Takayasu Arteritis

Etiology and Pathogenesis
Etiopathogenesis of TA is poorly understood, but is thought to be a cell-mediated process. Infections such as tuberculosis and an autoimmune component have been accused of the development of TA. Evidence is mounting that heat shock protein (HSP)-65 may be one of the important antigens. HSP-65 is a major antigen of mycobacterium tuberculosis. Cross reactivity and sequence homology between HSP-65 and HLA class II molecules has been described (13,14). Moreover, expression of HSP-65, HLA class i and II antigens are also markedly increased in affected aortic tissue (15). Thus, genetically linked immune responses to unidentified antigen may incite autoimmune damage by cell mediated pathways, and may result in the disease and relapses.

The inflammatory lesions in TA originate in the vasa vasorum and are followed by cellular infiltration, mainly composed of T cells, but also of natural killer cells, dendritic cells, monocytes and granulocytes, invading the outer layer of the media and/or its neighbouring adventitia. T cells and natural killer cells infiltrate and incite the damage by liberating perforin on to arterial tissue. In patients with aorta arteritis, immunological investigations have shown a decrease in the titre of complement and phagocytic activity of neutrophil granulocytes, deep depression of T cell immunity, and hypergammaglobulinaemia (16-18). Low CD4+ lymphopenia was reported in a patient with TA (19). Chemokines and proinflammatory cytokines also seem to play a role in amplifying the inflammatory response that follows the primary immune reaction. Interleukin-6, interleukin-1 and RANTES are released in large amounts by infiltrating inflammatory cells within damaged tissue, as well as by circulating inflammatory cells, and very likely help maintain the aberrant immune activation, by promoting endothelial cells activation and by inducing lymphocyte infiltration. Although the nature of the antigen that triggers the auto-immune process is still unknown, the infiltrating T lymphocytes may recognize one or a few self-antigens processed and presented in association with HLA. It remains to be demonstrated that pentraxin PTX3 represents a novel active phase reactant produced at the sites of active vasculitis also in TA patients (20-22).
Histopathology
Histopathologically the inflammatory process is observed at the media of the arteries and extends to the adventitia and intima . The most characteristic lesion is destruction of the elastic fibers of the media, and is associated with the atrophy, disappearance and replacement with fibrosis of the smooth muscle of the media. In the initial acute stage of the disease, exudative and granulomatous inflammation occur, whereas fibrosis predominates later, but the two stages may co-exist. The cellular infiltrate characterising TA is primarily composed of lymphocytes, plasma cells and histiocytes, with a variable number of giant cells (23). Later in the disease process, nodular fibrosis in all layers of the artery is seen and the intima may become several times thicker than media obliterating the lumen. Rapid or more severe inflammation leads to vessel dilatation and aneurysm formation, but stenosis and occlusions are more common. Thromboses in stenosed arteries are sometimes seen. The corresponding organ shows ischaemic changes, and this ischaemia largely determines the clinical features of the disease (24).

Signs and symptoms
Systemic symptoms of fatigue, loss of weight, night sweats, arthralgia, myalgia and low-grade fever are common in early phase but the correct diagnosis of TA is seldom made in the early phase. Patients often look chronically ill. The active phase of the illness lasts for weeks to months, and may have a remitting and relapsing course. Clinical presentation may be insidious and diagnosis is often delayed. Physical examination typically reveals markedly diminished or absent pulses and low or unobtainable blood pressure in the involved arteries arising from the aortic arch. Unless there is an acquired coarctation, these contrast sharply with the generally brisk pulses in the legs, where the true blood pressure must be determined and followed. Bruits may be heard over partially narrowed arteries. Central blood pressure determinations should always be obtained in patients with extremity vessel stenosis to assess the reliability of conventionally obtained blood pressure measurements (1, 25, 26).

The clinical presentation is widely heterogeneous and involves two stages: (1) an initial inflammatory process or ‘prepulseless phase’ with variable systemic manifestations occurring, followed by (2) a later ‘pulseless phase’ with multiple arterial occlusions producing symptoms of cerebral, visceral, or extremity ischemia. Acute symptoms are usually of short duration, rarely lasting more than a few weeks, but may recur after intervals of weeks to years. This phase gradually subsides and is followed by a more chronic stage characterized by inflammatory and obliterative changes in the aorta and its branches. Narrowing, occlusion, and dilatation of the affected arteries cause a variety of vascular symptoms. Symptoms include intermittent claudication of the arms, legs and mesentery, decreased artery pulses, carotodynia, visual loss, stroke, aortic regurgitation, hypertension, and congestive heart failure. Reduced blood pressure in one or both arms is common with a differential of >10 mmHg between the arms. Diminished and asymmetrical arterial pulses and bruits over the affected arteries are usually heard. Stenotic lesions predominate and tend to be bilateral. In the late stage, weakness of the arterial walls may give rise to localized aneurysms. Nearly all patients with aneurysms also have stenoses and most have extensive vascular lesions. More acute progression causes destruction of the media of the arterial wall, leading to the formation of aneurysms or rupture of the vessels (25-30).

