Introduction {#S0001}
============

Until recently, thromboangiitis obliterans (TAO) had been known as a recurrent, non-atherosclerotic segmental inflammatory and occlusive peripheral vascular disease with unknown etiology that is typically seen only in young, male smokers.[@CIT0001] The dominant clinical manifestation of TAO is in the extremities and usually in the medium- to small-sized vessels of the lower and upper limbs, which can lead to limb loss.[@CIT0001] Because of the disease's unknown etiology, no treatment protocol is available for TAO, and management of TAO remains a medical challenge.

Although smoking cessation is known to be an important part of any suggested treatment, merely stopping smoking cannot prevent amputation and limb loss during disease flare-ups.[@CIT0002] Notably, one of the challenges of TAO management is in the patients whose other vascular beds are involved. For instance, in a TAO patient with coronary artery involvement, it remains a challenge to know whether to pursue invasive procedures or to continue medical treatment. In addition, the prevalence of TAO is low in comparison to other peripheral arterial diseases (PADs), even in countries in which TAO is common. Moreover, involvement of the visceral vessels is occasionally seen in TAO, which means that the involvement of other vascular beds is quite rare.

For these reasons, our understating of the involvement of other organs and their clinical manifestations and outcomes is poor. As a result, the aim of this review was to investigate reports of the involvement of the visceral vessels in TAO and the related clinical manifestations, management approaches and outcomes from January 1947 through December 2018.

Literature search {#S0002}
=================

A systematic search for relevant literature published between January 1, 1947 and December 31, 2018 was performed on the PubMed, Science Direct databases and Google Scholar. The search was done in the English language. The reference lists from the retrieved studies were then hand-searched. Search terms included "thromboangiitis obliterans", "Buerger's disease", "Arthritis", "Skin", "Cutaneous", "Nodular erythema", "Livedo reticularis", "Erythromelalgia", "Purpura", "Renal", "Kidney", "Cardiac", "Coronary", "Heart", "Lung", "Pulmonary", "Testis", "Genital", "Penis", " Nervous system", "Cerebral", "Ophthalmic", "Eye", "Muscle", "Muscular" "Hearing", "Ear", "Carotid", "Hematology", "Anemia", "Lymphadenopathy", "Bone", "Skeleton", "Stomach", "Liver", "Spleen", "Pancreas", "Bowel", "Intestine", "Mesenteric", "Celiac" with combinations being searched via Boolean operator.

For data extraction, the indices for the diagnosis of TAO from each article were evaluated. Articles whose angiography characteristics or pathology reports did not quite match TAO diagnosis were excluded from our study. We excluded articles for which the full-text was not in English or for which the full-text was inaccessible. The primary data extraction form included the year of publication, author name(s), number of patients, age, chief complaint, duration of disease, smoking status, disease diagnosis, suggested treatment and treatment outcome, all of which were assessed by the two independent reviewers (F.F. and B.F.).

Our search initially identified 210 studies. We checked for duplicates between databases. The remaining studies were further reduced to 173 after screening of the titles and abstracts. Finally, after applying the exclusion criteria, the total number of relevant studies was reduced to 83.

Result {#S0003}
======

According to our systematic review, 83 articles were included, 78 of which were case reports and 2 of which were case series papers, with the final 3 being original papers. Fifteen articles were published prior to the 1980s, and 68 articles were published after 1980.

According to the frequency of published articles, the organs most commonly involved were (1) the gastrointestinal (GI) tract, (2) the heart, (3) the central nervous system, (4) the eye, (5) the kidneys, (6) the urogenital system, (7) the mucocutaneous zones, (8) joints, (9) lymphohematopoietic system and (10) the ear. The search results for each organ are summarized in the following 10 tables.

