Abstract
Background:
The epidemiology and clinical features of thromboangiitis obliterans (TAO) in Japan have not been updated extensively.
Methods and Results:
This retrospective study used the Japanese Ministry of Health, Labour and Welfare (JMHLW) medical support system database and associated health insurance data. The number of medical financial support recipients registered as TAO patients and estimated prevalence of TAO decreased from fiscal year (FY) 2000 (10,089 and 7.95 [95% confidence interval, CI: 7.79–8.10] per 100,000 population) to FY 2010 (7,147 and 5.58 [95% Cl: 5.45–5.71] per 100,000) and leveled off until 2014. The prevalence of TAO among patients with peripheral arterial occlusive diseases declined from 7.15% (95% Cl: 7.00–7.31) in FY 2008 to 6.12% (95% Cl: 5.98–6.26) in FY 2014. Clinicodemographic features were obtained from 89 new recipients in FY 2013 and 2014: 12 (13%) women, 36 (40%) aged ≥50 years, 26 (29%) had probable onset age ≥50 years, 7 (8%) were non-smokers, and 12 (13%) had arteriosclerosis-related comorbidities. The symptoms were similar regardless of registration age, smoking history, or sex. Although 40 (45%) had digit ulcers, only 12 (13%) fulfilled Shionoya’s criteria. They rarely had infrapopliteal lesions combined with upper extremity involvement or phlebitis.
Conclusions:
The prevalence of TAO has decreased in Japan. In the current diagnosis of TAO, various clinical characteristics including late onset, arteriosclerotic factors, non-smoking, or mild symptoms should be considered.
Thromboangiitis obliterans (TAO), also known as Buerger’s disease, is an inflammatory segmental thrombotic condition of the medium- and small-sized arteries and veins in the distal extremities, often followed by rapid progression to peripheral necrosis. TAO occurs worldwide, but is a rare disease with an unknown etiology and an unclear epidemiology. Although angiography has reduced the misdiagnosis of TAO since the 1970s,1
no specific diagnostic markers and criteria have been established. Thus, direct comparisons of the reported incidence, prevalence, or clinical features of patients are difficult, not only across countries but also within countries. Based on a few and mostly hospital-based studies before 2000, the prevalence of TAO decreased in Western Europe and North America, accounting for <5% of peripheral artery diseases (PAD) in these areas. However, TAO is still reported to account for 15–66% of PAD cases in Japan and Korea,2,3
but this percentage in Japan is based on a single hospital study reported in 1974 that evaluated patients based on the diagnostic criteria by Shionoya.4
Although we suspect that the disease structure in Japan has changed in the clinical setting, the epidemiology of TAO has not been updated.
The Japanese Ministry of Health, Labour and Welfare (JMHLW) has designated several rare diseases as intractable diseases, covered part of the patients’ medical expense, and surveyed these diseases. TAO has been listed as an intractable disease since 1975. To be registered as a patient with TAO and receive financial support, a patient needs to annually submit a prescribed case report form (CRF) filled out by a clinician according to the JMHLW diagnostic criteria for TAO.5
Once registered, medical financial support recipients are managed as renewed recipients, even if they have a blank period of renewal until 2015. The JMHLW criteria for TAO are distal limb ischemia, typical angiographic findings for TAO, and distinguishable condition from other diseases. Unlike other conventional diagnostic criteria (Shionoya,4
Mills,2
Olin,3
and Papa et al6) that require young onset and smoking history, these elements were considered crucial but inessential in the JMHLW criteria because of their unclarified pathogenic roles.5–10
In 1993, the JMHLW research committee conducted a nationwide survey for TAO recipients aged ≥16 years.5
The response rate was 60% (3,722 of 6,209 hospitals), and 3,446 TAO recipients were identified. The number and prevalence of patients with TAO in Japan were estimated as 8,400–12,000 and 7–10 per 100,000 population, respectively. Clinical information was obtained from 850 recipients, including both newly registered and renewed recipients. Their mean age at diagnosis was 40.4 years (range: 14–74 years); 15.4% of them were aged ≥50 years at diagnosis, and women accounted for 9%.5
The same diagnostic criteria were applied from fiscal year (FY: from April 1 of the year to March 31 of the next year) 2000 through 2014, with indispensable submission of either the angiography imaging or the finding report (Table 1). In this period, almost all registered patients were able to receive the medical financial support, and thus almost all patients throughout Japan were considered to have applied for registration.
Table 1.
Diagnostic Criteria for Thromboangiitis Obliterans (TAO) by the Japanese Ministry of Health, Labour and Welfare
| 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 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 Behçet’s disease |
| <Diagnosis> |
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 have neither arteriosclerosis nor risk factors for arteriosclerosis such as diabetes mellitus, usually. 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, has difficulty 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. |
This study aimed to assess the current epidemiology and clinical features of TAO, as well as the prevalence of TAO among patients with peripheral artery occlusive disease (PAOD) in Japan. To attain this goal, we retrospectively evaluated the number of medical financial support recipients registered as TAO patients and the clinical information of newly registered TAO recipients.
Methods
Participants and Study Design
This retrospective cross-sectional study was conducted by the Japan Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis (JPVAS). The participants were medical financial support recipients registered as TAO patients in Japan. Prevalence data were collected from public websites managed by the Japanese Government. To analyze the clinical features of newly registered recipients, we used the CRF of TAO recipients in the JMLHW database for FY 2013 and 2014 (from 1 April 2013 to 31 March 2015). Anonymized CRF data were collected from the national database of JMHLW after JMHLW’s approval. The prescribed CRF data were sent from each local government to the central database; however, some recipient data were missing.
