distribution of patients with thromboangiitis obliterans in 2013.

Figure 2.

Distribution of estimated disease duration of patients with thromboangiitis obliterans in 2013.

Clinical Signs and Symptoms

The clinical signs and symptoms during the initial hospital visit are shown in Table 2. In comparison with the 3,140 PrePt, the proportion of patients with intermittent claudication or phlebitis among NewPt (n=80) was lower (45% in NewPt vs. 66.9% in PrePt, P<0.0001 and 8% vs. 16.9%, P=0.03, respectively) and the proportion of patients with digit pain at rest was higher (79% vs. 65.5%, P=0.02). In the PrePt, TAO signs and symptoms were observed in smaller percentages in the current survey than at the initial hospital visit, except for digit coldness, numbness, Raynaud’s phenomenon (83.2%), and intermittent claudication (50.4%), which were observed at a similar rates as at the initial visit.

Disease Severity

At the initial hospital visit, 1,471/3,220 (45.7%) patients showed mild disease severity grade (grade 1–2), and the patients could perform activities of daily living (ADL) with conservative treatment only (Table 2). The other 1,620 (50.3%) showed worse grades (grades 3–5) with severe pain/ulcer/gangrene and impaired ADL. Patient data on disease severity were missing for the remaining 129 (4.0%). The severity grade distribution was equal between the NewPt and PrePt. Among the PrePt, 2,720/3,140 (86.6%) had grade 1–2 disease severity within the preceding 6 months.

Surgical Extremity Amputation

A total of 546 (17.0%) patients underwent surgical extremity amputation; major and minor amputations were performed in 186 (5.8%) and 286 (8.9%) patients, respectively (data missing for other 74 patients) (Table 2). Based on symptoms at the initial hospital visit, the amputation rate was 29.2% in patients with digit ulcers at the initial visit (372/1,272 patients: 120 with major and 200 with minor amputations; 52 with missing data), 42.0% in patients with gangrene (298/709: 93 with major and 164 with minor amputations; 41 with missing data), and only 8.6% in patients with neither ulcer nor gangrene at the initial visit (164/1,917: 65 with major and 78 with minor amputations; 21 with missing data). The differences in amputation rates between patients with ulcer and with neither ulcer nor gangrene (P<0.0001; odds ratio [OR]=4.418, 95% confidence interval [CI]=3.616–5.398) and between patients with and without gangrene (P<0.0001; OR=7.750, 95% CI=6.229–9.643) were significant.

Data on time from disease onset to amputation were obtained for 325 of 546 patients who underwent amputation; the median was 3 years (IQR: 0–11, the longest: 48). The median time to a minor amputation was shorter (n=175; 2 [IQR: 0–9, the longest: 41] years) than to a major amputation (n=116; 6 [IQR: 1–14] years, the longest: 43 years, [P=0.0017]). It was 4 years (IQR: 0–14, the longest: 48) in 34 patients with unclear amputation level.

Patients with a smoking history showed higher disease severity grade distribution at the initial visit (P<0.0001, Table 3) and a higher amputation rate than those who never smoked (18% vs. 13%; P=0.02; OR=1.437, 95% CI=1.058–1.953).

Table 3. Relationship Between Smoking History and Disease Severity Grade at Initial Registration or Medical History of Extremity Amputation

	Smoking history			P value^a	Missing data (n=105)
	Overall (n=3,220)	With smoking history (n=2,715)	Never smoker (n=400)	P value^a	Missing data (n=105)
Disease severity grade at initial registration, n (%)
1	462 (14.3)	382 (14.1)	66 (16.5)	<0.0001	14 (13.3)
2	1,009 (31.3)	818 (30.1)	154 (38.5)		37 (35.3)
3	682 (21.2)	587 (21.6)	72 (18.0)		23 (21.9)
4	418 (13.0)	375 (13.8)	37 (9.2)		6 (5.7)
5	520 (16.2)	456 (16.8)	48 (12.0)		16 (15.2)
Missing data	129 (4.0)	97 (3.6)	23 (5.8)		9 (8.6)
Extremity amputation, n (%)	546 (17.0)	480 (17.7)	52 (13.0)		14 (13.3)
Major^b	186 (5.8)	156 (5.7)	21 (5.3)	0.02	9 (8.6)
Minor^c	286 (8.9)	261 (9.6)	22 (5.5)		3 (2.9)
Missing data of amputation level	74 (2.3)	63 (2.3)	9 (2.3)		2 (1.9)

Data are expressed as number of patients (column percentage). ^aComparison of percentages between patients with smoking history and never smokers. ^bAmputation above the ankle. ^cAmputation of the digits or distal to the ankle.