 {#S0004}

Gastrointestinal tract {#S0004-S2001}
----------------------

The systematic search returned 45 articles related to the gastrointestinal tract. We were not able to access the full text of nine articles published prior to 1985, and four articles were not in English. Therefore, these 13 articles were excluded from our study. In total, we reviewed 32 articles comprising 41 patients that were published between 1947 and 2016 ([Table 1](#T0001){ref-type="table"}). The mean age of the patients was 41±8 years. The mean number of cigarettes smoked daily was 32±12, and the duration of smoking before mesenteric ischemia was 22±8 years. Only one case was female. In 65% of these cases, TAO diagnosis had occurred approximately 8 years before the mesenteric ischemia. In the remaining cases, TAO was diagnosed at the acute abdomen, and the histology examination of the ischemic bowel confirmed TAO diagnosis. The clinical manifestations of the patients consisted of the onset of diffuse abdominal pain in 44% of the cases, weight loss in 20% of the cases, pain in the right lower abdominal quadrant in 12% of the cases, bloody stool in 10% of the cases, postprandial pain in 8% of the cases and epigastric pain resistant to antiulcer treatment in 6% of the cases.Table 1Data summary of patients with TAO and gastrointestinal tract involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12016Enshaei et al\
(Iran)[@CIT0003]139 yearsAcute abdominal painBelow-knee (BK) amputation 5 years earlier1.5 packs of cigarette for 25 yearsPrevious diagnosis of TAO\
Abdominal X-ray\
laboratory tests\
Angiographic and histhopathological examinationsResection the gangrenous part of ileum (25 cm) following ileostomyTwo more laparotomy after the initial one because of the bilious discharge.22016Bouomrani et al (Tunisia)[@CIT0004]142 yearsRecurrent duodenal ulcer lasting for 5 years which did not improve by the well- anti-ulcer treatmentDisease diagnosis 15 years earlier and two toe amputations during this timeTwo packs of cigarettes for more than 15 yearsPrevious diagnosis of TAO according to clinical features, angiography and laboratory tests\
Endoscopy and histological examination of the ulcerAnti-ulcer treatment in addition to anticoagulant and vasodilation treatmentUlcer healing after two months confirmed by endoscopy\
No ulcer recurrence after four years follow-up32016Shastri et al (India)[@CIT0005]153 yearsDiffuse abdominal pain with distention and constipation for 5 days following episodes of bloody stool, and bilious vomiting due to segmental ileum ischemiaCalf claudication 2 months earlier and gangrene of right 2nd and 5th toes 10 days earlierOne pack of cigarette for 20 yearsTAO diagnosis according to clinical examination and laboratory tests\
Histological examination of ileumResection of 167 cm of ileum following anticoagulant treatment.Recovery42014Kamiya et al (Japan)[@CIT0006]148 years (woman)Acute severe and persisted abdominal painTAO diagnosis three years earlier\
She underwent below-knee amputation 3 years earlier and the diagnosis of TAO was confirmed by histological examinationSmoking one pack of cigarette daily before the disease diagnosisAcute mesenteric artery occlusion in addition to multiple small infarctions in the kidneys was observed in the abdominal computed tomography\
Spleen infarction 1 day after the laparotomy\
The histological examination was not typical for TAO but more likely emboli. The source for emboli was thoracic aorta. However, the underlying cause of thrombus formation inside thoracic aorta remained elusive according to laboratory tests and intensive heart examination.Resection of entire small intestine and the right side of the colon.\
Anti-coagulation therapyTransient liver dysfunction after the surgery.52010Lee et al (Korea)[@CIT0007]2Case 1: 65 years\
Case 2: 39 yearsCase 1: Periumbilical and right lower quadrant pain with bloody diarrhea for 2 months. Pain worsening following constipation and abdominal distention in the last 3 days\
Case 2: Right lower quadrant pain and bloody stool for 5 days. Intermittent abdominal pain several months earlier.Case 1: TAO diagnosis 16 years earlier and right BK amputation 11 years before colon ischemia\
Case 2: TAO diagnosis 5 years earlier according to clinical manifestation and angiography. He underwent toe amputation during this timeCase 1: smoking one pack of cigarette for 20 years but stopped smoking 3 years before colon ischemia.\
Case 2: one pack of cigarettes for 16 yearsCase 1: Abdominal\
computed tomography\
Histological examination\
Case 2: Abdominal\
computed tomography\
Mesenteric angiographyCase 1: Rectosigmoid resection\
Case 2: Conservative treatmentCase 1- Recovery\
Case 2- Recovery62009Çakmak et al (Turkey)[@CIT0008]148 yearsPostprandial abdominal pain and 25 kg weight loss within a year.TAO diagnosis 14 years earlier and toe amputations during this time (Angiography confirmation)Two packs of cigarette for 25 yearsCT angiography of celiac trunk and superior and inferior mesenteric arteries\
Histophatological confirmation after hemicolcetomy and ileum resectionFirst approach was angioplasty and stenting\
After 2 years, right hemicolectomy and partial ileum resection because of revascularization failureRecovery72009Turkbey et al (Turkey)[@CIT0009]135 yearsIncrease in abdominal pain that was ongoing for 4 monthsTAO diagnosis 20 years earlier and history of two BK amputationUnknownAbdominal CT angiographyResection 200 cm of jejunumRecovery82006Leung et al (NewYork, USA)[@CIT0010]134 yearsAbdominal pain, nausea and vomiting with weight loss about 10 kg over 6 months.TAO diagnosis according to clinical manifestation and angiography several weeks before mesenteric ischemia\
The patient was under treatment with anticoagulants and calcium channel blockerLengthy history of smokingAccording to Magnetic resonance imaging and abdominal CT scan\
Small splenic and renal infarction was also observed\
Histological examination of small intestine and superior mesenteric artery confirmed the diagnosis of TAOResection of the of almost all of the small and large bowelsDischarged from hospital with hospice care at home.92005Cho et al (Korea)[@CIT0011]137 years2-day history of diffuse abdominal pain and a 2-month\
history of claudication of his left handTAO diagnosis according to angiography and histological examination of small bowelOne pack of cigarette for 20 yearsAbdominal CT scan\
Histological examination of small intestine confirmed the diagnosis of TAOResection of small bowel (40 cm)Recovery102003Kobayashi et al (Japan)[@CIT0012]142 yearsAbdominal pain with muscle guardingTAO diagnosis according to Shionoya's criteria and excluding other types of vasculitis 8 months earlier and he had one BK amputation during this time. He was under treatment of warfarin and ticlopidine.Two packs of cigarettes for 20 yearsAngiography\
According to autopsy and histological examination including posterior tibialis artery the diagnosis of TAO was confirmedThe ileum end, cecum and proximal side of the ascending colon and sigmoid colon were necrotic and resectedDeath112003Cho et al (Korea)[@CIT0013]138 yearsObstipation and diffuse abdominal pain with 5 days durationTAO diagnosis according to clinical manifestation and histological confirmation of minor amputation 14 years earlier\
The patient also underwent BK amputation during this timeOne pack of cigarette for 18 daysPhysical examination and emergency laparotomy\
Histology confirmed TAO diagnosisResection of 100 cm of small bowelUnknown122003Kurata et al (Japan)[@CIT0014]135 yearsSudden onset of abdominal painTAO diagnosis 10 months earlier and lumbar sympathectomy during this time\
(Angiography chractristics for TAO)One pack of cigarette for 15 yearsAbdominal X-Ray and emergency laparotomy\
Histology confirmed TAO diagnosisResection of small bowel including ileocecal (54 cm)Recovery132001Sidiqqui et al\
(NewYork, USA)[@CIT0015]151 years7-month history of abdominal pain and under corticosteroid treatment by the diagnosis of Crohn's disease\
Acute abdominal pain in the hospital due to non-healing ulcer of ingrown toenailTAO diagnosis\
at the onset of acute abdomen by lower limb angiography\
The diagnosis was confirmed by histological exam after autopsySmoking for 26 yearsAbdominal CT scan\
-Aortogram\
-Angiography\
Histology confirmed TAO diagnosisPlasmapheresis and high-dose steroids\
temporary improvement but small bowel resection (36 cm) 2 months laterDeath due to recurrent intestinal ischemic perforations, and sepsis142001Hassoun et al (Belgium)[@CIT0016]150 years3-month history of postprandial epigastric pain, vomiting, and diarrhea and weight loss around 15 kg over the past 5 monthsTAO diagnosis 30 years earlier and one BK and several minor amputations during this timeOne pack of cigarette for 32 yearsAbdominal CT scan\
AngiographyConservative treatmentRecovery151998Iwai\
(Japan)[@CIT0017]3Case 1: 51 years\
Case 2: 43 years\
Case 3: 43 years (identical twin of case 2)Case 1: Epigastric pain\
Case 2: Postprandial abdominal pain for 2 years following 15 kg weight loss in one year\
Case 3: abdominal anginaCase 1: TAO diagnosis according to clinical manifestation and angiography 10 years earlier\
Case 2: TAO diagnosis according at the time of abdominal pain according to clinical manifestation and lower limb angiography\
Case 3: TAO diagnosis at the time of abdominal angina according to clinical manifestation of lower limbs and angiography and aortographyCase 1: one pack of cigarettes for 30 years\