Prevalence of TAO in the Overall Population and in PAOD Patients
We estimated the prevalence of TAO using the number of TAO recipients from FY 2000 to 2014 (from 1 April 2000 to 31 March 2015) that was quoted from the database of the Number of Recipient Certificates Issued for Specific Disease Treatment, Japan Intractable Disease Information Center.11
During this period, the JMHLW diagnostic criteria (Table 1) were used. The population number of Japan was sourced from the Portal site for Japanese Government Statistics (e-Stat), Demographics of Japan 2000–2015 (updated 28 June 2017).12
The prevalence of TAO among patients with PAOD was calculated from the number of TAO recipients and the estimated number of patients with a main or subdiagnosis of PAOD in the national health insurance system of Japan only in FY 2008, 2011, and 2014 (Summary of patient survey, Japan Ministry of Health, Labor and Welfare; Portal site for Japanese Government Statistics [e-Stat]):13–15
because available data were published only for these years.
Clinical Features of New Medical Financial Support Recipients Registered as TAO Patients
First, we reviewed the distribution of sex and probable age at onset from available CRF data, including those from renewed recipients. Next, we extracted the data of new recipients and analyzed their registration age, probable age at onset, sex, smoking history, arteriosclerosis-related comorbidities (diabetes mellitus, hypertension, dyslipidemia, or arteriosclerosis), chief complaints at initial visit, signs and symptoms at initial visit, arterial involvement, arteriography findings, affected extremities, disease severity grade, and medical history of surgical treatment for TAO. In each survey item analysis, we evaluated only recipients with complete subitem data. As the chief complaints at initial visit had been reported with free-style descriptions, we categorized them into items modeled on the list of the signs and symptoms at initial visit. All chief complaints and signs and symptoms of a patient were counted in each analysis if multiple ones were listed. Regarding arterial involvement, some arterial anatomical segments were missing in the prescribed CRF; hand and digital arteries were missing in the list of the upper extremity arteries (including subclavian, axillary, brachial, and forearm arteries), and femoral, foot, and toe arteries were missing in the list of lower extremity arteries (including aorta, iliac, popliteal, and tibial arteries). Therefore, patients with upper or lower extremity involvement without a check in the arterial segments list were categorized as “unchecked.” Disease severity grade was classified according to the most severe condition within 6 months before registration following the JMHLW grading (Table 1). In addition to presenting an overall summary of data for every survey item, we compared the data between patients divided according to factors that are considered important for the diagnosis of TAO: age at registration (<50 years vs. ≥50 years), smoking history, and sex. We also examined the percentages of patients diagnosed using the JMHLW diagnostic criteria who met other diagnostic criteria for TAO, namely those by Shionoya4, Mills,2
or Olin.3
Statistical Analysis
Age distributions were described according to 5-year age groups (starting from 10–14 to 80–84 years). Continuous variables were expressed as medians (quartile 1–3 [Q1–Q3]) and were compared using the Wilcoxon rank-sum test. Categorical variables were expressed as percentages and were compared using the Fisher’s exact test (2-sided) for 2 categories and the Pearson’s Chi-squared test for more than 2 categories. Statistical significance was defined as P<0.05. All statistical analyses were performed using JMP statistical software (version 13.2.0; SAS Institute, Cary, NC, USA).
Results
Estimated Prevalence of TAO in the Overall Population and in PAOD Patients
Both the number of TAO recipients and the estimated prevalence of TAO decreased from FY 2000 (10,089 and 7.95 [95% confidence interval, CI: 7.79–8.10] per 100,000 population) to FY 2010 (7,147 and 5.58 [95% Cl: 5.45–5.71] per 100,000) and leveled off thereafter (Table 2). The estimated prevalence of TAO in PAOD patients also declined from 7.15% (95% CI: 7.00–7.31) in FY 2008 to 6.12% (95% CI: 5.98–6.26) in FY 2014.
Table 2.
Estimated Prevalence of TAO in the Overall Population and in PAOD Patients in Japan
| Fiscal year* |
Total number
of recipients† |
Population,
×105 ‡ |
Estimated
prevalence of TAO,
/105 (95% CI) |
Estimated prevalence of TAO in
the overall PAOD population,§
% (95% CI) |
| 2000 |
10,089 |
1,269.26 |
7.95 (7.79–8.10) |
|
| 2001 |
10,051 |
1,273.16 |
7.89 (7.74–8.05) |
|
| 2002 |
9,758 |
1,274.86 |
7.65 (7.50–7.81) |
|
| 2003 |
9,085 |
1,274.69 |
7.13 (6.98–7.27) |
|
| 2004 |
8,642 |
1,277.87 |
6.76 (6.62–6.91) |
|
| 2005 |
8,371 |
1,277.68 |
6.55 (6.41–6.69) |
|
| 2006 |
8,121 |
1,279.01 |
6.35 (6.21–6.49) |
|
| 2007 |
7,950 |
1,280.03 |
6.21 (6.07–6.35) |
|
| 2008 |
7,789 |
1,280.84 |
6.08 (5.95–6.22) |
7,789/108,900, 7.15% (7.00–7.31) |
| 2009 |
7,591 |
1,280.32 |
5.93 (5.80–6.06) |
|
| 2010 |
7,147 |
1,280.57 |
5.58 (5.45–5.71) |
|
| 2011 |
7,282 |
1,278.34 |
5.70 (5.57–5.83) |
7,282/111,300, 6.54% (6.40–6.69) |
| 2012 |
7,109 |
1,275.93 |
5.57 (5.44–5.70) |
|
| 2013 |
6,979 |
1,274.14 |
5.48 (5.35–5.61) |
|
| 2014 |
7,043 |
1,272.37 |
5.54 (5.41–5.66) |
7,043/115,1000, 6.12% (5.98–6.26) |
*Fiscal year spans from April 1 of the year to March 31 of the next year. †The total number of medical financial support recipients registered as TAO patients was obtained from the Number of Recipient Certificates Issued for Specific Disease Treatment database, Japan Intractable Disease Information Center.11 ‡The Japanese population was sourced from the Portal site for Japanese Government Statistics (e-Stat). Demographics of Japan 2000–2015. [updated 28 June 2017].12 §The estimated number of peripheral artery disease (PAD) patients who visited the hospital was obtained from the Summary of patient survey, Japan Ministry of Health, Labor and Welfare. Portal site for Japanese Government Statistics (e-Stat).13–15 CI, confidence interval; PAOD, peripheral arterial occlusive diseases; TAO, thromboangiitis obliterans.
