Version May 2024
INTRODUCTION — Thromboangiitis obliterans (TAO), also called Buerger disease, is a nonatherosclerotic, segmental, inflammatory disease that most commonly affects the small to medium-sized arteries and veins of the extremities (upper and lower) [1-3]. TAO is characterized by highly cellular and inflammatory occlusive thrombus with relative sparing of the blood vessel wall [4]. Patients are young smokers who present with distal extremity ischemia, ischemic digit ulcers, or digit gangrene [5]. The disease is strongly associated with the use of tobacco products, and smoking cessation is important to decrease the risk for amputation. Cannabis arteritis is clinically and pathologically indistinguishable from TAO but occurs less commonly compared with tobacco-related TAO.
The epidemiology, clinical manifestations, diagnosis, and treatment of TAO are reviewed here.
EPIDEMIOLOGY AND RISK FACTORS — TAO is observed worldwide but is more common in countries where tobacco is heavily used, especially among people who make homemade cigarettes from raw tobacco (sometimes mixed with cannabis) [6]. As such, TAO is most prevalent in the Mediterranean, Middle East, and Asia [7,8]. In other parts of the world, among patients with arterial occlusive disease, the prevalence varies widely, ranging from 0.5 to 5.6 percent in Western Europe, 15 to 66 percent in Korea and Japan, and as high as 45 to 63 percent in India [9-11].
Because of a decline in the rate of cigarette smoking and the use of stricter criteria for the diagnosis, the prevalence of TAO has declined in North America and Western Europe [2,8,12]. Evidence for the decline in the prevalence of TAO comes from a study that identified patients with TAO between 2015 and 2018 where hospital admissions for TAO represented 0.3 percent of all peripheral vascular disease admissions. There was a dramatic decrease in smokers from 2005 to 2019 (21 versus 14 percent of the population) [13]. Whether vaping (aerosol inhalation that includes nicotine or other substances) will affect the incidence of TAO is unknown. (See "Vaping and e-cigarettes", section on 'Adverse health effects'.)
Males are more commonly affected than females. Of patients diagnosed with TAO, 70 to 91 percent are male and 11 to 30 percent are female [14]. However, there are reports of increasing prevalence of disease in females, possibly due to the increasing use of cigarettes among females [5,12,14-20]. The majority of patients present before the age of 45. However, a report from Japan suggests that the epidemiology may be changing, with a higher percentage of patients over the age of 50 on initial diagnosis [10]. It appears the clinical spectrum of Buerger disease has changed over the last 40 years [21].
Risk factors — The use of tobacco is essential for the initiation and progression of TAO [22-24]. There has never been a well-documented case of TAO in a patient who was proven not to be using tobacco or cannabis in some form (ie, as confirmed by measuring urine nicotine or cotinine levels and toxicology screen).
Patients are generally heavy cigarette smokers. In one study, patients diagnosed with TAO smoked an average of 23 years [24]. TAO has also been reported in cigar smokers, marijuana users (cannabis arteritis), and those who use smokeless tobacco such as chewing tobacco and snuff [4,5,15,25-29].
Chronic anaerobic periodontal infection may also play a role in the development of TAO [30-32]. Nearly two thirds of patients with TAO have severe periodontal disease. In one study, DNA fragments associated with anaerobic bacteria were found within both the arterial lesions and oral cavities of patients with TAO [31]. However, the prevalence of periodontal disease in smokers without TAO is similarly high, and thus the association may be confounded.
PATHOPHYSIOLOGY — TAO is a segmental inflammatory, nonatherosclerotic, occlusive vascular disease that affects the small and medium-sized arteries and veins of the upper and lower extremities. Despite its strong association with tobacco exposure, the general pathophysiology of the disease is still not well known.
Histologically, the condition is distinguished from other forms of vasculitis by a highly cellular, inflammatory intraluminal thrombus with relative sparing of the vessel wall and, more specifically, sparing of the internal elastic lamina [33,34]. Although the disease was recognized and the pathology described over 100 years ago, its pathogenesis remains poorly understood with little progress in understanding the pathogenesis or in the treatment of TAO [35,36].
Three pathologic phases are described (picture 1) [34,37]:
●In the acute phase, inflammatory thrombi develop in the arteries and veins, typically of the distal extremities. The thrombus is occlusive, and polymorphonuclear leukocytes, microabscesses, and multinucleated giant cells may be present, but there is no evidence of fibrinoid necrosis [33,34]. Although the external elastic lamina may show some disruption, the internal elastic lamina is intact. (See 'Biopsy' below.)
●The intermediate (subacute) phase is characterized by progressive organization of the thrombus in the small to medium-sized arteries and veins. A prominent inflammatory infiltrate is still present within the thrombus but is less in the vessel wall.
●In the chronic phase, inflammation is no longer present and only organized thrombus and vascular fibrosis remain. The pathological appearance in the chronic phase is indistinguishable from all other types of occlusive arterial disease.
Although smoking tobacco is central to the initiation, continuation, and recurrence of disease, the specific role of smoking in the pathogenesis of thromboangiitis is unknown. It is postulated that smoking may cause a delayed type of hypersensitivity or toxic angiitis. Immunohistochemical analyses indicate an inflammatory and immunologic pathogenesis [23,38-43]. An increased production of cytokines and a role of notch signal activation may contribute to the inflammatory response observed in patients with Buerger disease [44,45].