Case 2: unknown\
Case 3: unknownCase 1: Upper GI series showed deformity of the duodenal bulbus and ulcer formation. Histology of right gastric artery was compatible with diagnosis of TAO\
Case 2: Aortography\
Case 3: Aortography\
Histology of splenic artery was compatible with TAO diagnosisCase 1: Gastrectomy\
Case 2: bypass revascularization and sympathectomy of mesentric and celiac ganglia\
Case 3: Bypass surgeryCase 1- Recovery\
Case 2- Failure of vascular reconstruction two years after bypass surgery\
Case 3- Recovery161998Michail et al\
(Greece)[@CIT0018]142 yearsHistory of chronic abdominal pain\
Reported with\
acute abdominal pain and vomitingTAO diagnosis according to clinical manifestation and angiography at the time of hospital admissionHeavy smoker for 24 yearsAbdominal X-rays\
Angiography\
Histology confirmed TAO diagnosisPartial enterectomyRecovery171998Lie\
(California, USA)[@CIT0019]4Range from 35 to 41 yearsUnknownDuration of the disease is unknown but all the cases had at least one leg amputationsUnknownUnknown\
But Ileum, ascending colon, jejunum and sigmoid colon were infarcted or gangrenous in the four casesResection of ileum and ascending colon in two cases\
Other two cases died before surgical intervention50% Death181996Sauvaget et al\
(France)[@CIT0020]136 yearsDysentery associated with a weight loss of 12 kg following acute abdomenTAO diagnosis at the workup for the cause of dysentery\
Angiography of the lower limbs were characteristics for TAO17 pack-yearColonoscopy which showed diffuse superﬁcial ulcerations, with a deep ulceration of the sigmoid colon.\
Unresponsive to amebicides\
Histology exam confirmed TAO diagnosisResection of sigmoid 17 cm\
Intravenous heparin and prostacyclinRecovery191995Burke et al\
(Washington, USA)[@CIT0021]2Case 1: 39 years\
Case 2: 48 yearsUnknownUnknownHeavy smokersUnknown\
Histology exam confirmed TAO diagnosisUnknownCase 1-Recovery\
Case 2-recurrecnt strictures at bowel anastomosis during 4 years follow-up201994Schellong et al\
(Germany)[@CIT0022]123 years9-month history of postprandial abdominal pain and weight loss about 15 kg\
Referred from another hospital by diagnosis of mesenteric ischemia confirmed by angiographyTAO diagnosis at the workup for the acute abdominal pain20--30 cigarettes for 5 yearsAbdominal examination\
Angiography\
Raising liver enzymes\
-Histologic examination was compatible with TAOThrombectomy and short vein bypass from the aorta to the\
common hepatic arteryRecovery211994Saboya et al\
(Brasil)[@CIT0023]134 yearsBecause of 8 hrs intestine pain in the lower abdomen and obstipationTwo BK amputations 2 years earlierUnknown but give up smoking for 2 yearsLaparotomy due to abdominal examination and laboratory tests\
Histology was supportive for TAOResection of sigmoid colon (28 cm was necrotic) and rectumDischarged with colostomy221993Ito et al\
(Japan)[@CIT0024]142 yearsAcute right lower quadrant pain and with severe\
tenderness and slight muscle guarding\
previous history of abdominal colicky pain and vomitingTAO diagnosis 14 years earlier and two BK amputations during this time and several toe amputations30 cigarettes daily for 20 yearsLaparotomy by primary diagnosis of diverticulitis (The patient had appendectomy before)\
Postoperative aortography and histology of cecum and small mesenteric vessels confirmed TAO diagnosisIleocecal resectionRecovery231993Broide et al\
(Israeal)[@CIT0025]120 yearsSevere abdominal pain and vomiting of 3 days\
durationTAO diagnosis 2 years after acute abdomen according to clinical manifestations, laboratory investigation and angiographyTwo to three packs of cigarette for 5 yearsRetrograde diagnosis of TAO for mesenteric ischemiaResection of jejunum\
Histology demonstrated well-organized thrombi in branches of superior mesenteric arteryRecovery241983Soo et al\
(Australia)[@CIT0026]148 yearsAbdominal pain in right iliac fossa with rebound and tendernessTAO diagnosis 7 years earlier according to clinical manifestation\
The patient underwent one BK amputation and several toe amputations\
Histology examination confirmed the diagnosis of TAOThree packs of cigarette a dayThe pre-operative diagnosis was appendicitis\
During the surgery 8 cm infarcted sigmoid colon was observed.\
Histology study confirmed the diagnosis of TAO in the colon.\
Appendix was macroscopic and microscopic normal.Resection of sigmoid colonRecovery251979Borlaza et al (Michigan, USA)[@CIT0027]136 years2-week history of abdominal pain with nausea and vomiting and weight lossTAO diagnosis after abdominal pain according to clinical manifestation, angiography of lower limbsTwo packs of cigarettes per day for 21 yearsLaparotomy by initial diagnosis of intussusception and resection if ileum\
Histology findings was suggestive for BD\
Aortography was also supportive for visceral TAOResection of ileum (30 cm)Recovery261979Sobel et al\
(California, USA)[@CIT0028]135 yearsDuring hospital admission for non-healing wound of amputation stump, the patient developed abdominal pain following decreased consciousness and generalized seizureTAO diagnosis 10 years earlier and one BK amputation\
Histology had confirmed TAOOne to two packs of cigarette for 25 yearsIn autopsy necrotic pancreas and infarcted spleen due to occlusion of celiac and splenic artery and hemorrhagic bilateral adrenal necrosis and hemorrhagic infarction of pituitary and cerebral cortices\
Histology of celiac artery was supportive for TAO diagnosisNothing for the abdominal pain due to acute renal failureDeath271977Sachs et al\
(Texas, USA)[@CIT0029]145 yearsConstant left upper quadrant abdominal pain\
History of 1 year anorexia and weight lossTAO diagnosis at the time of admission for abdominal painTwo packs of\
cigarettes for 30 yearsBarium enema and aortography\
Histology was supportive for TAO diagnosisResection of transverse colonUnknown281972Wolf et al\
(Washington, USA)[@CIT0030]2Case 1: 53\
Case 2: 43Case 1: Obstipation and persistent abdominal pain with vomiting\
Case 2: Reporting with gastrointestinal hemorrhage and shock\
Nausea and cramping abdominal pain 5 days before admission.Case 1: BD diagnosis 18 years earlier and one BK amputation during this time\
Case 2: BD diagnosis 2 years earlier and one BK amputation\
Histology confirmed the diagnosis of TAOCase 1: 30 cigarettes per day for 38 years\
Case 2: 20 to 40 cigarettes per day for 30 yearsCase 1: Abdominal examination and exploring laparotomy which showed two small abdominal wall abscesses\
Since the abscesses could not explain the pain of the patient, biopsy from jejunal mesenteric arcade was obtained\
The histological findings were supportive for visceral BD\
Case 2: At autopsy, thrombosis of portal vein, which extended\
into the superior mesenteric vein and the infarction of jejunum histology demonstrated neutrophilic infiltration of vein wallCase 1: Unknown\
Case 2: Intravenous infusion of salineCase 1: Unknown\
Case 2: Death291968Herrington et al (Tennessee, USA)[@CIT0031]2Case 1: 33 years\
Case 2: 42 yearsCase 1: Several days of cramping, left lower quadrant abdominal pain following severe tenderness\
Case 2: 8 months cramping abdominal pain, anorexia, and weight loss of 20 pounds following severe abdominal painCase 1: TAO diagnosis at the onset of acute abdomen according to past medical history and clinical manifestation and histology exam of the sigmoid colon\
Case 2: TAO diagnosis at the onset of acute abdomen. Angiography of upper and lower limbs confirmed the diagnosis of TAOCase 1: Smoking for years\
Case 2: Smoking 60 cigarettes per day for 24 yearsCase 1: Laparotomy by the suspicious of sigmoid diverticulitis\
Histology confirmed TAO diagnosis\
Case 2: laparotomy by the primary diagnosis of appendicitis. However, appendices was normal but jejunum was ischemic.Case 1: Resection of sigmoid colon\
Case 2 Resection of jejunum (60 cm)Case 1: Recovery\
Case 2: Recovery after resection of jejunum but 1 month later he had massive melena and then death301966Rob et al\
(New York, USA)[@CIT0032]146 yearsCramping and spasmodic, central abdominal pain associated with diarrhea and weight lossTAO diagnosis many years earlier and two BK amputations during this timeUnknownAbdominal X-ray\
Aortography was normal however the histological exam of the resected bowel confirmed the diagnosis of TAO in the thrombotic occluded vessels in the mesenteryResection the ischemic part of small bowelUnknown311953Kilbourne et al (Chicago, USA)[@CIT0033]135 yearsEpigastric pain, vomiting and blood loss in stoolTAO diagnosis 1 year earlier and one BK amputationHeavy smokersLaparotomy by primary diagnosis of superimposed polyps or Carcinoma.\
During the surgery stomach was found to be 3 to 4 times\
normal thickness and somewhat spongy from cardia to antrum, where there was an abrupt change to normal consistency and thickness.\
perigastric nodes were enlarged up to 4 by 2 cm\
Histology demonstrated no malignancy but perivascular inflammation without thrombotic occlusion.The involved portion of the stomach was resectedRecovery321947Garvin\
(Pennsylvania, USA)[@CIT0034]133 yearsAbdominal pain, distention and vomiting\
History of same presentation 8 years earlierTAO diagnosis 8 months earlierUnknownLaparotomy by diagnosis of mesenteric ischemia\
The histology was supportive for TAO diagnosisResection 45 cm of gangrenous proximal iliumUnknown

