Large Vessel Vasculitis

Epidemiology

TAK is a rare disorder that has variable incidence and prevalence depending on the country where it has been studied. In the United States, incidence estimates from Olmstead County, Minnesota, are 2.6 cases/million/year, whereas in Sweden they are 1.2 cases/million/year. Autopsy studies in Japan document a high prevalence, with evidence of TAK found in 1 of every 3000 individuals. Similar postmortem studies have not been performed elsewhere to provide comparative data. Approximately 90% of patients with TAK are female. The peak incidence of TAK is in the third decade of life. However, the distinction between TAK and GCA with large artery involvement can be difficult, and the diagnosis a patient, who presents after age 50 years, receives may vary by geographic location and specialty.

Pathogenesis

The etiopathogenesis of TAK is unknown. Differences in disease prevalence and characteristics among different racial and ethnic cohorts suggest a genetic predisposition for TAK, and recent data are finding some allelic associations that have provided intriguing leads to pathogenic pathways of disease susceptibility. There has long been speculation that, because of the increased prevalence of Mycobacterium tuberculosis (TB) infection in countries with a high prevalence of TAK (e.g., India, Korea, Mexico), mycobacterial infection may play a role in the etiology TAK. However, this theory has not been consistently upheld and a causal link has not been established. Interestingly, the current treatment approaches to TAK include medications that could promote reactivation of mycobacterial infection.

Clinical Manifestations

Systemic symptoms and signs occur in less than half of all patients and include fever, weight loss, malaise, and generalized arthralgias and myalgias. Patients more often present with signs and/or symptoms of tissue ischemia, never having had more diffuse constitutional symptoms. The most common symptom of TAK is upper-extremity claudication, occurring in more than 60% of patients and reflecting disease predilection for aortic arch vessels (~ 90% of cases) ( Figs. 40.1–40.3 ). The most frequent clinical findings include blood pressure asymmetry in paired extremities and bruits found most often over the carotid, subclavian, and aortic vessels. Aneurysms most often affect the aortic root and lead to stretching of the atrioventricular annulus and producing valvular regurgitation (~ 20% of patients) that often eventually requires surgical intervention. Hypertension occurs in at least 40% of patients in US cohorts and is even more common in Japanese and Indian cohorts (80%). Hypertension is most frequently due to renal artery stenosis, but it may also result from suprarenal aortic stenosis ( Figs. 40.4–40.6 ). However, the diagnosis of hypertension can easily be missed in patients with disease involving both upper extremities where peripheral cuff measurements in either arm will be an inaccurate reflection of central aortic pressure. Hypertension with vascular bruits or claudication, especially in younger patients, should lead to a suspicion of TAK and to further evaluation of all four extremity pulses and blood pressures for asymmetry. Vascular imaging of the entire aorta and primary branch vessels should then confirm anatomical abnormalities compatible with the diagnosis and delineate the extent of disease and types of lesions.

Coronary artery disease in TAK may be the result of either coronary arteritis, obstruction of the coronary arteries at their take off from an inflamed aorta, or coronary artery aneurysms. Young women with TAK who present to medical attention with chest pain are often not immediately evaluated for possible angina due to lack of understanding and knowledge about TAK on the part of the evaluating physician; such delays in care can be fatal. Angina should be considered not a rare event in patients with TAK who present with chest pain. However, aortitis without coronary artery involvement can also be a TAK-related cause of chest pain, as can aortic dissection.

The most common morbidity in TAK results primarily from extremity claudication leading to discomfort and reduced functional capacity that may affect the patient’s ability to work. Less common but regularly seen and highly problematic are cardiac, renal, and central nervous system manifestations that include myocardial infarction, renal artery hypertension, heart failure, and stroke. Undetected and/or untreated hypertension is a significant cofactor in these disease sequelae. Causes of death include stroke, congestive heart failure, sudden death of uncertain cause, unrecognized or inadequately treated hypertension, and infection secondary to effects of immunosuppressive medications.

Differential Diagnosis

A thorough and careful investigation is necessary to distinguish TAK from its mimics ( Box 40.1 ). Congenital and acquired disorders of tissue matrix may present with aortic root dilation, valvular insufficiency, and aneurysms in other sites; however, the findings are not generally associated with large vessel stenoses, the hallmark of TAK. In many cases, there are also genetic studies and extravascular features that help to identify the syndromic disorders (e.g., Marfan, Loeys-Dietz, Ehlers-Danlos syndromes). Exceptions better known for matrix abnormalities usually leading to stenoses are fibromuscular dysplasia and Grange syndrome. The most common disease process that needs to be differentiated from TAK is atherosclerosis, which can result in all of the arterial lesions seen in TAK. Although lesions of TAK generally have a different appearance than atherosclerotic lesions, there is a major unmet need to develop imaging or other approaches to improve the identification of each type of arterial pathology. Furthermore, inflammatory disease and atherosclerosis may coexist, especially as patients age.