Current Daily Occupation

The percentage of workers/students among the total patient population was 50.4% (1,624/3,220), but was lower in the post-amputation patients than in the amputation-free ones (37.9% [207/546] vs. 53.0% [1,417/2,674]; P<0.0001; OR=0.542, 95% CI=0.449–0.654; Figure 3, Table 4). This tendency was observed in all age groups, particularly in the productive ages. The difference was significant in the 40–49 (61% [35/57] vs. 82.1% [243/296]; P=0.0012; OR=0.347, 95% CI=0.189–0.636) and 50–59 (70% [62/88] vs. 86.9% [371/427]; P=0.0003; OR=0.360, 95% CI=0.211–0.614) age groups. It was not statistically significant in the 30–39 (73% [19/26] vs. 85.2% [121/142]; P=0.16; OR=0.471, 95% CI=0.180–1.126) age group. Additionally, there was a lower percentage of workers/students among patients after major amputation compared with the corresponding patients after minor amputation (22.6% [42/186] vs. 47.9% [137/286]; P<0.0001; OR=0.317, 95% CI=0.210–0.480).

Figure 3.

Distribution of current daily occupation (life status) and percentage of workers/students in each age group. Actual numbers of patients and percentages of their occupations (house worker, care patient [home care patient, hospitalized, residential care patient], other, and missing data) are detailed in Table 3. The bar “10–29” comprises age groups 10–19 and 20–29; “80–99” comprises age groups 80–89 and 90–99. (A) Overall patients. (B) Patients after surgical extremity amputation. (C) Amputation-free patients. *P<0.001 for difference between patients after amputation and amputation-free patients.

Table 4. Current Daily Occupation and Comparison by Medical History of Surgical Extremity Amputation

Age, years	Overall	10–19	20–29	30–39	40–49	50–59	60–69	70–79	80–89	90–99
All patients
No. of patients	n=3,220	n=4	n=25	n=168	n=353	n=515	n=1,028	n=821	n=299	n=7
Worker/student	1,624 (50.4)	4 (100)	21 (84)	140 (83.3)	278 (78.8)	433 (84.1)	589 (57.3)	145 (17.7)	14 (4.7)	0
Houseworker	619 (19.2)	0	0	8 (45.8)	31 (8.8)	36 (7.0)	181 (17.6)	291 (35.4)	71 (23.7)	1 (14)
Cared for*	716 (22.3)	0	3 (12)	14 (8.3)	30 (8.5)	29 (5.6)	182 (17.7)	282 (34.4)	170 (56.9)	6 (86)
Other	46 (1.4)	0	1 (4)	1 (0.6)	4 (1.1)	3 (0.6)	13 (1.3)	19 (2.3)	5 (1.7)	0
Missing data	215 (6.7)	0	0	5 (3.0)	10 (2.8)	14 (2.7)	63 (6.1)	84 (10.2)	39 (13.0)	0
After amputation
No. of patients	n=546	n=0	n=1	n=26	n=57	n=88	n=150	n=157	n=66	n=1
Worker/student	207 (37.9)	0	1 (100)	19 (73)	35 (61)	62 (70)	70 (46.7)	20 (12.8)	0	0
Houseworker	96 (17.6)	0	0	2 (8)	10 (18)	9 (10)	22 (14.7)	44 (28.0)	9 (14)	0
Cared for*	198 (36.3)	0	0	3 (12)	11 (19)	12 (4)	49 (32.7)	71 (45.2)	51 (77)	1 (100)
Other	5 (0.9)	0	0	1 (4)	1 (2)	1 (1)	1 (0.6)	1 (0.6)	0	0
Missing data	40 (7.3)	0	0	1 (4)	0	4 (5)	8 (5.3)	21 (13.4)	6 (9)	0
Major amputation
No. of patients	n=186	n=0	n=0	n=6	n=21	n=27	n=49	n=60	n=23	n=0
Worker/student	42 (22.6)	0	0	3 (50)	12 (57.1)	11 (40.8)	14 (28.6)	2 (3.3)	0	0
Houseworker	36 (19.4)	0	0	0	4 (19.1)	6 (22.2)	9 (18.4)	15 (25)	2 (8.7)	0
Cared for*	88 (47.3)	0	0	3 (50)	5 (23.8)	8 (29.6)	24 (50.0)	31 (51.7)	17 (73.9)	0
Others	1 (0.5)	0	0	0	0	0	0	1 (1.7)	0	0
Missing data	19 (10.2)	0	0	0	0	2 (7.4)	2 (4.0)	11 (18.3)	4 (17.4)	0
Minor amputation
No. of patients	n=286	n=0	n=1	n=18	n=34	n=52	n=79	n=68	n=33	n=1
Worker/student	137 (47.9)	0	1 (100)	14 (77.8)	23 (67.7)	45 (86.6)	44 (88.7)	10 (14.7)	0	0
Houseworker	52 (18.2)	0	0	2 (11.0)	6 (17.6)	3 (5.8)	11 (13.9)	23 (33.8)	7 (21.2)	0
Cared for*	81 (28.3)	0	0	0	4 (11.8)	2 (3.8)	17 (21.5)	32 (47.1)	25 (75.8)	1 (100)
Other	3 (1.1)	0	0	1 (5.6)	1 (2.9)	0	1 (1.3)	0	0	0
Missing data	13 (4.5)	0	0	1 (5.6)	0	2 (3.8)	6 (7.6)	3 (4.4)	1 (3)	0
Amputation-free patients
No. of patients	n=2,674	n=4	n=24	n=142	n=296	n=427	n=878	n=664	n=233	n=6
Worker/student	1,417 (53.0)	4 (100)	20 (83)	121 (85.2)	243 (82.1)	371 (86.9)	519 (59.1)	125 (18.8)	14 (6.0)	0
Houseworker	523 (19.6)	0	0	6 (4.2)	21 (7.1)	27 (6.3)	159 (18.1)	247 (37.2)	62 (26.6)	1 (17)
Cared for*	518 (19.4)	0	3 (13)	11 (7.8)	19 (6.4)	17 (4.0)	133 (15.1)	211 (31.8)	119 (51.1)	5 (83)
Others	41 (1.5)	0	1 (4)	0	3 (1.0)	2 (0.5)	12 (1.4)	18 (2.7)	5 (2.1)	0
Missing data	175 (6.5)	0	0	4 (2.8)	10 (3.4)	10 (2.3)	55 (6.3)	63 (9.5)	33 (14.2)	0