Amongst the included articles, occlusion of the superior mesenteric artery occurred in 53% of the cases, of the inferior mesenteric artery in 12.5% of the cases, of both the superior and inferior mesenteric arteries in 22% of the cases and of the celiac artery and its branches in 12.5% of the cases. Notably, the involvement of the bowels was almost segmental.

However, as observed through aortography, corkscrew collaterals and skip lesions were less prominent than those observed in the lower extremities. The histology study of the visceral vessels and microvessels revealed the same characteristics as the peripheral vessels in TAO. The mortality rate of the patients due to mesenteric ischemia was 16%. Approximately 12% of the patients without signs of peritonitis underwent conservative medical treatment, all of whom improved, although one developed onset of mortal mesenteric ischemia two months after receiving a high dosage of corticosteroids. Endovascular treatment failed in 50% of the four patients in whom it was attempted. The outcome of 12% of the patients has not been reported.

Heart and coronary arteries {#S0004-S2002}
---------------------------

According to a systemic search, we found 20 related articles. We could not have access to the full text of an article in 1986 and four articles were not in English. In one article published in 1977, the diagnosis of TAO was very uncertain according to the clinical manifestations and histology report, and there was no angiography report for that case to support TAO diagnosis. As a result, the article was excluded from our study. In total, 14 articles related to the heart or coronary arteries published between 1985 and 2018 were included, comprising 14 patients ([Table 2](#T0002){ref-type="table"}). The mean age of the patients was 39±10 years. The mean number of cigarettes smoked daily was 27±13 and the duration of smoking before mesenteric ischemia was 21±14 years. Only one patient was female. In 66% of the cases, TAO diagnosis was made approximately 12 years before cardiac event, and in 34% of the cases, TAO diagnosis occurred soon after hospitalization due to cardiac event.Table 2Data summary of patients with TAO and coronary arteries involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12018Tekin et al (Turkey)[@CIT0035]145 yearsAcute chest painTAO diagnosis 2 years earlier25 pack/yearAngiography coronary dissection in LADBypass surgery using saphenous veinRecovery no data about further follow-up22016Atay et al (Turkey)[@CIT0036]126 yearsChest pain\
and myocardial infarction two times in 1 yearTAO diagnosis before the chest pain confirmed by angiographyUnknownCoronary angiography 70% stenosis of LADAngioplasty with drug-induced stent\
Balloon angioplasty for in-stent thrombosis and thrombolytic therapy\
CilostazolStent thrombosis 5 months later\
No more data about the condition of the patient after balloon angioplasty and receiving Cilostazol32013Mitropoulos et al (Greece)[@CIT0037]152 yearsMyocardial infarctionTAO diagnosis 25 years earlier\
One BK and several minor amputationsHeavy smokerCT angiography 80--90% stenosis of LADBypass surgeryRecovery and improved ejection fraction after one year follow-up42013Akyuz et al (Turkey)[@CIT0038]143 yearsOnset of severe chest pain and loss of consciousness due to inferior and right myocardial infarctionTAO diagnosis 5 years earlierUnknownCoronary angiography showed total occlusion of mid-portion LAD and proximal RCA without any flowUnsuccessful endovascular procedure and because of unstable hemodynamic could not be candidate for bypass surgery\
Tissue plasminogen activator (tPA) and glycoprotein IIb/IIIa inhibitorRecovery\
No data about further follow-up52007Hsu et al (Taiwan)[@CIT0039]132 yearsAcute chest tingling for 2 hrs with V1-V6 ST elevation which recovered spontaneously.\
Also frequent episodes of accelerated idioventricular rhythmPrevious TAO diagnosis with angiography confirmationUnknownCoronary angiography 90% stenosis of proximal LADStent implantationRecovery\
No data about further follow-up62007Abe et al (Japan)[@CIT0040]138 yearsUnknown but coronary angiography was performed during the hospital admission of the patient for ischemic leg pain at restTAO diagnosis 13 years earlierUnknownCoronary angiography complete occlusion of the middle segment of LAD and corkscrew collaterals and intact right coronary artery supplied blood stream distallyUnknownUnknown72006Miranda (Lebanon)[@CIT0041]160 yearsNon--ST-elevation myocardial infarction and dyspnea after left upper lobe lung resection for non-small-cell lung cancer.A known case of TAOUnknownCoronary angiography showed a 90% stenosis of the distal RCA with distal flow via collaterals\
Chest CT scan showed thrombosis in the left upper pulmonary veinRCA stenting\
Oral anticoagulationRecovery and complication after 3 months follow-up82005Hong et al (Chicago, USA)[@CIT0042]161 yearsReferred for a positive stress testTAO diagnosis 32 years earlier\
One BK, one above elbow and several minor amputations50 pack/yearCoronary angiography\
No significant narrowing of LAD, the first diagonal artery, there were multiple, sequential, intraluminal filling defects in a beaded pattern. The left circumflex artery had a 40% stenosis in its proximal portion with 2 filling defects at the onset of the first obtuse marginal artery. The right coronary artery had a focal 60% stenosis in its mid portion with an overlying filling defect resulting in a 90% stenosisAsprin and WarfarinNo change in the angiography after 2 months follow-up92002Becit et al (Turkey)[@CIT0043]136 yearsAcute chest pain, palpitation and sweating due to acute anteroapical myocardial infarctionTAO diagnosis 12 years earlierOne pack of cigarette per day for 8 years previous to TAO diagnosisCoronary angiography revealed total occlusion of the proximal segment of LAD and plaque at RCA.\
Histology examination of an endarterectomy specimen showed specific feature of TAOClosed endartrectomy and bypass surgery using saphenous vein and left internal mammary arterySymptoms free up to 7 months after bypass surgery because of the occlusion of distal bypass graft.102002Hoppe et al (California, USA)[@CIT0044]139 years (woman)Three-hour of retrosternal chest pain.\
History of similar episode of chest pain, which resolved spontaneously, 2 weeks earlierHistory of TAO diagnosisUnknown (Smoker)Coronary angiography a proximally occluded LAD that ﬁlled distally via right to left collaterals, a 50% proximal left circumﬂex coronary and a dominant right coronary artery that had proximal to mid-vessel beaded irregularities\
The histology examination of the left internal mammary artery confirmed TAO diagnosisBypass surgeryRecovery\
No data about follow-up111997Francesco Donatelli et al (Italy)[@CIT0045]139 years (woman)Unstable angina\
History of 2 years epigastric pain of unknown origin and sporadic episodes of typical angina for the past 8 monthsTAO diagnosis according to histology examination of internal thoracic artery and excluding other types of vasculitis\
No more information about the extremitiesShe had never smokedCoronary angiography, stenosis of LAD artery and RCA.\
Histology examination of dissected internal thoracic arteries was compatible with TAO diagnosis.Bypass surgery of three vessels with saphenous veins\
Internal thoracic arteries were not suitable for grafting because of diffuse narrowing at the proximal end and occlusion at the distal end.\
Note: satellite lymph nodes were enlarged.Recovery and no onset of any angina during 8 months follow-up121993Mautner et al (New York, USA)[@CIT0046]137 yearsProlonged chest pain with T-wave inversion in leads I, aVL, and V4 to V6TAO diagnosis is unknown because the histology report of coronary arteries during autopsy is more supportive for diffuse atherosclerosis\
5 years earlier history of acute femoral artery occlusion and above knee amputation of both legs with one year intervalsOne pack of cigarettes for 15 yearsCoronary angiography\
About 75% stenosis of left circumflex coronary arteryIntravenous streptokinaseDeath due to mesenteric ischemia131987Kim et al (Korea)[@CIT0047]129 yearsContinuous substernal chest pain for 3 days due to anterior myocardial infarctionTAO diagnosis at the time of admission for chest pain confirmed by upper and lower limbs angiographyUnknownCoronary angiography\
Segmental occlusion of proximal LAD\
Complete occlusion of the first diagonal branch of LAD in the distal portion, irregular and tortous contour of RCA without obvious luminal narrowingConservative treatment with nitrate, beta blocker and calcium channel blockerRecovery\
No data about the duration of follow-up141985Ohno et al\
(Japan)[@CIT0048]132 yearsSevere chest pain at rest for 3 hrs due to acute myocardial infarctionTAO diagnosis 6 years earlier and one BK and one toe amputation during this time41--60 cigarettes per day for 12 yearsCoronary angiography revealed 70% stenosis of RCA and the proximal LADUrokinase\
Discharged with vasodilator and anticoagulant therapyRecovery\
(About 1 month follow-up)