Endothelial dysfunction may also be involved in the pathogenesis of TAO [38,46-48]. High titers of antiendothelial antibodies have been detected [46]. Vascular invasion of the tunica intima and also the tunica media is clearly demonstrated in affected vessels using endothelial cell-specific antigens. There also appears to be impaired endothelium-dependent vasodilation in angiographically normal appearing limbs of patients diagnosed with TAO [49]. Abnormalities in endothelin may also play a role [50].
Prothrombotic factors may also play a role in the pathogenesis of TAO. The presence of anticardiolipin antibodies has been reported to be associated with an increased risk and severity of disease [38,51,52].
CLINICAL FEATURES — TAO typically presents in young smokers less than 45 years of age. Vascular involvement in TAO usually begins with the distal arteries and veins, followed by more proximal arterial occlusive disease. Two or more extremities are usually involved [4,19]. A seasonal variation has also been reported with patients more likely to present in the winter [24].
Presentations
Superficial thrombophlebitis — A migratory superficial thrombophlebitis can occur as a very early disease manifestation even before other symptoms and signs (picture 2), such as extremity pain or digital ischemia, become clinically evident. The phlebitis consists of tender nodules that follow a venous distribution and frequently parallels arterial disease activity [15,53].
When superficial nodules are present, they should be biopsied to establish a histologic diagnosis, since these lesions are most likely to show the acute phase of TAO. (See 'Biopsy' below.)
The presence of superficial phlebitis distinguishes this disorder from other occlusive vascular diseases, though phlebitis may also be observed in Behçet syndrome. (See 'Differential diagnosis' below.)
Cold sensitivity/Raynaud phenomenon — Another early manifestation is cold sensitivity with initial presentations of TAO more common in winter months. Secondary Raynaud phenomenon occurs in more than 40 percent of patients and may be asymmetric. The frequency of Raynaud phenomenon may depend upon the population studied [30]. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)
Cold sensitivity may be due to markedly increased muscle sympathetic nerve activity, which has been demonstrated in patients with TAO compared with control subjects, or it can be related to ischemia [54].
Digital ischemia — Digital (toe, finger) ischemia is the most common presentation of TAO. Patients usually note pain, and subsequently the extremities, particularly the digits, may be characterized by either rubor or cyanosis. This discoloration has been termed "Buerger's color." Ischemia can progress to ulcerations in the upper or lower extremity (picture 2) with accompanying ischemic pain or gangrene of the fingers or toes (picture 3).
●In one review of 112 patients, 66 percent had ischemic ulcerations at the time of presentation [15].
●Lower extremity ulcers occurred in 46 percent, upper extremity ulcers in 28 percent, and ulcers in both upper and lower extremities in 26 percent in one series [55]. In another review, combined upper and lower extremity disease occurred in 20 percent of patients [20]. In a series of 323 patients who presented with upper extremity ischemia from 2000 to 2016, TAO was the cause in 30 (9.3 percent [56].
●Another group reported that two limbs were affected in 16 percent of patients, three limbs in 41 percent, and all four limbs in 43 percent [14]. As a general rule, TAO always involves more than one limb.
As the disease progresses, it may involve the more proximal arteries. While unusual, when large artery involvement is present, it rarely occurs in the absence of small vessel occlusive disease [19]. In one retrospective review, the outcomes of 30 of 83 patients with large artery TAO (36.1 percent) were compared with 53 of 83 patients with small artery TAO (63.9 percent). The symptoms and signs, and the proportion of patients with tissue loss was significantly higher for the large compared with small artery group (13.3 versus 0 percent) [57]. While the authors stated they followed strict criteria for the diagnosis of TAO, it is unclear if those with large vessel involvement had histopathologic proof of TAO as suggested in many of the published criteria [58].
If vessels proximal to the wrist or ankle become involved, the patient may complain of claudication of the feet, calves, thighs, or pain in the hands or arms with activity [4]. Symptoms of claudication due to TAO may be indistinguishable from other vascular occlusive diseases. Foot claudication is often mistaken for an orthopedic problem. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)
Other organ ischemia — Although TAO most commonly affects the small and medium arteries of the extremities, pathologic findings have been reported in cerebral, coronary, internal thoracic, renal, and mesenteric arteries [59-61]. Symptoms from intestinal or multiorgan involvement are rare but have been reported [62,63]. Involvement of large vessels, such as the aorta and iliac arteries, is rare; it was noted in just one report [57]; occlusive disease of these vessels is more likely to be due to atherosclerotic arterial occlusive disease [19]. With patients with TAO living longer, it is not uncommon to see features of both TAO and atherosclerosis.
Joint complaints — In a minority of patients, joint complaints may be the first indication of clinical disease. In one study, arthralgias and arthritis were reported in 12.5 percent of patients, typically in the preocclusive phase [53]. The most commonly affected joints were the wrists and knees. The duration of joint symptoms prior to the digital ischemia can be months to years. The joint manifestations of TAO do not lead to erosive arthritis and are frequently episodic, generally resolving within two weeks.