Collected Data From the CRF Database
The CRF database contained data of 3,221 recipients from FY 2013 (46% of the 6,979 recipients in FY 2013) and of 1,007 recipients from FY 2014 (14% of the 7,043 recipients in FY 2014). Because the recipients must submit the CRF annually, the non-duplicated number of recipients with data during FY 2013 and 2014 was 3,521 (3,073 [87%] men and 448 [13%] women). Data on probable age at onset were available in 2,577 of the 3,521 recipients (73%). The median (Q1–Q3) age was 42 (35–50) years, and 1,679 of 2,577 recipients (65%) were aged <50 years at onset. There were 98 newly registered recipients: 80 in FY 2013 (2.5% of the 3,221 recipients in FY 2013) and 18 in FY 2014 (1.8% of the 1,007 recipients in FY 2014). Because of the multiple unfilled items, we excluded 9 of the 98 new recipients and enrolled the remaining 89 for the following analyses of clinical features.
Characteristics of the New Recipients
Among the 89 new recipients, 77 (87%) were male and 12 (13%) were female (Table 3). The male/female ratio was equal to that of the overall 3,521 recipients. The most common registration age was 35–39 years, and 36 (40%) had registered at age ≥50 years (Figure A). The median probable age at onset as determined from 75 patients was 1 (Q1–Q3, 0–2) year younger than the median registration age (Figure B), and 56 (63%) of the 89 new recipients were aged <50 years at onset. This percentage was also equivalent to that of the overall 3,521 recipients. At least 26 (29%) recipients were aged ≥50 years (14 [19%] were aged ≥60 years) at onset. In 10 female patients, both the registration age and the probable age at onset were ≥40 years. The median time interval between probable onset and initial visit to the hospital was 0 (Q1–Q3, 0–1) years. The median time interval between initial visit and registration was as short as 0 (Q1–Q3, 0–0) years. In total, 7 patients (8%) had no smoking history. Neither the proportion of patients with smoking history nor the number of cigarettes smoked per day obtained from data of 73 patients differed between the registration age groups and between men and women. Arteriosclerosis-related comorbidities were observed in 12 patients (13%), including 2 (4% of 53) with a registration age <50 years.
Table 3.
Characteristics of the New Medical Financial Support Recipients Registered as TAO Patients
| |
Overall
(n=89) |
Age at registration |
Smoking history |
Sex |
<50 years
(n=53) |
≥50 years
(n=36) |
P value |
Patients
with a
smoking
history
(n=82) |
Never
smokers
(n=7) |
P value |
Men
(n=77) |
Women
(n=12) |
P value |
| Men, n (%) |
77 (87) |
47 (89) |
30 (83) |
0.54 |
71 (87) |
6 (86) |
>0.99 |
– |
– |
– |
| Age at registration |
| Years, median (Q1–Q3) |
44
(37–55.5) |
37
(34.5–42) |
60
(53–66) |
<0.001 |
46
(37–56.25) |
37
(21–52) |
0.19 |
44
(37–55) |
49
(41.5–57.5) |
0.48 |
| <50 years, n (%) |
53 (60) |
– |
– |
– |
48 (59) |
5 (71) |
0.70 |
47 (61) |
6 (50) |
0.54 |
| ≥50 years, n (%) |
36 (40) |
– |
– |
– |
34 (41) |
2 (29) |
|
30 (39) |
6 (50) |
|
| Probable age at onset |
| Years, median (Q1–Q3)* |
43
(35.75–53) |
37
(34–41.25) |
57
(50.5–67) |
<0.001 |
44
(36–53) |
37
(24–58) |
0.34 |
42
(36–53) |
47.5
(41–51.25) |
0.48 |
| <50 years, n (%) |
56 (63) |
53 (100) |
3 (6) |
|
51 (65) |
5 (71) |
0.32 |
50 (65) |
6 (50) |
0.59 |
| ≥50 years, n (%) |
26 (29) |
0 |
26 (72) |
|
25 (30) |
1 (14) |
|
20 (26) |
6 (50) |
|
| Unclear, n (%) |
7 (8) |
0 |
7 (19) |
|
6 (7) |
1 (14) |
|
7 (9) |
0 |
|
Interval between probable
onset of disease and initial
hospital visit (years),
median (Q1–Q3,
maximum)** |
0
(0–1, 8) |
0
(0–1, 8) |
0
(0–1, 8) |
0.85 |
0
(0–1, 8) |
0.5
(0–1, 1) |
0.49 |
0
(0–1, 8) |
0
(0–1, 8) |
0.35 |
Interval between initial
hospital visit and registration
(years), median (Q1–
Q3, maximum)† |
0
(0–0, 4) |
0
(0–0, 4) |
0
(0–0, 2) |
0.66 |
0
(0–0, 4) |
0
(0–0, 1) |
0.92 |
0
(0–0, 4) |
0
(0–0.75, 2) |
0.16 |
Patients with smoking
history, n (%) |
82 (92) |
48 (91) |
34 (94) |
0.70 |
– |
– |
|
71 (92) |
11 (92) |
>0.99 |
Cigarettes smoked per
day, median (Q1–Q3)‡ |
20
(20–30) |
20
(20–30) |
20
(20–33.75) |
0.50 |
– |
– |
|
20
(20–30) |
20
(10–30) |
0.43 |
Arteriosclerosis-related
comorbidities, n (%) |
12§ (13) |
2 (4) |
10§ (28) |
0.003 |
11§ (13) |
1 (14) |
>0.99 |
10§ (13) |
2 (17) |
0.67 |
| Diabetes mellitus, n (%) |
5 (4) |
1 (2) |
4 (11) |
0.16 |
4 (5) |
1 (14) |
0.35 |
4 (5) |
1 (8) |
0.53 |
| Kidney disease, n (%) |
0 |
0 |
0 |
|
0 |
0 |
|
0 |
0 |
|
| Hypertension, n (%) |
3 (3) |
0 |
3 (8) |
0.07 |
3 (3) |
0 |
>0.99 |
3 (4) |
0 |
>0.99 |
| Dyslipidemia, n (%) |
1 (1) |
1 (2) |
0 |
>0.99 |
1 (1) |
0 |
>0.99 |
1 (1) |
0 |
>0.99 |
| Arteriosclerosis, n (%) |
4 (5) |
0 |
4 (11) |
0.025 |
4 (5) |
0 |
>0.99 |
3 (4) |
1 (8) |
0.45 |
Categorical data are expressed as n (column percentage). Continuous variables are expressed as median (quartile 1–3 [Q1–Q3]). *Probable age at onset was evaluated in 75 of 89 patients with complete data (46/53 of the patients with age at registration <50 years, 29/36 of the patients with age at registration ≥50 years, 70/82 of the patients with smoking history, 5/7 of the never smokers, 63/77 of the men, and all of the 12 women). **Among 82 patients with complete data of both probable onset year and initial visit date (50/53 of the patients with age at registration <50 years, 32/36 of the patients with age at registration ≥50 years, 76/82 of the patients with smoking history, 6/7 of the never smokers, 70/77 of the men, and all of the 12 women). †Among 88 patients, except for one male smoker patient with age at registration ≥50 years whose initial visit date was unclear. ‡Among 82 patients with smoking history, only 73 patients with data on cigarettes smoked per day were evaluated (45/48 of the patients with age at registration <50 years, 28/34 of the patients with age at registration ≥50 years, 62/71 of the men, and all of the 11 women). §One patient had both diabetes mellitus and arteriosclerosis.