The occlusion of the left anterior descending artery (LAD) and its branches, including the diagonal and circumflex arteries, in addition to right coronary artery (RCA), was observed in 35% of the cases. The involvement of only the LAD occurred in 41% of the cases, of only the RCA in 18% of the cases, and of the circumflex artery in 6% of the cases. In 71% of the cases, coronary artery stenosis was observed, whilst in the remaining cases, complete segmental occlusion and corkscrew collaterals were noted. Approximately 38% of the patients underwent bypass surgery, 38% underwent medical treatment, including intravenous thrombolysis, and 24% underwent endovascular stenting or balloon angioplasty. The saphenous vein was most compatible for bypass surgery in comparison to the internal mammillary artery due to the involvement of that artery. Of the patients who underwent bypass surgery, 80% recovered without bypass graft occlusion due to follow-up occurring approximately 1 year after surgery. About 67% of the vascular stents became occluded between surgery and the 5-month follow-up. All of the patients who received only conservative treatment, including vasodilators, showed improvement, and 67% of the patients who received thrombolytic treatments recovered. None of the patients died as a result of a cardiac event.

Central nervous system {#S0004-S2003}
----------------------

The systematic review revealed 15 articles related to the central nervous system. Four of the articles had been published in a language other than English and were excluded from our study. In total, 12 articles were included that comprised 12 patients and were published between 1952 and 2016 ([Table 3](#T0003){ref-type="table"}). The mean age of the patients was 35±11 years and 81% of the patients were male. The mean number of cigarettes smoked daily was 30±11 and the duration of smoking before mesenteric ischemia was 24±18 years. In 54% of the cases, TAO diagnosis had been made approximately 5 years before neurological complications. In the remaining cases, diagnosis occurred during or after neurological symptoms had developed. The clinical manifestations of the patients consisted of hemiparesis in 27% of the cases, aphasia in 18% of the cases, hemianopia in 13.5% of the cases, behavioral and cognitive impairment in 13.5% of the cases, seizure in 13.5% of the cases, hemiplegia in 10% of the cases, and severe localized headache in 4.5% of the cases. All five patients who completely stopped smoking improved. Vasodilators and anticoagulants did also result in improvement. However, 50% of the patients who received only anticoagulants and anti-platelets showed improvement. The mortality rate due to cerebral ischemia was 8.3%.Table 3Data summary of patients with TAO and cerebral arteries involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease\
(amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12016Aydin et al (Turkey)[@CIT0049]130 yearsAcute onset left hemiparesisTAO diagnosis 8 years earlier\
Angiography of upper and lower limbs were compatible with TAO diagnosisUnknownMRI demonstrated showed infarct of right basal ganglia\
MRA and MIP of cerebral artery demonstrated segmental occlusions bypassed by collateralsUnknownUnknown22013Akyuz et al\
(Turkey)[@CIT0038]143 yearsBlurred consciousness and right hemiplegia and right hemianopsia during hospitalization for myocardial infarctionTAO diagnosis 5 years earlierUnknownCranial CT scan demonstrated left posterior cerebral artery territory infarctTissue plasminogen activator (tPA) and glycoprotein IIb/IIIa inhibitorFully recovered from hemiplegia and partially recovered from hemianopsia32012Hurelbrink et al\
(Australia)[@CIT0050]156 years\
(woman)Cognitive decline over 18 months started with global aphasia and gradually became dependent for the basic self-care activities. After then her memory and mood were also affectedTAO diagnosis according to the pathology report of white leptomeningeal vessels and excluding other types of vasculitis or hyper- coagulable state responsible for neurological manifestation25--30 cigarettes per day for more than 30 yearsMRI and cerebral angiography demonstrated terminal vessel occlusions associated with widespread proliferation of new vesselsSmoking cessationImprovement42007Huang et al\
(Taiwan)[@CIT0050]157 yearsSudden onset right limb numbness and crossed sensory deficit over the left side of his face and right side of his trunk and extremities, a left homonymous hemianopsia and limitation in eye movements.TAO diagnosis during hospitalization for neurological complaints by excluding other types of vasculitis or hyper-coagulable state and angiography of upper limbOne pack of cigarettes for 42 yearsAccording to neurological exam, diagnosis of left pontine infarct and right occipital infarct was madeSmoking cessation and vasodilators and anti-plateletsImprovement in acrocyanosis but unknown about neurological manifestation52005No et al\
(Korea)[@CIT0051]129 yearsSudden onset of 20-min episodes of a\
tingling sensation in his left face, arm and leg during a week.\
History of hemiparesis 6 years earlier which improved within a weekTAO diagnosis at the time of admission according to clinical manifestation, CT angiography and excluding other types of vasculitis vasculitis or hyper-coagulable stateMore than 40 cigarettes a day for 11 yearsBrain MRI\
angiography demonstrated multiple tandem arterial occlusions in the middle cerebral arteries with fine collaterals around the occluded segmentsIntravenous prostaglandin E1 following aspirin and Clopidogrel\
And smoking cessationRecovery and no recurrence of the symptoms in 1 year follow-up61998Bischof et al\
(Germany)[@CIT0052]126 years10-day history of severe left-sided headache and episodes of transient sensorimotor right sided hemiparesis and aphasia which lasted for 20 mins and resolved completely.TAO diagnosis 2 years earlier according to clinical manifestation, capillaroscopy and ultrasound examination\
Other types of vasculitis vasculitis or hyper-coagulable state were also excluded.20 cigarettes a dayBrain MRI demonstrated thrombosis of superior sagittal sinusIntravenous heparin which changed into oral anticoagulationRecovery and no relapse within 2 weeks follow-up71995Dotti et al\
(Italy)[@CIT0053]130 yearsBehavioral disturbances with severe cognitive impairment.\
History of grand-mal-type epileptic seizure at age 17TAO diagnosis 6 years earlier according to clinical manifestation and angiography and one BK amputation and two finger amputationsHeavy smoker for many yearsDigital angiography of the aortic arch and cerebral arteries showed occlusion of the left subclavian meningism and the presence of a corresponding collateral circulation\
Brain MRI showed mild atrophy of the corpus callosum, diffuse white matter signal alterations suggesting a process of gliosis and a small ischemic lesion of the thalamusUnknownUnknown81984Kessler et al (Germany)[@CIT0054]126 yearsRight optic neuritis\
History of major epileptic seizure with left spastic hemiparesis, left hyperesthesia, left hyper-reflexia with a left positive Babinski response 2 months earlier\
History of left hemiparesis 9 months earlier\
History of\
reeling gait and dizziness 1 year earlier\
History of blured vision of left eye for a few days 2 years earlierUnknown40 cigarettes per day from his early youthBrain CT scan showed small areas of hypodensity\
CSF examinationCorticosteroid therapyImprovement91982Drake (Ohio,USA)[@CIT0055]127 yearsOnset of right hemipharesis and sensory lossTAO diagnosis 5 years later according to clinical manifestation, angiography characteristics and normal laboratory tests50 cigarettes per day for 12 yearsBrain CT scan, CSF examination\
Angiography showed occlusion of posterior cerebral arteryAspirin\
DipyridamoleSome resolution of neurological deficit but relapses as dysarthria and new left-sided weakness 8 months later101981Biller et al\
(North Carolina, USA)[@CIT0056]133 years\
(Woman)Sudden inability to talk and swallow\
History of left hemiparesis 7 years earlierTAO diagnosis 6 years earlier confirmed by upper and lower limbs angiography and histology examination of toes and fingers amputations10 cigarettes a day for many yearsRadionuclide brain scan and CT scan showed an area of infarction in the left fronto-opercular area\
aortocranial arteriography showed exaggerated tapering of the proximal segments of both middle cerebral artery branches, predominantly at the level of the frontal operculaUnknownPartial improvement111958Wolman (UK)[@CIT0057]126 yearsPseudobulbar palsy after a severe seizure with gross emotional liability\
History of\
series of left sided seizures despite being on anticonvulsant treatment from 1 year earlier.TAO diagnosis by histology study after autopsyUnknownHistology examination of cerebral arteries following autopsy demonstrated TAO characteristics in the right and left middle cerebral arteries and their branchesAnticonvulsant drugsDeath121952Lippmann\
(New York, USA)[@CIT0058]134 yearsRight spastic hemiplegia, motor aphasia, right hemianestlhesia, right central facial palsy and right hyper-reflexia\
History of right hemiplegia and aphasia for 2 days\
History of a few days speech deteriorationTAO diagnosis 2 years earlier and one BK amputationHeavy smoker since early adulthoodAccording to clinical examination, diagnosis of left middle cerebral artery occlusionSmoking cessationNo progression in the disease, not in the limbs nor any neurological onset was observed during 31 years follow-up and the patient completely stopped smoking

