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Vasa 2014; 43: 337 – 350 P. Klein-Weigel & J.G.

Richter: TAO
© 2014 Hans Huber Publishers, Hogrefe AG, Bern DOI 10.1024/0301-1526/a000371

Review 337

Thromboangiitis obliterans (Buerger’s disease)


Peter F. Klein-Weigel1 and Jutta G. Richter2

1
HELIOS Klinikum Berlin-Buch, Klinik für Angiologie, Berlin, Germany
2
Poliklinik und Funktionsbereich Rheumatologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität,
Düsseldorf, Deutschland

Summary Zusammenfassung
Thromboangiitis obliterans (TAO, Buerger`s disease) is an in- Thrombangiitis obliterans
flammatory vascular disease affecting small and medium sized Die Thromboangiitis obliterans (Buerger`sche Erkrankung) ist
arteries and veins. It is characterized by segmental throm- eine entzündliche Erkrankung der kleinen und mittelgroßen
botic occlusions by highly mononuclear cellular thrombi. Its Arterien und Venen, die durch segmentale thrombotische Ge-
occurrence and re-occurrence is closely related to tobacco fäßverschlüsse mit hohem mononukleären Zellanteil gekenn-
use. Immunohistological examinations and the detections zeichnet ist. Das Auftreten und auch Rezidive sind eng mit
of various autoantibodies led to the new paradigm of an im- einem Tabakkonsum korreliert. Immunhistologische Unter-
munopathogenesis of TAO. Clinically it is characterized by suchungen und der Nachweis verschiedener Autoantikörper
distal ischemia syndromes in young people and high amputa- führten zu dem neuen Paradigma einer Immunpathogenese.
tion rates. This article summarizes the disease characteristics, Klinisch ist die Erkrankung durch distale Ischämiesyndrome
clinical features, and diagnostic and therapeutic approaches bei jungen Patienten und eine hohe Amputationsrate gekenn-
and focuses on new therapeutic options, i.e. stem cell derived zeichnet. Der Artikel fasst die Krankheitscharakteristika, das
therapies, immunoadsorption, and the endothelin-receptor- diagnostische Vorgehen und die therapeutischen Möglich-
blocking agent bosentan. keiten zusammen und fokussiert dabei auf neue therapeutische
Optionen wie die Stammzelltherapie, die Immunadsorption
Key words: Thromboangiitis obliterans, Buerger`s dis- und den Einsatz des Endothelin-Rezeptorblockers Bosentan.
ease, critical limb ischemia, vasculitis, immunoadsorption,
stem cell therapy, progenitor cell therapy, bosentan

Introduction leading to occlusion of the affected Europe to values as high as 45 to 63 %


vessels by the formation of a highly in India, 16 to 66 % in Korea and Japan,
In 1879 Felix von Winiwarter, a young cellular thrombus rich in mononu- and 80 % among Ashkenazi Jews [7].
assistant physician of Theodor Billroth clear cells [2 – 4, e5]. Nevertheless, in many countries
in Vienna, published the result of his In spite of its obviously inflamma- the reported prevalence of TAO has
pathologic examination of a lower tory character TAO is not listed in declined during the past decades
limb amputate of a 57 year old male the 2012 revised International Chapel [e10 – e12, 13]. There is conflicting
as „eine eigentümliche Form von En- Hill Consensus Conference Nomen- data about the reason for this obser-
dangiitis und Endophlebitis mit Gan- clature of vasculitides [e6]. vation. While some authors believe
grän des Fußes“ [e1]. Although this is the decline parallels the decrease in
considered to be the first case report of tobacco use, others believe it is more
thromboangiitis obliterans (TAO) the Epidemiology closely linked to changes in socioeco-
disease is nowadays more exclusively nomic conditions [13, 14].
linked to the American surgeon Leo TAO occurs world-wide [3 – 4, e5]. TAO is more common in men, but
Buerger, whose systematic work on It is relatively rare in North America an increasing prevalence in women
clinical and pathological aspects of and Western Europe compared to has been reported [e10 – e11, 15].
the disease built the fundaments of the Eastern Europe and high prevalence Disease characteristics and prognosis
modern understanding of TAO [2]. regions, which are located in the do not seem to differ between men
Mediterranean, the Middle East, and and women [15, e16].
India. Among certain ethnical groups
Definition Ashkenazi jews are predominantly af-
fected [3 – 4, e5, e7 – e9]. Etiologic, pathologic, and
TAO is characterized by a clinically The prevalence rates among all pa- pathogenetic aspects
undulating multilocular segmental tients with peripheral arterial disease
inflammatory disease affecting small have been reported to range from val- The etiology of TAO is still unknown.
and medium sized arteries and veins ues as low as 0.5 to 5.6 % in Western Regional and ethnic differences in
P. Klein-Weigel & J.G. Richter: TAO Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern

338 Review

the prevalence of the disease point preserved [e27, 30 – 31, e32]. Giant Reports on a possible causative as-
towards a genetic background de- cell formation and the appearance sociation between periodontal dis-
termining individual susceptibility. of so called “microabcesses” within ease and TAO are not very convinc-
HLA linked factors may play such a the mononuclear cell rich thrombus ing, as the prevalence of periodontal
role, like HLA A-9 und B-5, HLA-A, may occur [2]. infection is high in the typical risk
HLA-BW, O, J-1-1 and the missing Analysis of cytokine activation in group and similar associations have
of HLA A1 [e17], nevertheless, HLA TAO patients has revealed a pattern been reported for arteriosclerotic dis-
association studies have revealed of elevated pro- and anti-inflamma- eases and even rheumatoid arthritis
heterogeneous findings in different tory cytokines with up-regulation of [e46 – e49]. On the other hand, peri-
populations including findings of no tumor necrosis factor-α, Interleukin odontal infection might enhance
correlation at all [e18 – e22]. Pub- (IL)-1ß, IL-4, IL-17, and IL-23 [33, the inflammation level, endothelial
lished genetic polymorphisms consist e34]. Nevertheless, one has to be dysfunction, and hypercoagulability
of CD14 T7T-Polymorphism, eNOS aware that this pattern might have [e50].
gene 894 T/T -polymorphism as a been influenced by the presence of A prothrombotic state has been
protective factor and MyD88 rrs7744 chronic wounds and gangrenes as discussed as an important patho-
A-G polymorphismus, coding for a well as possible wound infections. genetical factor in TAO. Indeed,
Toll-like receptor signaling adaptor Various kinds of autoantibodies have some prothrombotic risk factors
[e23 – e25]. It must be stressed, that been identified in TAO-patients, in- and mutations like C 677 T meth-
methodological problems and the cluding anti-endothelial antibodies, ylentetrahydrofolate reductase
immanent diagnostic uncertainties antibodies directed against vessel (MTHFR)-polymorphism, hyperho-
may have substantially confounded wall structures like elastin and col- mocysteinaemia, and prothrombin
the results of the genetic studies as lagen, anti-cardiolipin-antibodies, G 20210 A-polymorphism have been
the number of included patients has and anti-neutrophil cytoplasmic described, but correlations might
been usually small. antibodies [e35 – e41]. None of be confounded by small numbers
There is a very tight correlation be- these have proved to be causative [e51 – e53].
tween the manifestation of TAO as or pathognomonic. Nevertheless,
well as between flaring and re-occur- autoantibodies may play an impor-
rence of the disease and tobacco use, tant role in the pathogenesis of the Social und psychosomatic
leading to the well known aphorism disease. More recently, a clustering aspects
“no tobacco, no Buerger`s disease” of agonistic autoantibodies directed
[3 – 4, e2,e5]. against α1-receptor loop 1 as well as TAO typically occurs in patients
Pathohistologically, TAO-lesions against endothelin-A-receptor loop with a low social status [14]. Some
are classified in acute, subacute, and 1 was identified potentially pro- authors described a Buerger-type
chronic types, the latter being un- moting vasospasm, compromising personality with manipulative and
distinguishable from other forms of microcirculation, damaging vessel auto-aggressive tendencies often
chronic arterial occlusive diseases [2, structures, and inducing prolifera- matched with denial, negligence,
e26]. Due to the undulating clinical tive processes [42]. or tendencies to minimize their ill-
course normal vessel segments and Alltogether, the findings are consis- ness, while others even presumed
different stages of TAO-typical vascu- tent with the assumption of an immu- typical morphological character-
lar lesions might be found simultane- nopathogenesis of TAO. A model of istics [e54 – e55]. Nevertheless, no
ously in the same patient [2]. this new paradigm has recently been systematic work has been done in
Signs of endothelial activation and published by Ketha SS und Cooper this field and the preliminary results
proliferation as well as the presence LT [43]. do not allow differentiating between
of immunocompetent cells are only Although concomitant cannabis ex- premorbid traits and conditions and
seen in the acute type-lesions. Im- posure might influence the age of on- psychological consequences of the
munoglobulin und complement de- set and the clinical presentation of chronicity and/or severity of the dis-
position as well as CD4+ and CD 8+ TAO, it does not seem to have a sig- ease or implications of chronic drug
T-lymphocytes, CD 20+ B-lympho- nificant influence on outcome [e44]. intake like morphine or opioids.
cytes, and S 100 positive- dentritic It is noteworthy that the clinical and
cells are found alongside the lamina histological pattern of cannabis-as-
elastica interna, which becomes sociated angiopathy cannot be sepa-
structurally altered but is typically rated from Buerger`s disease [e45].
Vasa 2014; 43: 337 – 350 P. Klein-Weigel & J.G. Richter: TAO
© 2014 Hans Huber Publishers, Hogrefe AG, Bern