Cardiac involvement
Hypertension in TA results from renal artery stenosis or aortic narrowing and aortic fibrosis. Arterial baroreceptor abnormalities can be hypothesized considering the high frequency of carotid arteries and aortic arch involvement. Hypertension is often severe and may cause hypertensive encephalopathy or heart failure. Heart failure from TA is common in children and is an important cause of mortality. Myocarditis, coronary arterial involvement, organic valvar involvement, or pulmonary artery involvement may cause or contribute to the heart failure (31). Coronary arterial involvement in TA is usually ostial and proximal, but diffuse lesions or arteritis and aneurysm rarely occur. Coronary arterial involvement may cause myocardial infarction, angina or heart failure and may necessitate angioplasty, or surgical treatment even in children. Occlusive changes in the descending thoracic aorta sometimes produce a form of acquired coarctation. The diagnosis of hypertension may be entirely missed if all the peripheral pulses are not carefully examined. Familiarity with the disease may suggest the correct diagnosis, even when no obvious pointers are present. Aortic regurgitation from a dilated aorta is rarely seen in children. Treatment of hypertension or aortic obstruction ameliorates the heart failure in the majority of children. Pulmonary arterial involvement is usually mild. A history of haemoptysis, chest pain, disproportionate pulmonary arterial hypertension, or abnormal ventilation-perfusion scan53 may suggest pulmonary involvement (32).

Renal involvement
The ostia of the renal arteries are commonly involved, but the intrarenal vasculature and small vessels are generally normal. Non specific ischemic glomerular lesions resulting from arterial narrowing or long-standing reno-vascular hypertension are the most common renal manifestations of TA. Primary glomerular diseases have been described rarely. Renal arterial stenosis may be bilateral and usually coexists with aortic involvement (33). Surgical correction of renal artery stenosis is usually an effective means of decreasing or eliminating hypertension (34).

Neurologic Findings
Neurological symptoms such as headache, visual disturbances and amaurosis fugax are common in TA. Visual disturbances are most often bilateral. Inflammation in the carotid arteries may cause visual problems or neurological problems such as dizziness or stroke. In children, cerebrovascular accidents are often secondary to severe hypertension and its complications. Hypertensive retinopathy is commoner than ischemic retinopathy in TA (25, 35).

Cutaneous manifestations
Erythema nodosum, erythema induratum and pyoderma gangrenosum have been described most frequently. It appears to be an autoimmune condition, where immune cells are wrongly targeted against the body's own tissues, and may involve other systems (36).

Diagnosis
Diagnosis of TA is often challenging because the clinical features are similar to those of other systemic inflammatory diseases. TA is relatively rare and may have a subtle and insidious presentation. Nevertheless, a prompt diagnosis is very important because failure to treat vascular inflammation in a timely manner may have serious consequences for the patient. Systemic symptoms are seen in a high proportion of children with TA. The usual presenting symptoms are due to hypertension, heart failure or a neurological event. A high index of suspicion, proper evaluation of the patient’s history, carrefully examination in search of arterial bruit, evaluation of all peripheral pulses, and recording of blood pressure in all 4 limbs would aid in early diagnosis of TA. The criteria for the diagnosis of TA as suggested by Ishikawa (37) are included in Table 1. The criteria adopted by the American College of Rheumatology are shown in Table 2 (38). Children with Takayasu’s arteritis have higher morbidity and mortality than adults. A familiarity with the radiographic, computed tomographic, magnetic resonance imaging, and angiographic features of Takayasu arteritis may permit and earlier diagnosis and treatment.

Laboratory
Anemia of chronic disease and marker of nonspecific inflammatory process, including an elevated erythrocyte sedimentation rate (ESR), increased serum C-reactive protein and alpha-2 globulin, and hypoalbuminemia are often present, but usually there is no increase in the white cell count (39). ESR is a good indicator of disease activity . Besides, an increased in serum soluble E-selectin and thrombomodulin have been reported, but their value in routine diagnosis or follow-up is uncertain (40,41).

To date, other surrogate markers of active disease (endothelins, von Willebrand factor antigen, factor VIII), have either not been adequately studied or have not been found to be superior to the erythrocyte sedimentation rate in monitoring patients (42). Raised interleukin-6 and RANTES have been reported to correlate with the disease activity, and may prove useful in the monitoring of therapy (44). Angiography is considered the gold standard in delineating abnormal vessels in patients with Takayasu arteritis (39).