Physical examination — All patients should have a thorough history and physical including a detailed vascular examination. The extremities should be inspected for superficial venous nodules and cords. The hands and feet examined for evidence of ischemia. Neurologic examination may document peripheral nerve involvement with sensory abnormalities in up to 70 percent of patients [4].
The physical examination alone cannot distinguish arterial occlusive disease due to TAO from other etiologies (table 1). Given that smoking is a common risk factor, it is not surprising that atherosclerotic peripheral artery disease (PAD) may be superimposed, particularly in older patients with TAO.
For patients with lower extremity signs and symptoms, an ankle-brachial index (ABI) should be performed. Similarly, a wrist-brachial index (WBI) can be performed in the upper extremity. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Wrist-brachial index'.)
A normal ABI or WBI does not exclude TAO, because disease may be limited to the distal vasculature. Thus, digit studies (pressures, waveforms) should be obtained for all patients in whom the diagnosis of TAO is considered. (See 'Vascular testing' below.)
An Allen test should also be performed (picture 4). A positive Allen test means there is occlusion of the radial or ulnar artery distal to the wrist. A positive Allen test at the wrist in a young smoker with lower extremity digital ischemia is suggestive of TAO (picture 5) [2]. Methods for performing the Allen test at the hand and foot, and adjunctive use of duplex ultrasound, are discussed in detail elsewhere. (See "Arterial blood gases", section on 'Ensure collateral circulation'.)
Laboratory studies — There are no specific laboratory tests to diagnose TAO. The purpose of laboratory studies is to exclude other entities that cause occlusive vascular disease (table 1), such as diabetes, the vasculitides (eg, lupus, mixed connective tissue disease, scleroderma, limited scleroderma [formally called CREST; calcinosis, Raynaud, esophageal dysmotility, sclerodactyly, telangiectasias] syndrome), and thrombophilias. (See 'Differential diagnosis' below.)
Patients should undergo a complete blood count with differential, a chemistry panel including fasting blood sugar, liver enzymes, renal function, urinalysis, and a serologic profile that includes the following [2,4]:
●Acute phase reactants – Westergren erythrocyte sedimentation rate (ESR), C-reactive protein (CRP).
●Immunologic panel – Antinuclear antibody (ANA), rheumatoid factor (RF), complement measurements, cryoglobulins, anticentromere antibody, and SCL70 (markers for scleroderma and limited scleroderma).
●Complete hypercoagulability screen – Coagulation tests, antiphospholipid antibodies (anticardiolipin antibodies, beta 2 glycoprotein, antiserine antibodies, and lupus anticoagulant) protein C, protein S, antithrombin, factor V Leiden, and prothrombin gene mutation.
●Toxicology panel – Cocaine, amphetamines [64], cannabis.
These tests usually are normal or negative in patients with TAO. However, anticardiolipin antibodies may be present in some patients with TAO [51,65]. For patients who deny smoking or using tobacco in any form (cigarettes, cigars, pipe, vape, chew, snuff) who present with findings suggestive of TAO, a urine sample for nicotine and cotinine should be obtained. In addition, cannabis arteritis, which is clinically and pathologically indistinguishable from TAO, also requires a positive urine screen for cannabis to make the diagnosis.
DIAGNOSIS — TAO is a predominantly clinical diagnosis that should be suspected in young patients who smoke and who present with ischemia of the hands and/or feet. However, the diagnosis of TAO may be a diagnosis of exclusion after ruling out other more common entities that may produce similar clinical symptoms. Biopsy provides a definitive diagnosis, although pathological evidence of acute TAO is most likely to be present when an area of superficial thrombophlebitis or subcutaneous nodules are biopsied. Some clinicians use a scoring system to diagnose TAO based upon clinical, angiographic, histopathological, and exclusionary criteria [5,66].
Clinical criteria — A clinical diagnosis can be established without the need for biopsy using the following commonly used criteria [67-70]:
●Age less than 50 years [69,70] (45 years in earlier studies [68])
●Current or recent history of tobacco use
●Distal extremity ischemia (objectively noted on vascular testing) (see 'Physical examination' above and 'Vascular testing' below)
●Typical arteriographic findings of TAO (see 'Vascular imaging' below)
●Exclusion of autoimmune disease, thrombophilia, diabetes, and proximal embolic sources (table 1) (see 'Laboratory studies' above)
Other criteria have been cited in the literature but are less commonly used [66,71].
Biopsy — Biopsy is rarely needed but is the only means to establish a definitive diagnosis. Patients in whom there is suspicion for TAO who have subcutaneous nodules or superficial thrombophlebitis should undergo biopsy. Biopsy of an involved superficial vein that demonstrates acute thrombophlebitis and the characteristic acute phase lesion (picture 1) confirms the diagnosis. (See 'Pathophysiology' above.)
Biopsy is also suggested if the patient presents with some clinical findings of TAO but unusual characteristics such as large artery involvement [57,58], age >50 years, diabetes, positive antinuclear antibodies, or the presence of elevated anticardiolipin antibodies. Patients with antiphospholipid syndrome exhibit thrombus without inflammation, ruling out a diagnosis of TAO [51].