Review 339

Diagnostic criteria years of age) in which other vascular ly present and usually argues more for
diseases preferentially affecting the other entities such as atherosclerotic
TAO patients usually present with skin same vascular beds (i.e. premature disease [e62 – e63]. Nevertheless, case
discolorations including Raynaud`s atherosclerosis, thrombembolic dis- reports of TAO-lesions in cerebral,
phenomenon, acute ischemic or infec- ease, diabetic angiopathy) or other coronary, and visceral arteries as well
tious acral lesions (ulcers, gangrenes, distinct vasculitides are excluded [13,
subungual infections, phlegmone), e57]. Diagnosis can also be made by
and/or thrombophlebitic nodules scoring systems, nevertheless these Table I: Common clinical presenta-
(Tab. I and Fig. 1)[3 – 4, e5]. Rarely, tools are not widely established in tions of TAO
non-erosive arthritis precedes isch- clinical routine care [e58].
emia for month or years [56]. Upper extremity involvement was Gangren
Diagnosis is usually based on clinical reported to increase during the last Acral ulcer
and angiographic criteria published decades [13]. Combined upper and Ischemic rest pain
by Olin et al. and Shinoya et al. [13, lower extremity involvement is pres- Subungual and skin infection,
e57]. Synoptically, it demands the ent in about 20 – 25 % of the cases [13, phlegmone
presentation of a more or less sym- e59]. An isolated affection of only one
(In-step-)claudication
metrical distal ischemic syndrome limb strongly argues against TAO.
or the presence of an acral-crural/ Thrombophlebitis is often of migra- Acral skin discoloration and
coldness, Raynaud’s phenomenon
antebrachial-acral type of arterial oc- tory type and precedes or parallels
clusion in two or more extremities arterial disease activity [60, e61]. Thrombophlebitic nodules or strings
(often migratory)
in young patients (typically < 45 – 50 Proximal arterial involvement is rare-