Chief Complaints at Initial Visit
The most common chief complaints were digit pain (43% of 89 patients), followed by digit coldness or numbness (40%) and changes in skin color in the digits (paleness, cyanosis, or Raynaud’s phenomenon; 26%). When digit coldness/numbness and skin color change were counted in the same category similarly to signs and symptoms, 45 patients (51%) had this category of complaints. Digit ulcer (19 patients, 21%) was also common, followed by intermittent claudication (8 patients, 9%), leg numbness (7 patients, 8%), gangrene (6 patients, 7%), and leg pain (4 patients, 5%).
Signs and Symptoms at Initial Visit
Of the 88 patients with complete data on signs and symptoms at initial visit, a majority (94% of 88) had coldness, numbness, or Raynaud’s phenomenon, and 76% had rest pain in the digit (Table 4). All patients with gangrene (25%) also had digits ulcer (45%). Gangrenes were observed more frequently in patients with a registration age ≥50 years (37%) than in those with a registration age <50 years (17%).
Table 4.
Signs and Symptoms at Initial Visit
| Variables |
Overall
(n=88) |
Age at registration |
Smoking history |
Sex |
<50 years
(n=53) |
≥50 years
(n=35) |
P value |
Current
smoker
(n=82) |
Never
smoker
(n=6) |
P value |
Men
(n=76) |
Women
(n=12) |
P value |
Digit coldness, numbness,
or Raynaud’s phenomenon |
83 (94) |
49 (92) |
34 (97) |
0.65 |
77 (94) |
6 (100) |
>0.99 |
71 (93) |
12 (100) |
>0.99 |
| Intermittent claudication |
39 (44) |
23 (43) |
16 (45) |
0.51 |
38 (46) |
1 (17) |
0.10 |
34 (45) |
5 (42) |
>0.99 |
| Rest pain in the digit |
67 (76) |
40 (75) |
27 (77) |
>0.99 |
64 (78) |
3 (50) |
0.15 |
56 (74) |
11 (92) |
0.28 |
| Digit ulcer |
40 (45) |
22 (42) |
18 (51) |
0.39 |
38 (46) |
2 (33) |
0.58 |
32 (42) |
8 (67) |
0.13 |
| Gangrene |
22 (25) |
9 (17) |
13 (37) |
0.045 |
21 (26) |
1 (17) |
>0.99 |
17 (22) |
5 (42) |
0.17 |
| Phlebitis |
6 (7) |
2 (4) |
4 (11) |
0.22 |
6 (7) |
0 |
>0.99 |
5 (7) |
1 (8) |
>0.99 |
Data are expressed as number of patients (column percentage).
Arterial Lesions
Arterial involvements in the upper and lower extremities were observed in 54% and 69% of 89 patients, respectively (Table 5). The tibial arteries were the most commonly affected (58%), followed by the forearm arteries (56%) and the popliteal artery (16%).
Table 5.