If there are no nodules or superficial thrombophlebitis and the patient fulfills the above criteria, a biopsy of an artery can be done, or examination of the vein or arteries in an amputated digit or limb may provide a diagnosis; however, this is rarely done.
DIFFERENTIAL DIAGNOSIS — TAO is differentiated from other entities that cause vascular occlusive disease (table 1). In a series of 323 patients who presented with upper extremity ischemia from 2000 to 2016, TAO was the cause in 30 (9.3 percent). Other common causes were cardioembolic (18.3 percent), systemic sclerosis (16.1 percent), idiopathic (11.7 percent), and iatrogenic (9.3 percent) [56]. The most common of which are presented briefly below (table 2 and table 3) and discussed in further detail in the linked topics:
●Peripheral artery disease (PAD) – The distal nature of TAO and involvement of both the lower and upper extremities helps to distinguish TAO from PAD. Other risk factors for peripheral artery disease, such as hypertension or hypercholesterolemia, may be absent. In the absence of a histologic diagnosis of the acute phase lesion, a diagnosis of diabetes mellitus excludes TAO. (See "Overview of lower extremity peripheral artery disease".)
●Thromboembolic disease – Patients with TAO will not have a proximal source for embolism (cardiac, aneurysm, atherosclerotic plaque) or laboratory evidence of a thrombophilia, though anticardiolipin antibodies may be present. (See "Embolism to the upper extremities" and "Embolism to the lower extremities" and "Thromboembolism from aortic plaque" and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".)
●Vasculitis – Although distal vessel involvement causes distal ischemia, many types of vasculitides and serologic markers are negative in TAO. (See "Overview of and approach to the vasculitides in adults" and "Overview of the management of vasculitis in adults".)
●Repetitive trauma – These patients have an occupational history (eg, jackhammer operator or other vibratory tools) explaining the mechanism of small vessel disease. The severity of disease depends on degree of vibration, total hours of use, grip force, handle size, and the combined association with other conditions that cause Raynaud phenomenon [72]. Chronic trauma may lead to aneurysm of the distal ulnar artery (ie, hypothenar hammer syndrome), which can then embolize to the hand. It is very important to take a detailed occupational history in every patient with digital ischemia.
●Medication effects (eg, amphetamines or cocaine). (See 'Laboratory studies' above.)
FURTHER EVALUATION
Vascular testing — Patients suspected of having arterial occlusive disease due to TAO should be referred to the vascular laboratory to confirm abnormal ankle-brachial index (ABI) or wrist-brachial index (WBI) findings and for additional studies, as indicated, to identify the level of obstruction (eg, segmental pressures, pulse volume recordings, digit pressures).
A normal ABI or WBI does not exclude TAO, because disease may be limited to the distal vasculature. The distal circulation can be evaluated using digit plethysmography, which may demonstrate one or more flattened digit waveforms supporting the diagnosis. Toe or finger pressures can also be obtained. However, these tests cannot distinguish disease due to TAO from other causes of small vessel occlusive disease that affect the digital arteries (eg, scleroderma). (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Digit waveforms' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Toe-brachial index'.)
Vascular imaging — Clinical examination along with testing to exclude other conditions usually suffices to establish the diagnosis [14,69,70,73]. However, for patients with arterial disease established on noninvasive vascular studies who have clinical symptoms and signs consistent with but not definitive for TAO, catheter-based arteriography may be obtained to look for features typical for TAO and identify the extent of disease [74].
Although gadolinium-enhanced magnetic resonance (MR) angiography or multidetector computed tomographic (CT) angiography can be used to image the vasculature, these modalities may still not provide sufficient spatial resolution to provide adequate anatomic detail of the vasculature of the hands and feet. (See "Advanced vascular imaging for lower extremity peripheral artery disease", section on 'Magnetic resonance angiography'.)
Because of the high prevalence of disease in multiple limbs, we image both of the upper and lower extremities, and the entire aorta (thoracic and abdominal), even in patients who present with clinical involvement of only one extremity. Angiographic abnormalities consistent with TAO can also be seen in limbs that are not yet clinically involved.
Arteriographic features suggestive of TAO include (image 1) [2,73-75]:
●No evidence of atherosclerosis
●No source for thromboembolism (eg, aneurysmal disease)
●Involvement of small and medium-sized vessels such as the plantar, tibial, peroneal, palmar, radial, and ulnar arteries
●Segmental occlusion with diseased segments interspersed between normal-appearing segments
●Collateralization around areas of occlusion (ie, corkscrew collaterals) (image 1)
Although the findings given above are suggestive, none are pathognomonic for TAO, since they may be found in patients with other causes of small vessel occlusive disease. Several studies using duplex ultrasonography have demonstrated corkscrew collaterals [76,77].
The arteriographic findings in patients with cocaine, amphetamine, or cannabis ingestion, including the presence of corkscrew collaterals, may mimic those of TAO [27-29,78,79]. Therefore, in patients who present with manifestations of TAO, it is advisable to obtain a toxicology screen for cocaine, amphetamine, and cannabis. (See 'Laboratory studies' above.)