Figure 1: Typical clinical presentions of Thromboangiitis obliterans


P. Klein-Weigel & J.G. Richter: TAO Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern

340 Review

Table II: Angiographic signs of TAO Diagnostic measures tion is performed diagnosis should
be confirmed by histopathologic ex-
Segmental distally located Distal pulses are usually absent or amination. Besides arterial segments
multisegemtal vessel occlusions diminished, but can be normal in thrombophlebitic nodules are suit-
Smooth vessels in non-affected case of distal disease manifestations. able for this purpose (Figure 3).
regions, no calcifications Allen-Test often reveals an upper ex- Due to often long-time and heavy
Cut-off-occlusions tremity involvement. smoking features of arteriosclerotic
Corkscrew-, tree-root-, and Ankle brachial index or forearm- disease might be seen to some degree.
spider-leg collaterals brachial-index is usually reduced, They do not per se exclude the diag-
Martorell-sign (i. e. formation of but might be normal in cases with nosis of Buerger`s disease. Differen-
collateral vessels within the occluded very distal disease. Digital pulse re- tial diagnosis is outlined in Table III.
lumen of the affected vessel) cordings are characterized by low
No-refill phenomenon of the amplitudes and delayed slopes, anar-
original vessel chic or silent pulse curves. Repeated Markers of disease
Standing wave phenomenon examination after thermal or phar- activity
macological provocation should be
Vasospasm
performed as vasospasm is usually There are no commonly accepted
present. criteria defining disease activity in
Angiographically a typical but not TAO hampering direct comparisons
pathognomonic pattern has been of clinical studies. Systemic inflam-
described that substantiates the di- matory laboratory markers are usu-
agnosis [e55]. This pattern might ally absent or only slightly elevated
also be identified by careful duplex and are therefore unsuitable for as-
ultrasound examination, although at sessment of disease activity. If pres-
least in cases of critical ischemia angi- ent, they point towards concomitant
ography should always be performed. infections or argue for other enti-
Table II summarizes the angiographic ties. Clinical disease activity criteria
signs of TAO, while Figure 2 demon- proposed by the authors is shown in
strates a typical angiographic feature. Table IV.
Embolic disease has to be ruled out
by electrocardiography, transesopha-
geal echocardiography, computer to- Therapy
mography angiography, and duplex
ultrasound of the aorta and proximal Smoking cessation
extremity arteries. The most important therapeutic in-
Capillary video microscopy is often tervention in TAO is smoking ces-
limited by hornification. It often re- sation [3 – 4, e5]. Its overwhelming
veals unspecific morphologic chang- effect for the prevention of limb am-
es, bleedings, and a diminished capil- putation has been impressively shown
lary density [e69 – e70]. Elongation of [13]. TAO patients should not only
capillary loops as presumably more be prevented from active smoking
typical alterations have also been de- but also from alternative consump-
scribed [e70]. tion modi, as passive smoking as well
There are no specific laboratory (bio-) as chewing of tobacco, and snuffing
markers for TAO [3 – 4, e5]. Never- have been identified as causes of
Figure 2: Typical angiographic theless, laboratory tests are important disease flare-up and re-occurrences
feature of TAO to exclude other entities such as dia- [e71 – e73].
betes, connective tissue disease, vas- Tobacco dependency usually is con-
culitides, or congenital or acquired sidered to be exceptionally strong
as even with multiple organ involve- thrombophilia [3 – 4, e5]. in TAO patients, but in a prospec-
ment and failure have been published If a biopsy can be performed without tive study addressing this question
[e64 – e68]. endangering the limb or if an amputa- the degree of tobacco dependence
Vasa 2014; 43: 337 – 350 P. Klein-Weigel & J.G. Richter: TAO
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Review 341

Table III: Differential diagnosis of TAO

Disease Exclusion predominantly by


Diabetic angiopathy HbA1c, fasting glucose, glucose tolerance test
Embolic disease Electrocardiogram, transesophageal echocardiography,
computed tomography angiography, duplex ultrasound,
angiographic pattern
(Premature) Atherosclerosis Presence of classic cardiovascular risk factors, duplex
ultrasound, angiographic pattern
Hypercoagulability/thrombophilia Blood count, markers of thrombophilia
Vasculitis/connective tissue disease Blood sedimentation rate, C-reactive protein, antinuclear
antibodies, antineutrophil antibodies, cryoglobulin,
eosinophiles, immunoglobulines, capillary microscopy,
duplex ultrasound, biopsy
Drug-associated vaculitis (cocaine, amphetamine) History, drug screening
Ergotamine, lead, or drug poisoning History, biochemical/drug screening
Occupational diseases (chronic vibration syndrome, Occupation, angiographic or duplex ultrasound pattern
hypothenar-hammer-syndrome)