Arterial Lesions
| |
Overall
(n=89) |
Age at registration |
Smoking history |
Sex |
<50 years
(n=53) |
≥50 years
(n=36) |
P value |
Patients
with
smoking
history
(n=82) |
Never
smokers
(n=7) |
P value |
Men
(n=77) |
Women
(n=2) |
P value |
| Arterial involvement |
| Upper extremity* |
49 (54) |
29 (55) |
20 (56) |
>0.99 |
45 (55) |
4 (57) |
0.91 |
42 (55) |
7 (58) |
0.81 |
| Subclavian artery |
0 |
0 |
0 |
|
0 |
0 |
|
0 |
0 |
|
| Axillar artery |
1 (1) |
0 |
1 (3) |
0.41 |
1 (1) |
0 |
>0.99 |
1 (1) |
0 |
>0.99 |
| Brachial artery |
5 (6) |
4 (7) |
1 (3) |
0.82 |
4 (5) |
1 (14) |
0.34 |
4 (5) |
1 (8.3) |
0.52 |
| Forearm arteries |
32 (36) |
20 (37) |
12 (33) |
0.43 |
30 (37) |
2 (29) |
0.70 |
29 (38) |
3 (25) |
0.53 |
| Unchecked |
16 (18) |
8 (15) |
8 (22) |
0.42 |
15 (18) |
1 (14) |
0.60 |
12 (16) |
4 (33) |
0.22 |
| Lower extremity† |
61 (69) |
37 (70) |
24 (67) |
0.82 |
56 (68) |
5 (71) |
0.87 |
52 (67) |
9 (75) |
0.61 |
| Aorta |
0 |
0 |
0 |
|
0 |
0 |
|
0 |
0 |
|
| Iliac artery |
4 (4) |
2 (4) |
2 (7) |
>0.99 |
4 (5) |
0 |
>0.99 |
4 (4) |
0 |
>0.99 |
| Popliteal artery |
14 (16) |
7 (13) |
7 (13) |
0.56 |
13 (16) |
1 (14) |
>0.99 |
13 (17) |
1 (8) |
0.69 |
| Tibial arteries |
52 (58) |
30 (57) |
22 (61) |
0.83 |
48 (59) |
4 (57) |
>0.99 |
48 (58) |
4 (33) |
0.12 |
| Unchecked |
8 (9) |
7 (13) |
1 (3) |
0.14 |
7 (8) |
1 (14) |
0.50 |
4 (4) |
4 (33) |
<0.01 |
| Number of affected extremities per patient |
| One, n (%) |
24 (27) |
14 (26) |
10 (28) |
|
22 (27) |
2 (29) |
|
21 (27) |
3 (25) |
|
| An upper extremity |
11 (12) |
7 (13) |
4 (11) |
|
10 (12) |
1 (14) |
|
10 (13) |
1 (8) |
|
| A lower extremity |
13 (15) |
7 (13) |
6 (17) |
|
12 (15) |
1 (14) |
|
11 (14) |
2 (17) |
|
| Two |
47 (53) |
28 (53) |
19 (53) |
|
44 (54) |
3 (43) |
|
41 (53) |
6 (50) |
|
| Both upper extremities |
17 (19) |
9 (17) |
8 (22) |
|
16 (20) |
1 (14) |
|
15 (19) |
2 (17) |
|
| Both lower extremities |
27 (30) |
17 (32) |
10 (28) |
|
25 (30) |
2 (29) |
|
24 (31) |
3 (25) |
|
An upper extremity
and a lower extremity |
3 (3) |
2 (4) |
1 (3) |
|
3 (4) |
0 |
|
2 (3) |
1 (8) |
|
| Three |
3 (3) |
2 (4) |
1 (3) |
|
2 (2) |
1 (14) |
|
3 (4) |
0 |
|
Both upper extremities
and a lower extremity |
1 (1) |
1 (2) |
0 |
|
0 |
1 (14) |
|
1 (1) |
0 |
|
Both lower extremities
and an upper extremity |
2 (2) |
1 (2) |
1 (3) |
|
2 (2) |
0 |
|
2 (3) |
0 |
|
| Four |
15 (17) |
9 (17) |
6 (17) |
|
14 (17) |
1 (14) |
|
12 (16) |
3 (25) |
|
| Arteriography findings‡ |
(n=87) |
(n=52) |
(n=35) |
|
(n=80) |
(n=7) |
|
(n=76) |
(n=11) |
|
Multiple segmental
occlusion§ |
46 (53) |
31 (60) |
15 (43) |
|
43 (54) |
3 (43) |
|
42 (55) |
4 (36) |
|
| Secondary thrombosis§ |
37 (43) |
24 (46) |
13 (37) |
|
35 (44) |
2 (29) |
|
35 (46) |
2 (18) |
|
Abrupt or tapering
occlusion§ |
84 (97) |
51 (98) |
33 (94) |
|
77 (96) |
7 (100) |
|
73 (96) |
11 (100) |
|
Bridging or corkscrew
collaterals§ |
52 (60) |
27 (52) |
25 (71) |
|
50 (63) |
2 (29) |
|
47 (62) |
5 (45) |
|
No evidence of
atherosclerosis§ |
74 (85) |
46 (88) |
28 (80) |
|
71 (89) |
3 (43) |
|
64 (84) |
10 (91) |
|
Data are expressed as number of patients (column percentage). There was no difference in the number of affected extremities according to age at registration (<50 years vs. ≥50 years: P=0.87) smoking history (smoking history vs. never smokers: P=0.89), and sex (men vs. women: P=0.68). There was also no difference in the distribution of affected parts according to age at registration (<50 years vs. ≥50 years: P=0.99), smoking history (with smoking history vs. never smokers: P=0.10), and sex (men vs. women: P=0.94). *Hand and digital arteries were missing in the list. †Femoral, foot, and digital arteries were missing in the list. ‡Two patients were excluded because of lacking data. §Column percentage in 87 patients with arteriography findings.
In total, 65 patients (73%) had multiple affected extremities. The number of affected extremities and the distribution of diseased extremities did not differ between the registration age groups (P=0.87 and 0.99, respectively), the smoking history groups (P=0.89 and 0.10, respectively), and the sex groups (P=0.68 and 0.94, respectively). The most frequent combination pattern of diseased extremities was both lower extremities only (30%), followed by the both upper extremities only (19%), and both upper and lower extremities (17%). There were 28 patients (31%) without diseased lower extremities.
Arteriography findings in the extremities were analyzed in 87 patients. Abrupt or tapering occlusion was observed in 97% (84/87) of the patients. Only 74 patients (85%) showed no evidence of atherosclerosis. The remaining 13 patients included 6 men who had a registration age <50 years, and 3 of them were smokers. The other 7 patients who a registration age ≥50 years included 6 men and 1 woman. The woman had arteriosclerosis as comorbidity, and 2 men had diabetes mellitus.
Disease Severity
Of the 89 patients, 39 (44%) had mild disease severity (grade 1–2), and they could carry out activities of daily living (ADLs) with only conservative treatments (Table 6). The other 50 patients (56%) had worse disease severity (grade 3–5) with severe pain/ulcer/gangrene that impaired their performance of ADLs. Grade 5 disease severity was more frequent in patients who had a registration age ≥50 years (11/36 patients, 31%) than in patients who had a registration age <50 years (3/53, 6%). In total, 57% of never smokers had grade 1 severity.