Data are expressed as number of patients (column percentage in each category). *Includes home care patients, hospitalized patients, and residential care patients.

Current Comorbidities

Among 25 patients in their 20 s, diabetes mellitus was observed in 1 patient (4.0%). Among 168 patients in their 30 s, arteriosclerosis was observed in 4 (2.4%), diabetes mellitus in 3 (1.8%), heart disease in 6 (3.6%), and cerebrovascular disease in 1 (0.6%) (Table 5). These diseases were observed at higher percentages in the older age groups.

Table 5. Current Comorbidities in Patients With TAO

Age group, years	Overall (n=3,220)	20–29 (n=25)	30–39 (n=168)	40–49 (n=353)	50–59 (n=515)	60–69 (n=1,028)	70–79 (n=821)	80–89 (n=299)	90–99 (n=7)
Arteriosclerosis, n (%)	407 (12.6)	0	4 (2.4)	19 (5.4)	36 (7.0)	118 (11.5)	147 (17.9)	81 (27.1)	2 (29)
Diabetes mellitus, n (%)	381 (11.8)	1 (4)	3 (1.8)	27 (7.6)	40 (7.8)	133 (12.9)	133 (16.2)	43 (14.4)	1 (14)
Heart disease, n (%)	294 (9.1)	0	6 (3.6)	16 (4.5)	20 (3.9)	80 (7.8)	110 (13.4)	60 (20.1)	2 (29)
Kidney disease, n (%)	79 (2.3)	0	0	4 (1.1)	4 (0.8)	25 (2.4)	31 (3.8)	15 (5.0)	0
Cerebrovascular disease, n (%)	113 (3.5)	0	1 (0.6)	4 (1.1)	10 (1.9)	30 (2.9)	41 (5.0)	26 (8.7)	1 (14)
Hepatic disease, n (%)	91 (2.8)	0	1 (0.6)	7 (2.0)	6 (1.2)	36 (3.5)	30 (3.7)	11 (3.7)	0
Visceral artery occlusive disease, n (%)	9 (0.3)	0	0	0	2 (0.4)	1 (0.1)	4 (0.5)	2 (0.7)	0
Other^a, n (%)	744 (23.1)	0	14 (8.3)	49 (13.9)	112 (21.7)	237 (23.1)	227 (27.6)	104 (34.8)	1 (14)

Data are expressed as number of patients (column percentage of all patients within age group). ^aIncludes hypertension and malignancies. TAO, thromboangiitis obliterans.