in subjects with TAO was similar to


that in subjects with coronary artery
disease [74].
Individual strategies for smoking
withdrawal have to be discussed, in-
cluding in- and outpatient-treatment
in specialized institutions [e75 – e76].
Unfortunately, the percentage of
those who maintain smoking cessa-
tion is low [e75 – e76]. In one study,
the continuous abstinence rate de-
creased from 29 % at the end of treat-
ment to 18.5% at 12-month follow up
[e76]. Overall, best results might be
achieved by structured and guided
peer group programs starting already
during hospital stay or shortly there-
after [e77 – e78].

Prostanoid therapy
The effectiveness of prostanoid ther-
apy was elucidated in two older ran-
domized trials and in two more re-
cently published trials prospectively
assessing clinical outcome in addition
to smoking cessation or compared to Figure 3: Histologic feature of thrombophlebitic nodule in TAO
sympathectomy [79 – 82]. Iloprost, a
prostacyclin analogon, is the drug of
choice. Although often used in clini-
cal routine effectiveness of iloprost re- randomly allocated 152 patients with disease) and pain from critical leg
mains controversial. Fiessinger et al. thromboangiitis obliterans (Buerger’s ischemia (98 patients suffered from
P. Klein-Weigel & J.G. Richter: TAO Vasa 2014; 43: 337 – 350
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342 Review

Table IV: Disease activity criteria in TAO (proposed by the authors) clopidogrel in TAO [3 – 4, e5, 79]. The
same is true for oral anticoagulants
(Re-)appearance or worsening of preexisting distal ischemic syndromes i. e. rest [3 – 4,e5,79].
pain or trophic lesions (ulcers, necrosis, and gangrene)
(Re-)appearance of new thrombophlebitic nodules or strings Vasodilatating drugs
Persistence or relaps of tobacco-use or passive exposure Some reports including TAO-patients
have been published addressing the
use of calcium-channel-blockers to
reduce vasospasm and improve walk-
leg ulcers) to intravenously applicat- the acute phase of Buerger`s disease ing distance [e83 – e84]. In the older
ed iloprost or low-dose aspirin for in 158 patients with rest pain and/ literature pentoxifyllin was often rec-
28 days in a double-blind trial. After or ischemic ulcers [82]. Treatment ommended, but evidence of clinical
exclusion of 19 patients not meeting started with 0.5 ng / kg / min and was improvement in TAO is missing [for
the inclusion criteria, retrospectively, aimed to reach 1 ng/kg/min if toler- overview see e9, e55]. Cilostazol is ad-
58 (85 %) of 68 iloprost-treated pa- ated. Aspirin was given, but any drugs vocated in one review, again without
tients showed ulcer healing or relief with vasodilating or hemorheologic proven evidence in Buerger`s disease
of ischaemic pain versus 11 (17 %) properties as well as epidural anaes- [e85].
of 65 in the aspirin-treated group. thesia were prohibited throughout
43 (63 %) on iloprost treatment had the observational period of 6 months. Analgesia
complete relief of pain, compared After exclusion of 8 cases with an in- Effective analgesia is crucial as isch-
with 18 (28 %) on aspirin [79]. These sufficient data set the primary end emic and neuropathic pain in TAO