Table 6.
Disease Severity and Surgical Treatment Before Registration
| |
Overall
(n=89) |
Age at registration |
Smoking history |
Sex |
<50 years
(n=53) |
≥50 years
(n=36) |
P value |
Patients
with
smoking
history
(n=82) |
Never
smokers
(n=7) |
P value |
Men
(n=77) |
Women
(n=12) |
P value |
| Severity grade |
|
|
|
0.025 |
|
|
0.23 |
|
|
0.10 |
| 1 |
21 (24) |
14 (26) |
7 (19) |
|
17 (21) |
4 (57) |
|
19 (25) |
2 (17) |
|
| 2 |
18 (20) |
11 (21) |
7 (19) |
|
17 (21) |
1 (14) |
|
16 (21) |
2 (17) |
|
| 3 |
22 (25) |
14 (26) |
8 (22) |
|
22 (27) |
0 |
|
21 (27) |
1 (8) |
|
| 4 |
14 (16) |
11 (21) |
3 (8) |
|
13 (16) |
1 (14) |
|
9 (12) |
5 (42) |
|
| 5 |
14 (16) |
3 (6) |
11 (31) |
|
13 (16) |
1 (14) |
|
12 (16) |
2 (17) |
|
Surgical treatment
before registration |
20 (22) |
11 (20) |
9 (25) |
0.80 |
18 (22) |
2 (29) |
0.65 |
17 (22) |
3 (25) |
0.73 |
| Revascularization |
12 (13) |
6 (11) |
6 (17) |
0.54 |
11 (13) |
1 (14) |
>0.99 |
11 (14) |
1 (8) |
>0.99 |
Surgical
revascularization |
5 (6) |
3 (6) |
1 (3) |
|
4 (4.8) |
1 (14) |
|
5 (6) |
0 |
|
Endovascular
treatment |
5 (6) |
3 (6) |
3 (8) |
|
5 (6) |
0 |
|
4 (5) |
1 (8) |
|
| Unclear |
2 (2) |
0 |
2 (6) |
|
2 (2) |
|
|
2 (3) |
0 |
|
| Amputation |
3 (3) |
2 (4) |
1 (3) |
>0.99 |
3 (4) |
0 |
>0.99 |
2 (3) |
1 (8) |
0.36 |
| Minor |
3 (3) |
2 (4) |
1 (3) |
|
3 (4) |
0 |
|
2 (3) |
1 (8) |
|
| Major |
0 |
0 |
0 |
|
0 |
0 |
|
0 |
0 |
|
Sympatholytic
procedure* |
7 (8) |
3 (6) |
4 (11) |
0.44 |
6 (7) |
1 (14) |
0.45 |
6 (7.7) |
1 (8) |
>0.99 |
Data are expressed as number (column percentage). *Sympathectomy or sympathetic nerve block.
A total of 20/89 patients (22%) had undergone surgery within 1 year before registration, except 1 patient who had an unclear date of revascularization. Five surgical and five endovascular revascularizations had been performed, all for the lower extremities except for 1 patient who had an upper extremity. No patient had undergone major amputation, but 3 patients (3%), including one who also underwent revascularization and a sympatholytic procedure, had underwent minor amputation.
Patients Who Fulfilled Other Diagnostic Criteria for TAO
Only 12 of 89 patients (13%, 11 men and 1 woman) met Shionoya’s criteria (Table 7). The patients were not only young at onset, but they also rarely had infrapopliteal lesions combined with either upper extremity involvement or phlebitis. Meanwhile, 33 patients (37%) met criteria set by Mills, and 35 (39%) met the criteria set by Olin. The highest barrier for meeting these criteria was the age of onset criterion.
Table 7.
Patients Who Fulfilled Other Diagnostic Criteria for Thromboangiitis Obliterans
| Diagnostic criteria |
Shionoya4 |
(n=89) |
Mills2
(Major criteria) |
(n=89) |
Olin3 |
(n=89) |
Patients who fulfilled
the criteria |
|
12 (13) |
|
33 (37) |
|
35 (39) |
Patients who met each
criterion |
| Age at onset |
<50 years |
58 (65) |
<45 years |
41 (46) |
<45 years |
41 (46) |
| Smoking history |
+ |
82 (92) |
+ |
82 (92) |
+ |
82 (92) |
| Vessel lesions |
Infrapopliteal arterial
occlusions |
51 (57) |
Distal occlusive disease |
89 (100) |
Distal extremity ischemia
with consistent
arteriographic findings |
89 (100) |
| |
Either upper limb
involvement or
migratory phlebitis |
53 (60) |
Undiseased arteries
proximal to the popliteal
or distal brachial level |
80 (90) |
Biopsy shows unusual
characteristics |
N/A |
| Exclusion |
Atherosclerotic risk
factors other than
smoking |
77 (87) |
Proximal embolic source,
autoimmune disease,
hypercoagulable states,
trauma and local lesions |
89 (100) |
Proximal embolic source,
autoimmune diseases,
hypercoagulable states,
diabetes mellitus |
84 (94) |
Data are expressed as number of patients (column percentage). N/A, not applicable.
Discussion
We showed herein the current trends of TAO prevalence in Japan through a cross-sectional nationwide study using the fixed diagnostic criteria (i.e., the JMHLW diagnostic criteria for medical financial support) for the first time. Further, this is also the first study that clarified the clinical features at registration for medical financial support recipients registered as TAO patients. The number of TAO recipients had declined gradually. Despite the less stringent diagnostic criteria, the estimated prevalence of TAO in the overall population and in PAOD patients in 2014 was still as low as 5.5 per 100,000 population and 6.12%, respectively. In total, 13% of the new recipients were women, at least 29% had probable age at onset ≥50 years, 8% were never smokers, and 13% had arteriosclerosis-related comorbidities. The clinical features were broadly similar between the age groups, between the smoking history groups, and between the sex groups. However, although 45% of the patients had severe symptoms of ulcer or gangrene at the initial visit, disease severity was frequently milder in non-smoking patients. The new patients rarely had infrapopliteal lesions combined with either upper extremity involvement or phlebitis.