A cardiac source or other source of embolism should also be ruled out. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism" and "Embolism to the upper extremities" and "Embolism to the lower extremities".)
If evaluation suggests the presence of concomitant ischemic heart disease that requires subsequent cardiac catheterization, then consideration should be given to performing arteriography of the internal thoracic arteries. As noted above, involvement of these arteries may occasionally occur in TAO, and planning for coronary bypass surgery is facilitated if their patency is assessed prior to heart surgery.
MEDICAL MANAGEMENT — There has been no significant change in the way a patient with TAO is medically treated, with only incremental new information published since the 1960s [33,36,80,81]. Based on a handful of small observational studies, the most effective way to "treat" TAO is to convince the patient that complete abstinence of tobacco and cannabis use will substantially lessen the likelihood of amputation [15]. Although a number of other therapies have been investigated, these should be considered palliative.
Digital ulcerations are managed as with other ischemic wounds, including debridement and an appropriate dressing. Negative pressure wound therapy is becoming popular for the management of open wounds and has also been used in the management of open wounds associated with TAO [82]. General considerations for the clinical assessment and management of chronic ulcers are discussed elsewhere. (See "Clinical assessment of chronic wounds" and "Negative pressure wound therapy".)
Smoking cessation — In addition to other benefits associated with smoking cessation, we recommend that patients discontinue cigarette smoking and the use of any other tobacco products, as well as to abstain from cannabis in any form. Smoking cessation is the only effective strategy for reducing symptoms in patients diagnosed with TAO, and in virtually every study published, it decreases the risk for major amputation. In a small retrospective review, all 38 patients were asked to stop smoking 15 days before an interventional procedure [83]. In the 24 individuals who were able to stop smoking, the technical success rate 96 percent compared with 65 percent for the eight patients who did not stop smoking. The outcome at one month was also improved in those that stopped smoking. (See 'Outcomes' below.)
Complete abstinence from tobacco products is the only means by which to halt the progression of TAO [4]. The disease may be activated by smoking as little as one or two cigarettes a day. Transdermal nicotine patches and nicotine chewing gum should also be avoided because they may also keep the disease active; however, bupropion or varenicline can be used as aids to smoking cessation. Inpatient nicotine dependence treatment is an alternative for recidivist smokers [84]. (See "Overview of smoking cessation management in adults".)
While urine assays are used frequently in research studies to verify smoking cessation, they are not routinely obtained in the general clinical setting. However, since the correlation between smoking and disease activity is so strong, measurement of urinary nicotine and cotinine (a byproduct of nicotine) should be performed if the disease is active despite patient claims of tobacco cessation [85].
Patients can be reassured that if they are able to discontinue tobacco use, the disease will remit and the need for amputation will be low. However, patients may continue to experience intermittent claudication or Raynaud phenomenon.
Unfortunately, only about half of patients are able to maintain smoking cessation long term [4,15,81,86]. In one series of 110 patients, only 41 (37 percent) were able to discontinue smoking [86]. In the author's series, among 120 patients with Buerger disease, 43 percent had discontinued cigarette smoking after an average of 7.6 years of follow-up [4,15,68]. Overall, 94 percent of those who quit smoking avoided amputation. If there was no gangrene when the patient discontinued smoking, amputation did not occur. Among the 43 percent of those who continued smoking, one or more amputations was required. In another series, among 48 patients who experienced amputation, 89.6 percent were current smokers [81]. (See 'Outcomes' below.)
Intermittent pneumatic compression — While there are limited data, specifically in TAO, intermittent pneumatic compression (IPC) is effective for the treatment of small vessel occlusive disease of many etiologies. IPC is an option for patients with painful ulceration when there is no viable revascularization option. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease", section on 'Pneumatic compression'.)
Application of IPC to the calf augments popliteal artery flow through a decrease in peripheral arterial resistance. Peak systolic and end diastolic flow velocities are increased on Doppler ultrasound [87]. In one study, complete healing of ischemic ulcers occurred in patients with small vessel occlusive diseases such as scleroderma, CREST, and TAO [88]. While effective, it often takes months to achieve ulcer healing and patients must use the pump for about six hours a day, but pain may decrease even before complete ulcer healing occurs.
Vasodilators — Vasodilators can be used in patients with TAO to help alleviate symptoms. Pharmacologic agents that have been predominantly investigated in TAO include prostacyclin analogues and phosphodiesterase inhibitors. Other vasodilators such as calcium channel antagonists, alpha-adrenergic receptor antagonists, and transdermal nitrates may be helpful in patients who experience vasospasm, but these have not been prospectively studied for the treatment of TAO.
Intravenous prostaglandins — Iloprost, a prostacyclin analog, is the best studied vasodilator and is used frequently in European and Asian countries. Intravenous iloprost is used since oral prostaglandin does not appear to be effective for healing lesions [89]. While there are randomized data to suggest that intravenous iloprost may be helpful [80,90-92], its practicality is limited because in the clinical trials, the patients received a six-hour infusion every day for 28 days and were hospitalized the entire time. Thus, we do not routinely use intravenous iloprost to treat patients with TAO. The main benefit of iloprost may be in helping patients with severe ischemia get through the period of initial smoking cessation. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia", section on 'Intravenous prostaglandins'.)