Eye {#S0004-S2004}
---

We located six articles related to the eye as a result of the systematic review. One article, published in 1988, reported on three cases of temporal arteritis for which TAO diagnosis was made after histology of the temporal artery. However, in the histology exam, the prominent infiltrating cells were eosinophils. Also, no additional data were available about the clinical manifestation of TAO in the extremities or any angiography examination. Therefore, due to its doubtful diagnosis of TAO, this study was excluded from our review. In total, we included five articles covering five patients that were published between 2006 and 2018 ([Table 4](#T0004){ref-type="table"}). The mean age of the patients was 57±10 years. All cases were male. The mean number of cigarettes smoked daily was 15±7 and the duration of smoking before mesenteric ischemia was 31±11 years. In all cases, eye involvement was observed after TAO diagnosis, which had occurred approximately 18 years earlier. The retinal artery was the most commonly involved artery. Receiving anti-platelets, either with or without corticosteroids, led to partial improvement. However, the treatment strategies and outcomes for 40% of the studies are unknown.Table 4Data summary of patients with TAO and eye involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12018Korkmaz et al (Turkey)[@CIT0059]143 yearsOnset of low vision in the left eye due to nonarteritic anterior ischemic optic neuropathyTAO diagnosis 7 years earlier according to clinical Shionoya's criteria, CT angiography and excluding other types of vasculitis or hyper-coagulable state\
He was under treatment of CilostazolOne pack of cigarette a day for 20 yearsEye examination including fluorescein angiography brain/orbits MRI and MR venography with and without contrastAspirin (300 mg/daily) and oral steroid (prednisone, 1 mg/kg/daily, 14 daysPartial improvement at the 4th day of treatment22017Eris et al (Turkey)[@CIT0060]164 yearsOnset of acute painless vision loss in his left eye due to central retinal artery occlusionTAO diagnosis from 32 years earlier and one BK amputation during this timeSmoking for 43 yearsEye examination including fluorescein angiographyHyperbaric oxygen therapy for 20 sessionsPartially improvement32015Marques et al (Portugal)[@CIT0061]164 yearsProgressive bilateral visual acuity decrease and nyctalopia due to extensive chorioretinal atrophyTAO diagnosis about 30 years earlier and several minor amputations during this timePrevious smoker (15 pack/year)Eye examination including fluorescein angiographyAspirin (150 mg/daily)Partially improvement during 1 year follow-up42014Koban et al (Turkey)[@CIT0062]148 yearsAcute vision loss in the left eye due to acute inferonasal branch retinal artery occlusion and bilateral normal tension glaucomaTAO diagnosis 12 years earlier and two BK amputations during this timeUnknownEye examination including fluorescein angiography\
Cranial MRIUnknownUnknown52006Ohguro et al (Japan)[@CIT0063]166 yearsProgressive visual field disturbance in the left eye due to normal tension glaucoma with branch retinal artery occlusionTAO diagnosis 10 years earlier and history of myocardial infarction during this timeUnknownEye examination including fluorescein angiography\
Cranial MRIUnknownUnknown

Genitalia {#S0004-S2005}
---------

According to a systemic search, we found six related articles. One article was not in English; therefore, it was excluded from our study. Totally, five articles were included which consisted of five patients in total and published between 1968 and 2016 ([Table 5](#T0005){ref-type="table"}). The mean age of the patients was 44±20 years and, in 60% of the cases, TAO diagnosis had occurred approximately 13 years before the urogenital events. No pharmaceutical treatment had been pursued for these patients.Table 5Data summary of patients with TAO and genitalia involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12016Pham et al *(Massachusetts, USA)*[@CIT0064]156 yearsGangrenous glans penis history of recurrent penile and scrotal ulcers during 1 yearTAO diagnosis 4 years earlier80 pack-year from his earlier teensPhysical examinationPartial penectomy with urethral reconstruction\
Histology confirmed TAO diagnosisUnknown22016Roberts et al (Australia)[@CIT0065]117 years3 weeks history of testicular mass and a painless swelling in the left hemiscrotumTAO diagnosis according to testicular histology examinationTobacco and cannabis smokerPhysical exam, ultrasonography and laboratory tests\
Histology showed multiple infarcts of the testicular parenchyma with an obliterated artery adjacent to each infarct. The histology of occlusions was compatible with TAO diagnosisLeft inguinal orchiectomy byNo further follow-up32008Aktoz et al (Turkey)[@CIT0066]147 yearsScrotal and penile necrosisTAO diagnosis 1 year earlier according to clinical manifestation and MRA imaging of the lower limbs and one AK amputationTwo packs of cigarettes for 30 yearsPhysical exam\
Histology examination of scrotal tissues was compatible with TAO diagnosisPartial penectomy, scrotal debridement and urethra-cutaneous anastomosisUnknown42004Orhan et al (Turkey)[@CIT0067]170 yearsPainful gangrene half of the penile shaft and the glansTAO diagnosis 34 years earlier and two AK and several minor amputations during this timeSmoking for 55 yearsPhysical examination\
Pathology examination confirmed TAO diagnosisPartial penectomyUnknown51968Herrington et al (Tennessee, USA)[@CIT0031]133 yearsSuddenly thrombosis of the dorsal vein of the penis and gangrene of the distal two thirds of that organ with perforation of the urethra during hospitalization for mesenteric ischemiaTAO diagnosis at the onset of acute abdomen according to past medical history and clinical manifestation and histology exam of the sigmoid colon before penile gangreneSmoking for yearsPhysical examinationExtensive plastic and urologic procedures.No more relapses during 5 years follow-up