The global prevalence and incidence of TAO remain unclear due to the limited number of population-based studies and potential biases from conflicting diagnostic criteria between studies.1,2,16
The incidence in North America in the 1960s–1980s was as low as 8–11.6 per 100,000;17
this rate includes an estimated 7–8 per 100,000 population annually in white young men from a study involving World War II Army patients.18,19
In Southwest Poland, also a country with low TAO prevalence, a study in 2000 reported that TAO was prevalent in 8.1 per 100,000 population. In that study, TAO was defined as young male smokers with distal-extremity ischemia or patients with typical arteriography findings.20
Recently, a study in Taiwan using the national database reported a very low incidence of TAO at 0.1 per 100,000 population per year in 2002 and 0.04 per 100,000 population per year in 2011, but the diagnostic criteria were unclear.21
In our study, although the exact number of new TAO recipients per year was unavailable, the proportions of new recipients in terms of overall recipients in the CRF database were ∼2% both in FY 2013 and 2014, and the total number of recipients in Japan was ∼7,000. Thus, the incidence of TAO in Japan in these years can be estimated to be as low as 0.11 (95% CI: 0.09–0.13) per 100,000.
The estimated prevalence of TAO in Japan has definitely decreased. The Japanese nationwide survey in 1993 had already reported the similar estimated prevalence of 7–10 per 100,0005
to that in Southwest Poland.20
Our study additionally showed a comparable estimated prevalence in 2000 (7.95 [95% CI: 7.79–8.10] per 100,000) and a further decrease in the number of TAO recipients thereafter. Although there were no available data on the actual change in the number of new recipients or new patients, the decrease in the number of total recipients was probably attributed to the decrease in the number of new patients. This could be due to the decreased smoking rate in Japan from 24% in 2006 to <20% in 2014.22
Meanwhile, it is thought that many recipients must have discontinued their registration. The possible reasons for non-renewal included patients’ deaths, discontinuance of doctor visits due to physical difficulties or symptomatic relief, and disapprovals for the renewal after symptoms abated. However, patients generally need lifelong treatment for limb ischemia, even those who have symptomatic relief. Moreover, although medical support was reduced in line with the recipients’ income, patients with TAO often have work disabilities;23
it was found that over 50% of the new recipients in this study had grade 3 or higher disease severity with difficulties performing their ADLs. Therefore, we considered that the majority of the recipients had continued renewing their registration unless they died, and the decrease in the number of recipients strongly represented a decrease in the number of Japanese patients with TAO.
Between-country and longitudinal comparisons of the prevalence of TAO have often been conducted using the prevalence of patients with TAO in the overall PAD population in one institution.2,3,22
The prevalence of TAO in the Mayo Clinic, North America, declined from 104 per 100,000 patient registrations in 1947 to 12.6 per 100,000 in 1986, partly due to improvements in diagnostic accuracy.19
In Southwest Poland, the percentage of TAO in the PAD population also declined from 18% in 1971–1980 to 4% in 1990,20
and further declined thereafter.1
Meanwhile, the percentage of TAO in the PAD population remained high in India (45–63%) and Korea and Japan (15–66%).2,3,22
The data in Japan includes a result of Shionoya’s single-hospital study (16%) reported in 1974.4
Thereafter, Kobayashi et al, using Shionoya’s diagnostic criteria and in the same institution, reported the decreased ratio of TAO to arteriosclerosis obliterans (ASO) as 1:10 (9%) in 2000.24
In our study, the estimated prevalence of TAO in the PAOD population in 2008 was as low as 7% despite the less stringent diagnostic criteria, and this further decreased through to 2014. The decreased prevalence of TAO in the PAD population is likely to be seen also in other Asian and Middle Eastern countries. In a hospital in north Thailand, among the new patients with PAD, the proportion of patients with TAO diagnosed using Shionoya’s criteria decreased from 6.2% in 1988–1995 to 2.8% in 1996–2000.25
In Israel, Adar recently commented that the incidence of TAO had never exceeded 5% in his institutions.26
In an institute in southern India, the reported prevalence of TAO in the PAD population had decreased from 63.9% in 2001 to 37.2% in 2005, but this rate is still high. However, 72% of the patients with TAO were aged >40 years, and the diagnostic criteria were not reported.27
The actual prevalence of TAO and the longitudinal changes are still unclear globally.
The recipients in our study included many probable patients with TAO who were excluded from past studies that used more stringent diagnostic criteria. TAO occasionally develops in non-smokers, even in second-hand smokers. Our study showed that never-smoking patients had broadly similar manifestations to those with smoking histories, but they frequently had milder disease severity. This suggests that tobacco smoking is a key factor to the progression of TAO.3,16,28
Additionally, consistent with reports on the increased percentage of female patients with TAO due to increases in smoking habit among women,5,19
the percentage of female patients in this study was higher than that in the latest Japanese survey in 1993 (13% vs. 9.3%).5
In Japan, although the overall smoking population had decreased, the population of female smokers remain unchanged, and the proportion of women among all smokers even gradually increased.22
Our series possibly included patients who had not met the diagnostic criteria for other diseases (e.g., collagen diseases), owing to the difficulty in obtaining an exclusive clinical diagnosis of TAO, particularly in women. In women, “unchecked” arterial involvement, which might include those in digit, hand, or foot arteries, were relatively frequent in both the lower and the upper extremities. Additionally, the onset age of women partly overlapped with the peak age for onset of some diseases such as systemic sclerosis or mixed connective tissue disease. As previously stated, some women with collagen disease were initially misdiagnosed with TAO.29
However, in our series, patients whose conditions had been effectively treated using steroids or immunotherapeutic drugs were unlikely to have registered as having TAO because these drugs are not included in the medical coverage for TAO.