Discussion

This survey investigated the recent demographic and clinical features of patients with TAO in Japan. To our knowledge, this is the largest study analyzing the clinical status and living conditions of patients with TAO, including those with long-term illness. Since 2015, the eligibility for medical aid has been limited to patients with high severity grade TAO. Therefore, this is the last survey that could include all patients with various severity grades. The main observations were: (1) in FY2013, the majority of TAO patients were aged >60 years (some were ≥80 years); (2) at least 8.3% of the patients with a smoking history continued smoking; (3) almost half of the study patients had severely impaired ADL at the initial visit; (4) the PrePt had milder clinical symptoms at the current visit, although most of them showed symptoms of digit ischemia, (5) 17.0% of the total patients had undergone amputations, and >50% of the amputations were performed within 3 years of disease onset, (6) patients with a smoking history had more severe disease at the initial hospital visit and higher rates of amputation than those who never smoked, (7) the percentages of workers/students were lower among amputated patients than among the amputation-free patients, even at productive ages and particularly after major amputation, and (8) several young patients presented the risk of complicated comorbidities, such as arteriosclerosis-related diseases. This large data set strengthened the previous knowledge that the overall life expectancy of patients with TAO is satisfactory, but most patients suffer from symptoms throughout the disease course. Additionally, both the PrePt and the NewPt showed similar clinical features at the initial hospital visit, including the male-female ratio and the most common age at onset of approximately 40 years. This suggests that the studied patients received consistent diagnoses throughout the study period.

More than 65% of the patients in this study were >60 years of age, which represents satisfactory life expectancy. In previous cross-sectional studies conducted in Japan, 22.6% of the patients were aged >65 in 1993²⁰ and 51.4% were ≥60 in 2009.¹⁸ However, information on survival rates is lacking. As per the data from the Mayo Clinic, 15 of 111 patients died at 52.2 years of age on average.²³ However, a recent French nationwide study (analysis period: 1970–2016) reported only 1.4% morbidity rate in 5.7 years.¹¹ Further, the age-specific survival rates of new patients in South Korea (analysis period: 2006–2017) were similar to those of the general population.⁴ In a 2004 report from a single center in Japan, the survival rate after initial diagnosis was 97% at 5 years and 83.8% at 25 years.¹⁹

Extremity amputation impairs the patient’s quality of life (QOL). In this study, more than half of the amputations were performed within 3 years of disease onset. A 1996 study reported that most amputations occurred within 5 years, and the disease caused cessation of working life for 71% of the patients.²¹ In 2004, Ohta et al also found that amputation was closely associated with job loss, particularly in patients with major amputation, and 9.3% of the patients lost their jobs.¹⁹ In this study, in patients aged 30–59 years, only 61–73% of the amputated patients were workers/students compared with 82–87% of the amputation-free patients, although the difference in the 30–39-year age group was not significant due to the small sample size. Additionally, major amputation reduced the percentages further. The percentage appears lower than the general population rate (≈95%) of 25–54-year-old working Japanese men in 2013.²⁴ Additionally, in several reports the amputation rates in patients with TAO accumulated after 10 years from disease onset;²^,²³^,²⁵ for example, 26% and 34% at 10 and 15 years of follow-up, respectively.¹¹ In this study, most of the previously registered patients had ischemic symptoms. Prolonged ischemia may affect patients’ social well-being throughout their lives, and moreover, the interval from onset to amputations ranges widely.

The extremity amputation rate differed depending on the presence of digit ulcers or gangrene at the initial hospital visit. Additionally, smoking history worsened both the patient’s condition at the initial visit and the long-term amputation rate. The development of arteriosclerosis obliterans, a smoking-related disease, is a likely cause of amputation decades after TAO onset.²⁶ Therefore, smoking prevention and early detection of TAO before ulcers develop may lead to reduced likelihood of digits or extremity loss.

TAO is not usually considered life-threatening, but patients’ overall health and QOL may deteriorate.¹⁰^,¹⁹ Smoking-related diseases such as malignant neoplasms and respiratory diseases were not included in this study’s CRF list of comorbidities. However, the documented prevalence of cerebrovascular disease (3%) in the 60–69-year age group may be higher than that in the general population, estimated to be ≈1% in the 60–64-year age group in the male population in Japan according to the 2017 patient surveys by the JMHLW.²⁷^,²⁸ As for other comorbidities, although several cases of visceral artery TAO have been reported,²⁹^–³² all of the 9 patients with visceral artery lesions in this study were aged ≥50, and 6 of them also had arteriosclerosis. Therefore, their lesions were likely to be non-TAO lesions.