striking results could not be repro- point defined as complete ulcer heal- is usually severe. Combinations of
duced in the largest trial including ing without pain or major amputation morphine or opioids and NSAR are
319 patients when iloprost was ad- was met by 60 % of the patients. Pain- often required in high doses for pain
ministered orally in two dose regimes Scale values decreased from 7.07 ± control. Antidepressants might be of
and compared to placebo. The pri- 2.12 to 2.12 ± 2.18 and 1.72 ± 2.33 additional value. Epidural anaesthe-
mary end point, which was defined after 4 and 24 weeks. Ulcer size-re- sia, neuronal block, or local analgetics
as total healing of dominant ischemic duction at 4 and 24 weeks, as well as are often applied in inpatients [e86-
lesions was not significantly differ- standardized clinical status scaling, e88]. In selected cases with preserved
ent between the treatment groups. investigator, and observer grading microvascular reserve capacity, i.e.
Only relief of rest pain without need was also significantly improved at increase of tcpO2 of at least 10 – 15
of analgesics as well as a combined both time points. Reported side ef- mmHg in a postural test or during
secondary endpoint defined as alive fects consisted of headache in 39 %, trial spinal cord stimulation is in-
without major amputation, lesions, flushing in 32 %, nausea in 24 %, and dicated as it does not only improve
rest pain, and no intake of analge- abdominal discomfort in 8.5 % of the pain-control, but also improves per-
sics was significantly more preva- patients [82]. fusion by sympathicolysis and anti-
lent in the treatment group [80]. Iloprost is nowadays exclusively applied drome mechanisms [89, e90].
In the first study published by the intravenously in either body-weighted
Turkish Buerger’s Disease Research dose regimes (0,5 – 2 ng/kg/min) or in Revascularisation procedures
Group, complete ulcer healing rate a fixed daily dose regime with 20 μg Due to the distal localization of ar-
was 61.9 % in the iloprost group and dissolved in 0.9% saline over 5 – 6 h terial occlusions and the absence of
41 % in the lumbal sympathectomy per day for 2 – 4 weeks as intravenous recipient vessels interventional or
group (LS) at 4 weeks and 85.3 % application seems to be more effective surgical revascularization is impos-
versus 52.3 % at 24 weeks. Intake of and oral applications did not enter the sible in the majority of cases.
analgestics was lower in the iloprost market. If necessary, infusions might In an older series published in 1977
group and decrease in ulcer-size was be repeated. by Inada et al. only 11 (4.6 %) out of
significantly more pronounced [81]. 236 patients were eligible for bypass
More recently, the same group pub- Antiplatelet drugs and oral procedures. Primary and secondary
lished their results of a prospective antigoaculants patency during a mean follow-up of
multicenter observational trial con- Although widely used, there is no 2.8 years (4 month to 7 years) was
ducted to clarify the role of intrave- proven evidence for platelet func- reported to be 49.0 % resp. 62.5 %,
nous iloprost therapy for 28 days in tion inhibitors such as aspirin or respectively. [91]. Sayin et al. in 1993
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Review 343