Phosphodiesterase inhibitors — Cilostazol, a phosphodiesterase type 3 inhibitor with vasodilator properties, may become useful in the management of TAO [93]. Cilostazol is often used in the treatment of atherosclerotic peripheral artery disease. In one experimental study, cilostazol reduced the expression of inflammatory mediators in the plasma of patients with TAO [94]. Cilostazol has also improved healing of ischemic ulcerations in patients who were not candidates for revascularization, though not specifically in the TAO population [95]. Prospective trials are needed to establish clinical efficacy in patients with TAO. (See "Management of claudication due to peripheral artery disease", section on 'Cilostazol'.)
Sildenafil and tadalafil, which are phosphodiesterase type 5 inhibitors, are other potential options in this drug class that have been shown to help decrease the frequency and severity of Raynaud phenomenon. However, there are no data on the use of these agents in TAO. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Phosphodiesterase type 5 inhibitor'.)
Calcium channel blockers — When significant vasospasm as a manifestation of secondary Raynaud phenomenon is present in patients with TAO, dihydropyridine calcium channel blockers (eg, nifedipine) should be used [4,96]. (See 'Cold sensitivity/Raynaud phenomenon' above and "Treatment of Raynaud phenomenon: Initial management", section on 'Calcium channel blocker'.)
Investigational therapies — Cell-based therapies or gene therapy can be tried and may be an alternative for treating ischemic manifestations of TAO [55,97]. Another therapy under investigation is treatment with bosentan, which is an endothelin inhibitor [50,98]. Other investigational therapies used to treat atherosclerotic occlusive disease, most of which have not led to significant improvements in patients with TAO, are discussed separately. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease", section on 'Stem cell therapy' and "Investigational therapies for treating symptoms of lower extremity peripheral artery disease", section on 'Therapeutic angiogenesis'.)
Cell-based therapies (eg, autologous bone marrow mononuclear cell implantation, therapeutic angiogenesis using growth factors, and stimulation of autologous bone marrow) have been used with some degree of short-term success in patients with chronic limb-threatening ischemia, but longer-term studies are needed [99]. A confounding factor for many of these studies is that many of the patients concurrently ceased smoking.
The therapeutic angiogenesis by cell transplantation (TACT) trial, which included patients with TAO, randomly assigned patients to autologous bone marrow mononuclear cell injection versus placebo [100]. Significant improvements in leg pain scale, ulcer size, and pain-free walking distance were maintained at two years after therapy. Similar short-term improvements are reported in other small nonrandomized studies [58,101-104]. Most studies have not reported significant adverse events to angiogenic therapy; however, in one study, four of eight patients suffered significant clinical events, underscoring the need for long-term monitoring [105]. In a series involving 47 limbs in 27 patients with TAO, autologous bone marrow mononuclear cell (BM-MNC) implantation successfully prevented major limb amputation over a follow-up period of 12.0+8.6 years [106]. BM-MNC implantation is clearly much more effective in treating critical limb ischemia secondary to TAO compared with treating patients with atherosclerotic peripheral artery disease [77].
Intramuscular injection of growth factors and gene transfer has also been tried. In a trial of six patients with nonhealing wounds (>1 month), intramuscular vascular endothelial growth factor (VEGF) 165 was injected into seven affected limbs [107]. Ulcers completely healed in three of five limbs. In the other two patients, nocturnal rest pain was relieved, although both continued to have claudication. In all seven limbs, perfusion was improved on magnetic resonance imaging and newly visible collateral vessels were seen on contrast angiography. Another trial tested the safety of intramuscular gene transfer using naked plasmid DNA encoding the gene for VEGF in seven patients with TAO [108]. Ischemic pain in the affected limb was relieved or improved markedly in six of seven patients, and ischemic ulcers healed or improved in four of six patients.
Another therapy involves placing a Kirschner wire into the medullary canal of the tibia to stimulate angiogenesis. In a small study that treated 6 patients (11 extremities), rest pain was reduced, pain-free walking distance increased, and ulcer healing was reported [109]. However, in clinical practice, this technique is rarely, if ever, used.
INTERVENTION
Revascularization — Revascularization is not usually feasible nor indicated because the disease is so distal, involving the small blood vessels of the hands, fingers, feet, and toes, and also because most patients with TAO do well with smoking cessation. If there is an anatomic option for endovascular therapy, it is worth pursuing [110-115]. Surgical revascularization is less feasible but may be indicated for those with superimposed peripheral artery disease. (See "Management of chronic limb-threatening ischemia".)
Arterial bypass surgery may be considered in select patients with severe ischemia and suitable distal target vessels. Surgical bypass with autologous vein [116-118] or even omental graft may allow limb salvage [119,120]. Although long-term vein graft patency is less than that seen with atherosclerotic peripheral artery disease, limb salvage rates are reasonable and generally greater than 90 percent [7,121]. A possible explanation is that patent grafts, even over a short period of time, are sufficient to allow healing of ulcers in patients with TAO. Ulcers are not likely to develop or recur provided the patient is compliant with smoking cessation. As examples:
●In a retrospective review of 71 bypasses performed on patients with TAO, primary and secondary patency rates were 50 and 63 percent at 5 years, and 43 and 56 percent at 10 years, respectively [118]. The 10 year patency rate of the nonsmoking group was significantly higher compared with the smoking group (67 versus 35 percent).