Remarkably, young patients with comorbid risk conditions, such as arteriosclerosis, diabetes, hypertension, and dyslipidemia, were identified in this study. To prevent future development of arteriosclerosis in new patients, it is essential to initiate optimal management of these comorbidities. Additionally, the diagnosis of TAO is complicated in cases of comorbidities or old age. The traditional diagnostic criteria for TAO were based on differentiating it from arteriosclerosis obliterans;⁶^,²⁹^,³³^,³⁴ however, TAO can coexist with arteriosclerosis²⁶^,³³ or associated risk factors and can manifest in aged patients.²^–⁵^,³⁵ The presence of thrombophlebitis strongly supports the diagnosis of TAO, but was observed in this study in only 8% and 17% of NewPt and PrePt, respectively, and 10–40% in other reports.²^,¹¹^,¹⁸ Hence, more specific diagnostic methods, such as identifying etiologic agents or sensitive genes, are required.⁷^,³⁶^,³⁷ For accurate clinical diagnosis of TAO, its clinical features and inflammatory thrombotic pathology should be disseminated to clinicians who have limited experience with patients with newly developed disease.

Study Limitations

First, the patients’ inclusion criteria were not strict; we did not exclude patients by age, smoking history, or comorbidities. Therefore, details of even mild cases were included. Second, CRF data from only 46% of all recipients were analyzed, and we should consider some bias in using data from local government units. Third, the smoking history and status were based on patients’ self-declaration. More patients might have continued smoking at the current registration. However, the smoking-associated analyses defined patients with any smoking history as smokers. The results probably suggest minimum effects of smoking. Fourth, the amputations included only surgical amputations, not auto-amputations of the digits, which also interfere with patients’ daily life. This potentially affected the assessment of patients without amputation. Fifth, revascularization might have affected the amputation rate and ADL. However, we could not analyze medical histories of revascularization owing to the large amount of missing data. Finally, this cross-sectional study cannot assess causal relationships between factors and disease outcome or amputation. In terms of life expectancy, we had no information on patients who had died; thus, we could not assess survival rate, age at death, or cause of death. As for smoking, a well-known risk factor for amputation,¹⁰^,¹¹^,¹⁹^,²¹^,²³ the smoking history at initial registration was associated with severe initial disease and the total amputation rate. However, we could not evaluate the causal relationship between smoking status and the course of the disease because we did not have longitudinal information about when patients quit smoking. Smoking is also a risk factor for respiratory disease and malignant neoplasms, which may threaten the prognosis of patients with TAO. Longitudinal cohort studies are needed to investigate these issues.

Conclusions

This large survey confirmed that although TAO does not seem to be a life-threatening condition, it may lead to loss of extremities and thus negatively affect working and social life. Further, ischemic symptoms can bother patients throughout their lives. In Japan, more than half of the patients with TAO lived for >20 years after onset; however, most had digital ischemia, and 17% underwent extremity amputation. Smoking history worsened both the patient’s initial condition and the long-term amputation-free rate. However, at least 8% of the patients with a smoking history continued smoking. Additionally, early hospital visits before the development of digit ulcers or gangrene seemed important for reducing the amputation rate. Recently, arteriosclerosis-related comorbidities have been found to coexist in patients with TAO, even in the young ones. Therefore, long-term total health care for patients is required, including care of extremities, management of comorbidities and risk factors for arteriosclerosis, social life support, and optimum guidance on smoking cessation.

Acknowledgments

We thank Editage (available at: www.editage.jp) for English editing.

Disclosures

The authors declare that there are no conflicts of interest.

Funding / Support and Role of Funder / Sponsor

This study was supported by a grant from the JMHLW to the JPVAS (Grant no. H29-nanchitou [nan]-ippan-018 and 20FC1044). The sponsor had no direct role in the study design, data analysis, data interpretation, or report writing.

IRB Information

All patients agreed to the research use of the CRF data upon registration as medical recipients of TAO. Anonymized CRF data were obtained from the JMHLW database after approval. The ethics committees of the Tokyo Women’s Medical University (no. 5008) and Kawasaki Medical School and hospital (no. 3400) approved this study.

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