published a revascularization-rate of proved in 52.3 %, stable in 27.8 %, Starting calculated antibiotic therapy,
10 % [e92]. Shionoya and coworkers and worse in 19.8 % of the patients, one has to take anaerobic species and
reported in their series of 266 patients while 7 major and 36 minor ampu- multiple resistances into account.
a surgical reconstruction rate of 17.7 % tations were performed [e104]. On
with 38 bypass procedures, 7 thromb- the other hand, lumbar sympathec- Outcome and social
endarterectomies, and two replace- tomy was reported to be inferior to consequences
ments with an overall patency rate of intravenous iloprost applications by According to a literature survey con-
24 %, 0 %, and 100 % (only 2 cases) after the same group [81]. Thus, currently ducted by Börner et al. amputations
a follow-up period of 6 to 102 months there is no proven indication for sym- are being performed in 6.9 to 75 %
also stressing the importance of smok- pathectomy in TAO. of TAO patients within 3 to 10 years
ing cessation for a favorable outcome of follow-up. Minor amputations are
[93]. Sasajima et coworkers described Immunsuppressive drugs predominant; nevertheless, the major
primary and secondary patency rates Although widely used in former times amputation-rate was as high as 31 %
of 48.8 % and 62.5 % at 5 years, and there is no proven evidence for the [108]. The high amputation rates in
43.0 % and 56.3 % at 10 years, respec- use of steroids in TAO [for overview the relatively young patients signifi-
tively, in their series of 71 autogenous see e9, e55]. A small (n = 12) nonran- cantly contributes to the financial and
vein bypasses in 61 TAO-patients. The domized Indian trial of cyclophos- social burden of the disease, which
amputation rate in this series was 18 % phamide in the treatment of patients additionally includes job loss, early
[94]. In highly selected cases, collateral with advanced TAO has been pub- retirement, divorces, severence, and
artery bypass might be an option when lished with non-conclusive results us- subsequent social isolation [108].
the main arteries are affected by the ing 400 mg intravenously for 7 days
disease [e95]. followed by daily oral administration
Omentum-transfer, another surgi- of 100 mg for another 7 weeks [e105]. New treatment
cal procedure in non-bypass candi- Furthermore, a Russian group com- opportunities
dates, is almost unknown in Europe pared a single three day glucocorti-
or North America, but is commonly coid and cyclophosphamide pulse-
performed for limb salvage in some therapy in 16 patients to 12 controls Progenitor cell therapy
centers in India [e96 – e97]. under standard medical care and In order to improve outcome, new
Endovascular therapy might also be reported positive results, but out- experimental treatment approaches
effective even in extended femoro- come parameters focused mainly on have been published. In the last de-
tibial occlusions [e98]. Good out- inflammatory markers and the num- cade cell-based therapies with au-
come results have been published in ber of patients was far too small to tologous progenitor cells harvested
a recent series of 20 patients interven- draw any reliable conclusions about from bone marrow or peripheral
tionally treated in Italy, nevertheless limb salvage rates [e106]. Thus, out- blood have been advocated for critical
the reported numbers are small and side RCTs there are no indications for limb ischemia, including TAO. The
the role of endovascular therapy in immunosuppressive drugs in TAO. cell suspensions are usually applied
Buerger`s disease has yet to be de- by intramuscular injections alongside
fined [99, e100]. Wound management and the vascular bed of the limbs or by
There are some reports about effec- infection intraarterial injection [e109 – e111,
tive local thrombolysis without or Local wound management in isch- 112, 113, e114, 115].
in combination with angioplasty in emic lesions in TAO is based on mod- Metaanalyses have confirmed practi-
TAO, but controlled trials are missing ern wound care standards. Intermit- cability and safety as well as positive
[e101 – e103]. tent pneumatic compression might be therapeutic effects (including pain-
of additional value, although there is control, ulcer healing, pain-free walk-
Sympathectomy very limited published experience in ing ability, amputations-free survival)
In a cohort of 216 Turkish patients TAO [e107]. Wound-, soft tissue, and of cell-derived therapies in critical
sympathectomy, although unproven bone infections cause serious clinical limb ischemia [e109, 112, 115]. Prob-
by controlled trials in TAO, was pre- problems as they occur in often highly ably caused by higher progenitor-cell
ferred over open surgical reconstruc- ischemic states. Bacterial species and crop and better cell quality (younger)
tion or bypass procedures (81 % ver- resistance spectra vary widely with TAO patients have responded better
sus 19 %). Clinical outcome following gram-positive species dominating than (older) PAD-patients in some,
sympathectomy was considered im- our own series [unpublished data]. but not all studies [e116 – e118].
P. Klein-Weigel & J.G. Richter: TAO Vasa 2014; 43: 337 – 350
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344 Review