Kidneys {#S0004-S2006}
-------

According to a systemic search, we found seven related articles. We could not have access to the full-text of two articles and one article was not in English. Therefore, they were excluded from our study. Totally, 4 articles included which consisted of 19 patients in total and published between 1959 and 2015 ([Table 6](#T0006){ref-type="table"}). The mean age of the patients was 46±8 and all patients were male. In all cases, renal events had occurred approximately 8 years after TAO diagnosis. The pharmaceutical treatment for these patients is unknown. However, hepato-renal bypass grafting led to the improvement of renal function in one patient.Table 6Data summary of patients with TAO and renal involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (Amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12015Yun et al (Korea)[@CIT0068]151 yearsSevere left flank pain, hematuria, and oliguria for 3 days\
And history of 1 year hypertensionTAO diagnosis 10 years earlier\
confirmed by extremity angiography and Two big toes amputations under treatment with beraprostOne pack of cigarettes for 30 yearsAbdominal CT scan\
Aortography which demonstrated occlusion of superior and inferior mesenteric artery, both renal arteries and left common iliac artery with well-developed collateralsPeritoneal dialysis with warfarinPostprandial pain and ischemic transverse colon\
Dialysis changed into hemodialysis22006Goktas et al (Turkey)[@CIT0069]137 yearsFever, right flank pain and weakness due to right kidney infarctionTAO diagnosis 7 years earlierHeavy smokerAbdominal CT scan\
Angiography showed stenosis in the intra-renal branches of right renal arteryUnknownUnknown32003Stillaert et al (Belgium)[@CIT0070]151 yearsUncontrollable hypertension and episodes of oligo-anuria which developed during 2 weeksPrevious TAO diagnosis and two AK-amputations 8 years earlier20 cigarettes per dayMRA showed a severe stenosis of the right renal artery and an occluded left renal artery.Right hepato-renal bypass graftingNormal right renal function was maintained at 1-year follow-up.41959Fida et al (Italy)[@CIT0071]16 (16 out of 52 TAO cases)Ranged from 23 to 49 yearsDisturbed renal functionTAO diagnosis confirmed by angiographyUnknownUrine analysis\
GFR, RPF, RBF, Maximal rate of tubular excretion\
Renal biopsiesUnknownUnknown

Mucocutaneous zones {#S0004-S2007}
-------------------

According to a systemic search, we found four related articles which consisted of five patients in total and published between 1980 and 2013 ([Table 7](#T0007){ref-type="table"}). The mean age of the patients was 39±12 years and, in 40% of the cases, skin events had occurred approximately 1.5 years before TAO diagnosis. In 60% of the cases, skin events had occurred approximately 5 years after TAO diagnosis. Stopping smoking and immunosuppressants, including methotrexate and corticosteroids but not vasodilators or anticoagulants, improved the skin lesions.Table 7Data summary of patients with TAO and involvement of mucoucutaneous zonesNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (Amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12013Li et al (China)[@CIT0072]2 brothersCase1: 33 years\
Case2: 27 years1: Erythema nodosum in the bilateral lower leg extensors and the dorsum of the right foot, without evident causes\
2: Erythema nodosum on the left shank and the top of the left foot accompanied by numbness and pain in the feet, without evident reasonCase 1: 8 years earlier\
Case 2: 3 years earlierCase 1: 5--8 cigarettes per day for 10 years\
Case 2: 3--5 cigarettes per day for 4 yearsCase 1: Skin biopsy confirmed erythema nodosum diagnosis\
Case 2: Physical examCase 1: Immune suppression treatment with methotrexate, triptriolide, cyclophosphamide, prednisolone and methylprednisolone\
Case 2: Hormonal and microcirculation therapy (no more details)Case 1: Improvement with leaving a small level of pigmentation on the skin\
Case 2: Improvment22007Takanashi et al (Japan)[@CIT0073]133 yearsPainful nodular erythema with livedo reticularis in both lower extremitiesTAO diagnosis 2 years later according to clinical manifestation, angiography characteristics and histology examination of toe amputation30 cigarettes per day for 15 yearsSkin biopsyOral prednisolone (20 mg daily) and NSAIDsRecovery of skin symptoms31981Queneville et al (Canada)[@CIT0074]144 yearsPainful subcutaneous indurations, some\
nodular others string like, over the forearms and feet, and minute periungueal infarcts\
2 days later multiple inflammatory cords on the forearms, hands and feet and subungueal-splinter hemorrhageTAO diagnosis 1 year later according to clinical manifestation and excluding other types of vasculitis40 cigarettes per dayRuling out vasculitis and cancer but there was no idea about the underlying cause of subungueal-splinter hemorrhage until the diagnosis of TAOHeparin, steroids and vasodilatorsNo improvement during medical treatment but resolved later41980Rye et al (Washington, USA)[@CIT0075]157 yearsPainful swallowing and an ulcer in the mucosa of left posterior hard plate or due to Necrotizing sialometaplasiaTAO diagnosis 6 years earlier and minor amputationsOne pack cigarette dailyMucosal biopsy and histology examination confirmed necrotizing sialometaplasia and showed arterial organized thrombusSmoking cessationRecovery

Lymphohematopoietic system {#S0004-S2008}
--------------------------

According to a systemic search, we found six related articles. Three articles were not in English; therefore, they were excluded from our study. Totally, 3 articles were included which consisted of 28 patients in total and published between 1971 and 2016 ([Table 8](#T0008){ref-type="table"}).Table 8Data summary of patients with TAO and lymphohematopoietic system involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease\
(amputation)Smoking statusHow to diagnose the current diseaseSuggested treatmentThe outcome of treatment12016Akbarin et al (Iran)[@CIT0076]26\
(26 CBC and serum samples out of 37 documents and banked samples)27--49 years40±7 yearsUnknownMean cigarette consumption was 397.77 packs per year (minimum 60 packs and maximum1110 packs per yearAnemia defined as Hgb \<13.5 g/dL for males which could not be explained by anemia of chronic disease or iron deficiency according to several indices including MCV, MCH, LDH, ALT, ASTUnknownUnknown22010Takaoka et al (Japan)[@CIT0077]146 yearsOne month history of sharp rest pain in right calf and ischemic ulcer between the third and fourth toes of his right foot and lymphadenopathy in bilateral inguinal regionTAO diagnosis according to clinical manifestation and angiography pattern of lower limbsAbout 10 cigarettes per day for 25 yearsExcision biopsy of left inguinal nodule\
Histology examination demonstrated hyperplasia of lymphoid follicles with massive infiltration of eosinophil without malignancy\
CBC demonstrated eosinophiliaPrednisolon 40 mg per dayThe eosinophilia, the ulcer and rest pain of right foot improved quickly31971Ward et al\
(Colorado, USA)[@CIT0078]1\
(1 out of 31 cases of anemia suffering from chronic disease)UnknownUnknownUnknownUnknownLaboratory tests\
Low hematocrit, normal iron level, high iron saturation, increased bone marrow iron with normal erythropoietinUnknownUnknown