Radiology
Chest radiography
In several patients, chest radiography may be the first examination to suggest the diagnosis of Takayasu's arteritis. Chest radiographic features include an irregular outline and linear calcifications of the aorta, decreased pulmonary vessels, dilatation of ascending aorta, cardiomegaly and rib notching (1).

CT / MRI
CT and MRI techniques have been used in the last several years with increasing frequency in patients suspected of having TA. Both modalities are effective in the detection of vascular wall thickening of large arteries such as the aorta and pulmonary artery. CT is an excellent method for demonstrating pathologic changes of the aorta and large deep vessels, such as aneurysms, dissections, ruptures, thrombus formation and calcifications. The main indication for CT scanning in Takayasu disease is the morphologic evaluation of wall changes in the aorta and pulmonary artery; dynamic information about the mural inflammatory process are provided by spiral CT (44).
Major advantages of MRI are the low invasivity (lack of ionizing radiation and iodinated contrast material) and the ability to obtain high quality images in the different spatial planes. This is especially useful in the follow-up of chronic, late phase Takayasu's arteritis, when careful depiction of aortic lumen in its longitudinal plane and exact determination of the degree and extent of inflammatory mural changes are needed (44,45).

CT angiography is useful in depicting the aorta and brachiocephalic vessels, but its use is potentially limited by long reconstruction time and ionizing radiation. MR angiography is a non-invasive technique, which does not expose patients to ionizating radiation, and does not require the use of iodinate tracers. It provides high resolution anatomic information in a moltitude of obliquities, including lumen configuration and vascular wall thickness. CT and MR angiography are both very useful for evaluating the disease involvement of thoracic aorta and pulmonary arteries (44, 46-51).

Angiography
Angiography is still the gold standard technique for the diagnosis of vascular diseases conditioning luminal abnormalities. Because the clinical features of Takayasu's arteritis are determined by the extent of the specific artery involved in the occlusive phase of the disease, a pan-angiography is required (). The indications for intrarterial DSA are: 1) to show the extension and the degree of the vasculitic process by demonstrating the segmental narrowing, collaterals, and the distal intact portion of the involved arteries, 2) to show the subclavian steal phenomenon, 3) to confirm an extensive pulmonary artery involvement, 4) to perform follow-up studies for radiological or surgical intervention, 5) to guide and evaluate interventional procedures (52, 53).
Angiography
Aortography is the traditional imaging technique used in the diagnosis of the occlusive phase of Takayasu's arteritis, demonstrating luminal irregularity, vessel stenosis, occlusion, dilatation or aneurysms in the aorta or its primary branches. Conventional or digital subtraction angiography has been considered the gold standard for the diagnosis of Takayasu’s arteritis. In type i, the disease is localized to the aortic arch and its branches; in type II, the disease involves the descending thoracic and abdominal aorta and its branches; type III is the combination of type i and II; type IV is defined when the pulmonary artery is involved in any of the above groups . Type III is the most common, accounting for about 70 % of cases. Thoracoabdominal aortic involvement is commoner (type II/III) in children. A percutaneous transluminal angioplasty (PTA) has emerged as a viable alternative to surgery in recanalization of stenotic lesions. Simultaneuos evaluation of luminal and vascular wall changes may now allow a simpler diagnosis of this condition also in its early phase and the effective therapy monitoring (54-64).

Sonographic techniques
Ultrasonography is very sensitive method in detecting early vascular wall involvement or mild stenosis of the common carotid artery. Color Doppler sonography is actually the non invasive method of choice for evaluation of the neck vessels; moreover, color Doppler sonography can easily detect the hemodynamic changes occurring in common carotid artery occlusion, and is very helpful in distinguishing between high grade carotid stenosis and occlusion (65). High-resolution B-mode ultrasonography may provide useful information on the grade of the stenosis, and on thickening of the vessel wall, especially of carotid arteries. It is a non-invasive and not expensive test, which can be repeated routinely. In expert hands, it may represent an invaluable monitoring instrument.

Treatment
Treatment of Takayasu arteritis is difficult, but results with appropriate therapy are encouraging. Early detection is important. Steroids and immunosuppressive agents form the cornerstone of treatment, with surgery reserved for complications caused by narrowed arteries (66).

Medical Treatment
Glucocorticoids are still the mainstay of active disease treatment and effective in suppressing the systemic symptoms, arresting the progression of disease, and reverting the anemia and elevated acute phase reactants. A large proportion of patients with active disease respond to treatment with glucocorticoids, but a significant proportion will either require additional immunosuppression to prevent steroid toxicity or will remain unresponsive to treatment (67-69). Various cytotoxic drugs like cyclophosphamide or azathioprine have been used with variable success (70). Methotrexate is an alternative immunosuppressive agent to cyclophosphamide and may induce remission if other treatments have failed (71). The relapsing nature of the disease often required repeated courses of therapy. The duration of treatment varies empirically on clinical assessment of activity.