Distinguishing between TAO and ASO also remains complicated. Theoretically, no patient with simple ASO was included in our study because of the angiographical differentiation at their first registration. Arteriosclerosis-related comorbidities or evidence of atherosclerosis on arteriography were observed even in patients with TAO who registered at age <50 years. Arteriosclerosis might independently coexist with TAO in remote sites such as the cerebral arteries, coronary arteries, or aorta. Shionoya previously reported that autopsy findings in patients with TAO showed arteriosclerosis in the proximal arteries, whereas diseased peripheral arteries remained free from plaque.30
Current high-performance imaging modalities can detect early stage arteriosclerosis in the whole body easily. Previously, when only invasive arteriography with a narrow imaging range was used, young onset was indeed a useful criterion to rule out arteriosclerosis. However, arteriosclerosis begins histologically in childhood,31,32
and its incidence is increasing due to lifestyle changes. In the future, differentiating between TAO and arteriosclerosis according to age may become more difficult. Further, elderly onset of TAO has never been ruled out by any hypothetical etiology, including sensitive gene, immunological insufficiency, hypercoagulability, endothelial dysfunction, and infection.16,33–37
Current patients with probable onset age ≥60 years and patients registered at age <50 years also had similar clinical features; however, we cannot explain why our series had a larger proportion of patients with old probable age at onset compared with that found in 1993. Arterial imaging is not definitive because the typical arteriographic characteristics of TAO can also be observed in several non-arteriosclerotic PAOD.3
Additionally, no specific histopathology of TAO has been identified.38,39
Definitive non-invasive diagnosis methods should be established.
The arterial lesions in TAO typically occur in several extremities, but more frequently in the lower extremities than in the upper extremities, with superficial thrombophlebitis.2,3,30
Although it was unclear whether all asymptomatic extremities were subjected to imaging examinations, we found that 27% of patients had arterial lesions only in one extremity, and only 7% had experienced phlebitis. This is probably because many patients were in the early phase of the disease. As arteritis can progress irregularly in each extremity, phlebitis can appear later than arteritis and only in certain patients. Mills described that phlebitis occurs in 40–50% of patients with TAO and set phlebitis as a minor diagnostic criterion.2
Olin also reported that phlebitis occurs in 40% of patients, but did not include this as a diagnostic criterion.3
Moreover, phlebitis occurred in 40% of patients who had been followed up for a long time by Shionoya40
and in 34% of patients who underwent surgical treatment in the study by Igari et al.41
In the 1993 Japanese survey, 16% of overall recipients experienced phlebitis.5
Considering these findings, Shionoya’s criteria of lower extremity arterial lesions and either upper extremity involvements or phlebitis seem to indicate progression. The criteria set by Olin and Mills appeared less stringent than that proposed by Shionoya because they do not specify the extremity parts of arterial involvements or require an experience of phlebitis, but their onset age criteria are more restricted.3,8
These criteria sets seem certainly adequate for studies targeting only patients who are highly likely to have TAO. However, there are many patients who are clinically suspected to have TAO even they do not fulfill these criteria.2,6
TAO should be closely considered in the differential diagnosis of patients with mild symptoms as they may be in the early phase of the disease or are non-smokers.
Many current patients had digit ulcers or gangrenes at the initial examination, and some patients needed a digit amputation. The most severe disease grade and gangrenes were relatively frequent in patients with a registration age ≥50 years, possibly due to their poor vascular bed or long-term unnoticed disease progressions before the wounds had occurred. There were fewer patients with a chief complaint of intermittent claudication than those who actually had claudication. Because the arterial lesions of TAO usually develop starting from the distal extremities, the frequent primary symptom is foot or hand claudication, which can be mistaken as an orthopedic symptom. This clinical feature of TAO should always be remembered.
Limitations and Strength
This study has some limitations. First, the subjects were medical financial support recipients registered as TAO patients, and some patients with TAO who did not meet the JMHLW diagnostic criteria might not have been covered. Also, the numbers of PAOD patients were not the actual numbers, but rather estimated from the national health insurance system database. However, these were the most dependable general data provided by the Japanese government. Second, CRF data of some recipients were missing, and we should consider possible biases of using data from local government units. Third, we could not examine the actual angiography images. Finally, some patients misdiagnosed with TAO might have been included due to the less stringent diagnostic criteria. However, the criteria also enabled us to enroll patients with lower selection bias and to examine mildly symptomatic patients. Nevertheless, our data showed many difficulties in making a clinical diagnosis of TAO, regardless of using tolerant or stringent criteria. Only the establishment of a definitive diagnosis method for TAO will solve these problems.
Conclusions
The prevalence of TAO has decreased in Japan despite the use of standardized, less stringent diagnostic criteria. The new patients showed broadly similar clinical features regardless of onset age, smoking history, or sex, but never-smokers frequently had milder symptoms. Therefore, the varying clinical features of patients with late-onset TAO, arteriosclerotic factors, no smoking history, or mild symptoms should also be considered in its diagnosis. Additionally, the current study patients frequently did not meet the traditional diagnostic criteria for TAO for reasons other than the age at onset; that is, they had no phlebitis, diseased upper extremities, or diseased lower extremities. This is probably because of the short interval between onset and diagnosis. Collectively, these data indicate that the diagnostic criteria for TAO should be updated according to recent trends in its pathophysiology and epidemiology. Although TAO has become rare, public knowledge about this disease should be retained for early diagnosis.
Acknowledgments
The authors would like to acknowledge all investigators of JPVAS Large Vessel Vasculitis Group. We also thank Editage (available at: www.editage.jp) for English editing.
Sources of Funding
This study was funded by a Health Labour Sciences Research Grant to JPVAS from the Japanese Ministry of Health, Labour and Welfare (grant number, H29-nanchitou (nan)-ippan-018). The sponsor had no direct role in the study design, data analysis, data interpretation, or report writing.
Disclosures
The authors declare no conflicts of interest.
IRB Information
The ethics committee of the Tokyo Women’s Medical University (number 5008) and the Ethics committee of the Kawasaki Medical School and hospital (number 3400) approved the study.
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