●In another study, the overall limb salvage rate was 96 percent with 7 major and 36 minor amputations performed for the cohort (198 patients) [122]. Revascularization was performed in 19 patients, and the cumulative secondary patency rate was 58 percent at a mean of 5.4 years follow-up.
●In another small study of 27 patients with TAO who underwent revascularization, patency rates at 12, 24, and 36 months were 59, 48, and 33 percent, respectively [7]. However, the limb salvage rate was 93 percent.
Endovascular intervention including thrombolytic therapy or angioplasty has undergone limited investigation in patients with TAO [114,123-128]. Technical success rates range from 82 to 100 percent depending on the level of the lesion (higher for above the knee lesions).
●In a series 28 patients (32 limbs) undergoing endovascular procedures, 45 of 59 lesions below the knee were successfully treated, and only one major amputation occurred at 24 months follow-up [125]. The primary patency rate at 12, 24, and 36 months was 84, 78, and 75 percent, respectively; secondary patency was 87.5 percent at 12 and 24 months.
●In a trial of 82 patients, 52 patients were randomized to endovascular therapy and 30 to medical therapy alone [123]. Healing of ischemic ulcers, amputation-free survival, and ankle-brachial index measurements were more improved in the endovascular group.
●In a review of 41 patients (45 limbs), clinical improvement occurred in 35 limbs (77.7 percent) over a mean follow-up of 29.8 months [124]. Amputation-free survival and limb salvage occurred in 93.3 percent at one and two years. Reintervention was required in 14 patients (45 percent).
●In a systematic review, the early and late outcomes of endovascular revascularization was reported [128]. The pooled technical success rate among 402 endovascular procedures was 86 percent, with no in-hospital mortality and an extremely low complication rate. The limb salvage rate was 94.1 percent at 12 months and 89.1 percent at 36 months.
Other interventions
●Sympathectomy improves pain control in other vascular occlusive diseases [18,129-131]. Sympathectomy has been performed for TAO in the lower [130,132,133] and upper extremities [134]. Although sympathectomy anecdotally benefits some individuals, there are no data to guide patient selection. (See "Overview of minimally invasive thoracic surgery", section on 'Sympathectomy'.)
●As with other forms of chronic limb-threatening ischemia, spinal cord stimulation has also been used to manage pain in patients with TAO [135-138]. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease", section on 'Spinal cord stimulation'.)
OUTCOMES — Several studies have evaluated long-term outcomes, including rates for major and minor amputations, and survival in patients with TAO [15,16,81,86,96,127,139,140]. An important limitation of virtually every outcome study of TAO has been the failure to objectively determine whether the patient actually stopped using tobacco or cannabis; smoking status is usually self-reported.
In a study of 110 patients with TAO, patients were followed from 1978 to 2001 [86]. Cumulative survival by Kaplan-Meier life table analysis was 84 percent up to 25 years after the initial consultation (mean duration of follow-up 10.6 years). The rate for any kind of amputation (upper or lower limb) was 43 percent with major amputations occurring in 12 percent. Forty-one patients who stopped smoking did not undergo major amputation; among the 69 patients who continued smoking, 19 percent required major amputation. No ischemic ulcers occurred or recurred in patients older than 60 years.
In another study that followed 111 patients with proven TAO for a mean of 15.6 years, the incidence of major amputation was 11 percent at 5 years, 21 percent at 10 years, and 23 percent at 20 years [16]. The risk of amputation in former smokers was eliminated by eight years after smoking cessation; the risk of amputation continued in patients who continued to smoke. This study was the only study that found reduced life expectancy in patients with TAO compared with the remainder of the population in the United States. The average age of death was 52 years. Older age at time of diagnosis was associated with an increased risk of death.
The largest outcome series included 224 patients meeting the criteria for the diagnosis of TAO [81]. Patients who stopped using tobacco had a significantly lower risk of amputation compared with those who continued to smoke. This study spanned 46 years (1970 to 2016) to achieve a sample size of 224 patients and underscores the difficulties in performing a prospective randomized trial in rare diseases such as TAO. It is important to recognize that while this is the largest outcomes series published, there are limitations to the data since patients may have been evaluated and treated differently over the nearly half-century time span of the study [36].
Outcomes were as follows:
●The vascular event-free survival was 41 percent at 5 years, 23 percent at 10 years, and 19 percent at 15 years.
●Total amputation-free survival was 85, 74, and 66 percent at 5, 10, and 15 years, respectively.
●Major amputation-free survival rates at 5, 10, and 15 years were 94, 91, and 91 percent, respectively.
In this study, multivariate analysis identified not being from a White population (hazard ratio [HR] 2.35, 95% CI 1.30-4.27) and limb infection (HR 12.1, 95% CI 3.5-42.1) as predictors of a poor outcome [81]. While the baseline differences between the two groups were not different, we have no information about the different socioeconomic factors that may have existed between the groups. There is the suggestion in some studies that the lower the socioeconomic status, the worse the prognosis in TAO [86]. Thus, it may not be related to race but to other factors such as living conditions, income, and overall socioeconomic status. While the amputation rate is lower in this study than in other studies, the authors acknowledge that this may be because of the difference in severity of disease at presentation as compared with other studies. Thirty percent of TAO patients had ischemic ulcers or necrosis at baseline, whereas this was observed in 45 to 80 percent of patients in other series.