Surgical Treatment
Surgery continues to play a critical role in the long-term management of Takayasu's arteritis and is recommended when appropriate during inactive disease. The relevant role of surgery in TA is to ensure correct blood flow, by preventing or reducing the ischaemic damage caused by artery obstruction, and by preventing aneurysm rupture. Surgery is preferred when the disease is quiescent, and areas of arterial tree that are uneffected by disease are the preferred anastomotic sites (72). Previous studies have shown the increased risk for failure of surgical procedures during active disease.

Main indications for surgical interventions are renal vascular hypertension, cerebral hypoperfusion, and limb claudication. Cumulative incidence of undergoing a surgical procedure increased very quickly during the first phase of the disease. Indeed, renal arterial stenosis, often present at disease onset, is not eligible for medical treatment and requires a prompt surgical approach. On the contrary, severe hypoperfusion secondary to multiple vascular involvements occurs later and accounts for delayed procedures (73,74).

Percutaneous transluminal angioplasty (PTA), eventually with stent placement, may represent the treatment of first choice for patients with renal or subclavian artery stenosis (75). Balloon dilatation of aortic narrowing is highly effective even in diffuse, long segment stenoses . Close to 90% success rates have been reported for aortic angioplasty in children. However, the rate of re-stenosis are fairly high, probably because of the inflammatory characteristic of the disease. Because of the diffuse, inflammatory and possibly progressive nature of the disease, surgical treatment is not preferred for Takayasu’s arteritis except for undilatable symptomatic stenotic lesions and for large aneurysms (76). Renal autograft transplantation has been offered as a new technique in the management of hypertension in Takayasu's arteritis (77).

Assessment of disease activity
Criteria for active disease in patients with TA are fever, musculoskeletal pain, elevated erythrocyte sedimentation rate, features of vascular ischemia or inflammation, such as claudication, diminished or absent pulse, bruit, asymmetric blood pressure in either upper or lower limbs (or both), and typical angiographic features. Besides, computed tomography and magnetic resonance imaging can be conveniently used to during follow-up.

Mortality
The major morbidity and mortality of Takayasu’s arteritis results from stenosis and occlusion of the aorta, renal and carotid arteries. Widely varying mortality rates are documented, but obviously depend on the severity of the disease and therapeutic strategies. Five-year and 10-year survival rates of 80% to 90% have been reported from large series of patients (25, 31). Hypertension, cardiac involvement, aortic or arterial aneurysms (or both), and severe functional disability predict greater morbidity and mortality.

Prognosis
A mortality of 10-30% has been reported on followup of TA in children. The prognosis has significantly improved due to interventional procedures for the treatment of renal and aortic stenosis (25). The presence of severe Takayasu’s arteritis (defined as the presence of severe grades of hypertension, aortic regurgitation, retinopathy, or aneurysms), poor functional class or cardiac involvement, predicted a poorer outcome.

Summary
Takayasu’s arteritis is a chronic inflammatory disease that involves the aorta, its branches and the pulmonary arteries. The etiology remains obscure, with an autoimmune pathogenesis postulated. The inflammation results in varying degree of stenosis, occlusion or dilatation of the involved vessels. Early diagnosis and therapy, possibly aided by the newer imging techniques, is essential for a good prognosis. The chronicity and relapsing nature of the disease require treatment regimens of low toxicity. A combination of these modalities and surgical intervention may improve the outcome.

Conclusions
Minor abnormalities affecting aortic and pulmonary artery walls must be stressed; an early diagnosis and the institution of appropriate therapy may lead to a significant improvement of clinical and imaging findings, which might also prevent future occlusive changes.
According to the ACR 1990 criteria, a panangiography must be considered the first choice technique for confirming a suspicion of Takayasu's arteritis, by demonstrating the luminal abnormalities, which are typical of the late-phase, pulseless disease. In experienced hands, the color Doppler technique gives an accurate global evaluation of the arterial tree, by disclosing most of the inflammatory localizations in sonographically accessible arteries, thus being particularly useful in the long term evaluation of disease activity.
Early diagnosis followed by an aggressive treatment, with glucocorticoids and cytotoxic agents, may avoid rapid progression of the vascular lesions. Clinical parameters, acute phase reactants, and periodical vascular imaging techniques (e.g. duplex ultrasound examination) may more accurately detect disease activity. Furthermore, the radiological approach has proved to be very useful in the treatment of arterial stenosis in several districts through percutaneous transluminal angioplasty (PTA) and stenting.

Hazırlayan : Sera Şebnem KILIÇ
Uludağ Üniversitesi Tıp Fakültesi, Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Prof.Dr.

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