Although other autoimmune disorders can be associated with large vessel vasculitis, they are most often distinguished by their other associated disease manifestations and age preferences. Aortitis restricted to the aortic arch has emerged as one of numerous examples of single-organ vasculitis. Distinguishing it from TAK requires complete evaluation of the large vessel anatomy and careful follow-up over years to be certain that it is not the first sign of TAK. It is important to distinguish isolated aortitis from TAK because, after surgical intervention, further therapy may not always be required.

A significant and often underappreciated clinical variation exists between the clinical presentations of TAK and GCA. A comparative cohort study of TAK and GCA identified numerous shared features of disease, much of this coming to light with the advent and increased use of noninvasive vascular imaging studies. TAK and GCA may be indistinguishable in patients who present in middle age (45 to 55 years of age) with large artery stenoses and less often aneurysms, especially of the aortic root. This overlap in clinical manifestations of TAK and GCA has led some to propose using a similar set of outcome measures when studying these diseases. However, the different epidemiology between TAK and GCA, some differences in large arterial involvement, and the differences in genetic associations and response to targeted therapies found to date provide compelling evidence that these two diseases may be part of a clinical spectrum of vasculitis but have different etiologies or pathogenic mechanisms.

Infectious causes of large vessel aneurysms should always be considered irrespective of age or sex. Stenosis of large vessels is unusual in the setting of infection, where aneurysms dominate.

Diagnosis

Serological tests do not exist to identify TAK. Rarely, the diagnosis is first considered after a surgical procedure provides biopsy findings that are compatible with the diagnosis. Most often the diagnosis is based on clinical findings in the presence of compatible vascular imaging abnormalities. A delay in establishing a diagnosis is common; not infrequently, several years pass between an initial clinical symptom, such as upper limb claudication or even pulselessness, and diagnosis. Catheter-directed angiography allows for luminal imaging and pressure measurements and provides opportunities for intervention (e.g., angioplasty), but it provides little direct information about the vessel wall. Computed tomography (CT) or magnetic resonance imaging and angiography (MRI/MRA) are now the much-preferred imaging modality for establishing a diagnosis of TAK and provide more information regarding vessel wall thickening and edema, but the clinical implications of these findings, although suggestive of active vascular disease, do not always correlate with disease activity or progression. Studies examining the use of positron emission tomography (PET) imaging combined with either CT or MRA and are underway to determine whether more useful information may be derived about the vessel lumen and wall ( Fig. 40.7 ). The presence or absence of increased tagged glucose uptake within large vessels may have improved sensitivity and specificity for identifying active disease in TAK.

Although systemic signs and symptoms or elevated acute phase reactants, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), may be suggestive of active disease, they are inadequately sensitive in patients who have only vascular symptoms or findings. Sequential angiographic evaluations have revealed progression of disease, based on the presence of new vascular abnormalities, in more than 50% of patients with normal ESRs. In addition, histopathological proof of vascular inflammation has been documented in 44% of surgical specimens from patients with TAK who underwent bypass surgery at a time when their disease was believed to be quiescent. Thus among the major challenges in caring for patients with TAK is determining whether active disease is present.

Treatment

Essential to effective treatment is accurate determination of disease activity, a goal that may not always be possible. Often the development of new arterial lesions in TAK is a completely asymptomatic process until a critical stenosis occurs. In addition, because the time of progression of lesions is highly variable and often slow, collateral vessels often form around the site of stenoses. It is common for a patient with TAK to be declared to have active disease only when a new arterial lesion has been found on serial imaging. Thus the challenge is to determine when patients with TAK have active disease meriting treatment, as well as whether treatment is effective in halting progression of disease and/or preventing new disease activity. Compared with many other forms of systemic inflammatory disease, including some other forms of vasculitis, the current ability of physicians to determine disease state activity in TAK and predict outcome is poor. Nonetheless, an approach to treatment has been established and continues to develop as new treatments are tested in this complex disease.