On the other hand, another study reported a similar amputation rate with similar rates of ischemic ulceration and gangrene to the large study described above [96]. Thus, it appears that the milder the symptoms and signs at presentation, the lower the amputation rate. At first amputation, 5 (10.4 percent) of 48 patients stated they were not smoking, and at the next amputation 8 (23.5 percent) of 34 patients were not smoking. These amputation rates are high for patients who have stopped using tobacco or cannabis. On the other hand, why only 40 percent of patients who continue to smoke required an amputation and not more remains a question. Other factors may play a role in determining which patients are protected from amputation and which are more prone to amputation. In a French study, cannabis use was not independently associated with a worse prognosis as has been reported elsewhere [141]. In France, patients often mix cannabis with tobacco and hand roll their cigarettes. If this is the case, it would be very difficult to assess the role that cannabis played in vascular events and amputations in this series.
SUMMARY AND RECOMMENDATIONS
●Thromboangiitis obliterans – Thromboangiitis obliterans (TAO) is an inflammatory vascular disease of unclear etiology that affects medium and small arteries, veins, and nerves in the extremities, with rare involvement of visceral and cerebral vessels. Patients are predominantly young smokers who present with pain from distal extremity ischemia, ischemic digital ulcers, or digital gangrene. The disease is strongly associated with the use of tobacco products and also with cannabis. (See 'Introduction' above.)
●Pathophysiology – TAO is characterized by segmental inflammatory thrombotic vessel occlusions. It is distinguished pathologically from other forms of vasculitis by a highly cellular, inflammatory intraluminal thrombus but no fibrinoid necrosis and the presence of an intact internal elastic membrane. Although smoking is important to the pathogenesis, the specific etiologic mechanism remains unknown. Inflammatory, immunologic, and endothelial factors play a role. (See 'Pathophysiology' above.)
●Clinical features and diagnosis – The evaluation of TAO consists of history and physical examination, vascular evaluation, and laboratory examination to serologically rule out other etiologies that can cause small and medium vessel occlusive arterial disease. (See 'Clinical features' above and 'Diagnosis' above.)
•Clinical diagnostic criteria – A clinical diagnosis without the need for biopsy can be established with the following commonly used criteria (see 'Clinical criteria' above):
-Age less than 50 years (45 in some earlier series) (see 'Epidemiology and risk factors' above)
-Current or recent history of tobacco use (see 'Risk factors' above)
-Distal extremity ischemia (objectively noted on vascular testing) (see 'Vascular testing' above)
-Typical arteriographic findings of TAO (see 'Vascular imaging' above)
-Exclusion of autoimmune disease, thrombophilia, diabetes, and proximal embolic sources (table 1) (see 'Laboratory studies' above and 'Differential diagnosis' above)
•Vascular imaging – Imaging studies are not necessary to establish a clinical diagnosis but may be helpful in patients whose clinical features are not definitive. When imaging is performed, features suggestive of TAO include lack of atherosclerosis, no proximal source for embolism, the involvement of small and medium-sized vessels, segmental vascular occlusion, and collateralization around areas of occlusion (ie, corkscrew collaterals). However, such findings are nonspecific since they may be found in patients with other causes of small vessel occlusive disease. (See 'Vascular imaging' above and 'Differential diagnosis' above.)
•Biopsy – Biopsy of a subcutaneous nodule or vein with superficial thrombophlebitis that shows typical acute phase changes on histology provides a definitive diagnosis, but biopsy is not usually needed. (See 'Biopsy' above.)
●Management
•Smoking cessation – For patients who smoke, we recommend smoking cessation (Grade 1A). In addition to other demonstrated benefits, smoking cessation reduces symptoms and decreases the risk for major amputation. Continued smoking is associated with an overall amputation rate of 40 to 50 percent. (See 'Smoking cessation' above and 'Outcomes' above.)
•Vasodilators – For patients with ischemic pain, digit ulceration, or gangrene, intermittent pneumatic compression may improve pain by increasing blood flow. Calcium channel blockers may also help reduce vasospasm associated with Raynaud phenomenon. Other treatments that may be considered to manage pain include intravenous prostaglandin infusion, and possibly phosphodiesterase inhibitors. (See 'Vasodilators' above and 'Intermittent pneumatic compression' above and 'Other interventions' above.)
•Role of intervention – Revascularization is usually not indicated due to the distal nature of occlusive disease and because most patients do well with smoking cessation. However, there is a role for endovascular therapy in patients with TAO who are not responding to medical therapy alone. Bypass surgery may be considered in select patients with severe ischemia and suitable distal target vessels. Although the long-term patency rates are inferior to those seen with peripheral artery disease due to atherosclerosis, limb salvage rates are generally greater than 90 percent, but may be more correlated to smoking cessation. (See 'Revascularization' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.
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