Positive results of long-term effects tion-free survival was reported to be munoadsorption is an extracorporal
have been published for a limited 8 – 14 % lower [113]. Results of ran- procedure clearing plasma from im-
number of patients [113, e116 – e118]. domized double blinded studies are munoglobulines and circulating im-
Kinoshita and co-workers reporting being awaited. muncomplexes already successfully
outcome data up to week 208 post There seems to be a significant time applied in other immunmediated
CD34+ cell therapy in 17 patients lag of 4 – 8 weeks until an improve- diseases. It is being performed on 5
including 12 with Buerger`s disease ment of microcirculation becomes consecutive days for 5 – 6 hours per
published a critical limb ischemia- evident in responders after BM-cell session aiming for a clearance of ap-
free ratio of 88.2 % at week 52 and transplantation [e119]. This lag might proximately the 2.5 fold of patient`s
104, 92.5 % at week 156, and 94.6 % be problematic in case of severe isch- plasma volume [123, e124]. IA might
at week 208 as well as significant emia demanding a more urgent im- be followed by substitution of polyva-
improvement of toe-brachial pres- provement of perfusion. lent immunoglobuline to ameliorate
sure index, tcpO2, pain rating scale Further research relates to the op- infectious risks in patients with gan-
results, ulcer size, and exercise toler- timal cell type and dosage, the best grene or ulcers.
ance at various final evaluation time isolation methods, the role of colo- The pilot study revealed a fast im-
points [e116]. In the TACT-trial out- ny-stimulating factors, administra- provement of pain, a steep incline
come data of 41 patients with TAO tion routes, and supportive stimula- of tcpO2-levels, a steep decrease of
and 74 patients with atherosclerotic tion methods. More recently, Teraa tcCO2-levels, an improvement in
disease were reported for a median et al. published diverging results of ulcer healing, and a high return-to-
follow-up-time of 25.2 month, rang- placebo and non-placebo controlled work-rate of the patients [123]. Over
ing from 0.8 to 69 months. There was studies stressing the need of a pla- all, these positive results could be re-
significant improvement of pain and cebo controlled arm in randomized produced in a clinical routine setting
ulcer size as well as claudication-free controlled trials assessing treatment [e124].
walking distance in both groups. effects of BM-cell therapies in the The rapid effects have suggested a
Patients with TAO had a better am- future [115]. pivotal role of immune-mediated
putation-free survival [e117]. Mori- Intramuscular or intraarterial pro- vasospasm. More recently, a pos-
ya J et al. retrospectively analyzed genitor cell therapies compete against sible effective mechanism of IA was
the results of 42 patients including surgical concepts of stimulating an- elucidated as IA eliminates α- and
14 patients with TAO at 1, 6, 12, 24, giogenesis and arterialization in endothelin-receptor-agonistic au-
and 36 months after treatment and TAO patients based on tibia bone toantibodies that seem to cluster in
found improvement of rest pain in distraction or fenestration, or im- TAO [42].
72.2 % of patients with pain scale plantation of a Kirschner-wire in a
values normalizing after 12 months. medullary channel of the tibia [e120, Bosentan
Ulcer size decreased in 66.7 % of all 121 – 122]. These procedures were Referring to a first positive case re-
patients staying alive without ampu- also reported to result in improved port another Spanish group recent-
tation, but there was no significant outcome regarding pain-scores, ulcer ly published their results of a pilot
improvement in walking distance. healing, and walking distances [e120, study introducing the endothelin-
Patients with TAO and those with 121 – 122]. Nevertheless, they might receptor blocking agent bosentan
non-dialysis atherosclerotic disease be hampered by side effects as the in the treatment of digital ulcers in
experienced fewer amputations and operation takes place in an ischemic TAO patients [e125, 126]. Dosing
cardiovascular events, and had a environment. Controlled and com- was derived from the approved ap-
lower mortality-rate [e118]. Finally, parative studies are missing. plication for prophylaxis of digital
Lee et al. analyzed the outcome for ulcers in scleroderma patients. De-
90 limbs in 67 patients exclusively Immunadsorption (IA) spite the promising results about 1/6
suffering from TAO. Clinical and Based on the hypothesis, that TAO of the patients had to undergo minor
angiographic improvement was ob- is an immunmediated disease with digital amputations – a finding, not
served in 55.6 % and 43.2 % whereas humoral factors playing a major role necessarily arguing against the ef-
amputation-free survival for all limbs in the pathogenesis IA was success- fectiveness of bosentan as minor am-
after 1, 3, and 5 years was reported to fully introduced in a pilot study con- putations might have already been
be 91.9 %, 88.5 %, and 84.6 %, respec- ducted by Baumann and co-workers inevitable at presentation or might
tively. In patients initially suffering and later introduced in a clinical even have been made successfully
from critical limb ischemia amputa- routine care setting [123, e124]. Im- possible by the treatment – a find-
Vasa 2014; 43: 337 – 350 P. Klein-Weigel & J.G. Richter: TAO
© 2014 Hans Huber Publishers, Hogrefe AG, Bern

Review 345

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