Due to a chronic and relapsing pattern of disease in TAK, most patients are treated with chronic or repeated courses of immunosuppressive therapy, often for many years. Studies that have incorporated sequential angiography have demonstrated that the majority of patients continue to develop new lesions in new vascular territories, even if they appear clinically to be in remission. Because clinical symptoms and serological tests are often unreliable in monitoring disease activity, serial imaging studies are routinely used for assessment of disease progression.

Therapy with glucocorticoids induces improvement in nearly all patients and initial disease remission in approximately 50%, but in 96% of patients, relapses occur during the course of tapering medication (with a mean of 2.8 relapses per patient in one study). Therapy with other immunosuppressive agents may aid in achieving lower glucocorticoid requirements in such individuals or those with glucocorticoid-responsive and relapsing disease.

Many different nonglucocorticoid immunosuppressive agents have been proposed to treat TAK with evidence of efficacy stemming only from case series. Further complicating the comparison of studies of these agents is that the definitions used to assess the drugs’ efficacy were highly variable. Among the agents purported to be of possible benefit in the treatment of TAK include more traditional antirheumatic agents, often orally administered, including azathioprine, leflunomide, methotrexate, and mycophenolate mofetil. Cyclophosphamide, an alkylating agent with more substantial potential toxicities than the previously mentioned agents, is generally reserved for use in severe cases of TAK. There has been keen interest in the use of targeted biologic agents to treatment TAK. Tumor necrosis factor (TNF)-α inhibitors have been shown in multiple case series to seemingly provide benefit for some patients with TAK and allow for less use of glucocorticoids. Other biological agents of interest in the treatment of TAK include anti–interleukin-6 (IL-6) agents, ustekinumab (anti–IL-12/23), and rituximab (anti-CD20).

There have been only two randomized controlled trials conducted in TAK. The first trial, conducted by the Vasculitis Clinical Research Consortium in North America, tested the efficacy of abatacept (CTLA4-Ig) as adjunctive therapy to glucocorticoids and found no difference between treatment groups. The second trial was conducted in Japan and tested tocilizumab (anti–IL-6) and glucocorticoids versus glucocorticoids alone; this trial had equivocal results, but there were some outcomes indicating possible efficacy of the test drug. Additional randomized trials are critical to help demonstrate efficacy and safety of new or existing therapies for TAK.

Hypertension is a major source of morbidity and mortality in TAK. Delay in the diagnosis of hypertension is common because of the high frequency of subclavian and innominate artery involvement, which may result in markedly inaccurate and reduced measurement of blood pressure in the affected upper extremity; bilateral disease is common, making use of either upper limb inappropriate for clinical care and necessitating the use of lower extremity blood pressure measurements only. However, stenotic lesions also may be present in lower-extremity vessels, leaving some patients without any extremity capable of providing cuff blood pressure measurements that reliably represent those within the aortic root ( Figs. 40.8 and 40.9 ). This emphasizes the need for complete vascular imaging of the entire aorta and its primary branches at the time of diagnosis and during extended follow-up. If stenoses of extremity vessels and/or the abdominal aorta preclude accurate determination of central aortic pressure by using an extremity blood pressure cuff, invasive angiography should be considered to obtain direct central aortic pressure measurements and gradient determinations. Effective blood pressure management is crucial and can be complex in TAK. Even with reliable peripheral recordings, determining and attaining a target pressure range without causing compromised perfusion in the setting of arterial stenotic lesions affecting major organs (e.g., cerebral or coronary stenoses) can be challenging. For this reason, careful monitoring is essential when treatment for blood pressure control is necessary. In addition, medical management must take into consideration renal artery stenosis if present.

Arterial stenoses may affect any organ system. Intervention to correct lesions should be considered in the setting of severely impaired daily function or evidence of significant organ ischemia. Multiple studies demonstrate impressive initial patency rates of 80% to 100% with percutaneous angioplasty. However, the rates of vascular restenosis vary widely, from 20% to 71% of cases followed up to 45 months post procedure. The utility of drug-eluting stents in TAK is not clear.

Bypass procedures also may be complicated by vessel restenosis, but rates of sustained patency are higher than with angioplasty (65% to 88%; mean follow-up period 44 to 60 months). When interventions are planned, it is preferred that they occur in the setting of disease remission and it may be appropriate to consider prescribing a short course of glucocorticoids before and after any vascular procedure or surgery. When feasible, tissue should be obtained from the origin or insertion of grafts, because histopathological examination can provide critical information in assessing disease activity and later assist in medical management.

A multidisciplinary approach to the care of TAK patients is essential for optimizing patient outcomes. The team should include a rheumatologist, a radiologist expert in vascular imaging, and experts in cardiovascular medicine and surgery.