Joints {#S0004-S2009}
------

The systematic review revealed four articles related to arthritis. We were not able to access the full text of one article and one article had been published in a language other than English. In total, we included 3 articles covering 13 patients that had been published between 1981 and 2003 ([Table 9](#T0009){ref-type="table"}). The mean age of the patients was 45 years and, for one patient, TAO diagnosis was made after the experience of arthralgia. The medical treatment for the patients with arthralgia is unknown. However, one patient who received corticosteroids showed progression in the digital ischemia, despite joint improvement.Table 9Data summary of patients with TAO and arthralgia or arthritisNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (Amputation)Smoking statusHow to diagnose the diseaseSuggested treatmentThe outcome of treatment12003Johnson et al (Texas, USA)[@CIT0079]146 years3-week history of acute polyarthritisTAO diagnosis was made at the time of admission for working up arthritis according to clinical manifestation of the extremities, excluding other types of vascultiis and angiographyThree packs per day for over 30 yearsPhysical exam\
Laboratory testsCorticosteroid therapyImproved arthritis but progressive digital ischemia after 1 month21999Puéchal et al (France)[@CIT0080]11 (11 out of 83 TAO patients)UnknownRecurrent episodes of transient and migratory\
Arthralgia of large jointsTAO diagnosis 2--13 years earlierUnknownPhysical examination\
Laboratory tests\
Osteoarticular radiographsUnknownUnknown31981Queneville et al (Canada)[@CIT0075]144 years4-week history of severe acute articular and periarticular pain which was initially located to the MTP joints and rapidly spread to the small and large jointsTAO diagnosis one year later according to clinical manifestation and excluding other types of vasculitis40 cigarettes per dayRuling out vasculitis as underlying cause but there was no idea about the underlying cause of subungueal-splinter hemorrhage until the diagnosis of TAOUnknownUnknown

Ear {#S0004-S2010}
---

According to a systemic search, we found one related article which consisted of one patient in total and published in 1962 ([Table 10](#T0010){ref-type="table"}).Table 10Data summary of a patient with TAO and ear involvementNoYearAuthorsThe number of patientsAgeChief complaintDuration of disease (amputation)Smoking statusHow to diagnose the diseaseSuggested treatmentThe outcome of treatment11962Kirikae et al (Japan)[@CIT0081]140 yearsSuddenly fullness, roaring tinnitus, and hearing impairment and distortion of sound in the right ear due to basilar artery occlusion\
History of suboccipital painTAO diagnosis one year earlier according to clinical manifestation, angiography of upper and lower limbs and the diagnosis confirmed by histology examination of radial arteryHe is a moderate smokerAudiography\
Basiverterbal angiographyUnknownUnknown

Discussion {#S0005}
==========

The most challenging aspect of TAO management is its unknown etiology. Even its classification is challenging: it is usually viewed as a peripheral arterial disease rather than a type of vasculitis, and TAO patients are typically referred to angiologists or vascular surgeons as opposed to rheumatologists. This may be because of the unfavorable response of TAO to immunosuppressant medication and its favorable response to smoking cessation. Also, TAO is not known as a systemic disease and, in its diagnostic criteria, only the involvement of the small- and medium-sized arteries of the extremities is considered. Although Leo Buerger was the first to notice visceral arterial involvement in TAO in the first series of patients he evaluated, clinical manifestation of TAO in other organs is nonetheless known as an unusual or progressive form of TAO.

However, according to our systematic search, reports of the involvement of almost all organs have been made in relation to TAO. We also located several reports of TAO presentation in other organs before disease diagnosis, in which the involvement of the extremities presented after visceral involvement. Notably, the characteristics of the visceral arteries in several cases looked like the arteries of the extremities according to coronary angiography or aortography, including skip lesions and corkscrew collaterals. Also, in autopsies of TAO patients, the vascular involvement of multiple organs has been noted. In addition, in some studies, conservative, systemic medical treatment and smoking cessation have led to the recovery of the patient from the onset of visceral TAO.

On the other hand, TAO might be a systemic disease with a main clinical presentation in the extremities. For instance, approximately 30% of the TAO patients in the Fida et al study had abnormal urine analysis, although the patients were symptom-free.[@CIT0071]

Moreover, reports of visceral involvement in TAO might be much more numerous than what we uncovered in the literature due to several reasons. One reason is that TAO is not of particular interest to many journals in the fields of angiology and rheumatology, and such case reports are not pursued for publication. Another reason may relate to the poor follow-up of TAO patients. According to our own experience, the main obstacle to follow-up is the mandatory admonition of smoking cessation. For this reason, TAO patients may prefer to ignore the bearable symptoms or to change health care providers. In many cases, TAO patients do not know that other organs can be affected by TAO, as was seen in some studies in which the patients experienced years of postprandial pain or weight loss without any follow-up. In some TAO cases, when we called the patient for follow-up, the family reported that the patient had died after experiencing abdominal or chest pain at younger than 50 years of age. Whilst there were no autopsies, we cannot prove that they died of visceral TAO, but it remains a possibility.

Unfortunately, our search did not reveal any treatment modality for visceral TAO because most of the cases did not have long-term follow-up to evaluate further visceral episodes of the disease. However, according to the current data, smoking cessation seems to be very helpful in patients' recovery from visceral TAO. Also, more than 65% of the patients who received only medical treatment in the form of a combination of a vasodilator with anticoagulants showed improvement. Anticoagulants and anti-platelets without vasodilators led to an improvement in about 50% of the patients. Moreover, corticosteroids and immunosuppressants, but not anti-thrombotic or vasodilator treatments, did improve the skin and joint manifestations of the disease whilst aggravating the limb ischemia and, in a case of mesenteric ischemia, led to perforation of the bowel, followed by death.[@CIT0015],[@CIT0072],[@CIT0073],[@CIT0079] In terms of invasive treatments, bypass surgery had more acceptable outcomes in comparison to endovascular procedures, including stenting. However, more clinical evidence and clinical trials are needed to determine better management of patients with visceral TAO.

Conclusion {#S0006}
==========

All in all, this study reveals five main points that should be noted: If we maintain the belief that visceral involvement is an unusual manifestation of TAO and insist on localizing it to the extremities, we may be pursuing the wrong path in determining the etiopathology of the disease and appropriate treatment.All patients with a diagnosis of TAO should be aware of the possible involvement of other organs along with the attendant warning signs, such as postprandial pain, unexplained weight loss, chest pain, any episodes of transient hemiparesis and cognitive and behavioral changes.Early, systemic medical treatment of patients suffering from visceral TAO may lead to better outcomes and reduce the overall mortality rate.Corticosteroid therapy and endovascular stenting are not recommended for managing visceral TAO.More clinical evidence with long-term follow-up is needed to determine a treatment modality for visceral TAO.

Disclosure {#S0007}
==========

The authors declare that there are no conflicts of interest in this work.
