Takayasu arteritis (TA) is a rare chronic inflammatory disease of unknown cause that affects the large arteries. It most often affects the aorta and its primary branches. Although once thought to be a disorder that mostly affected young Asian women, TA has been identified in both sexes and many ethnic and racial groups worldwide. The incidence of TA has been reported to be 2.6 cases per million per year in Olmsted County, Minnesota (1). The prevalence of TA in an autopsy series in Japan was reported as 1 in 3,000 cases (2).
Few medical centers in the US have had adequate experience with TA to enable comparisons of disease features and outcomes with cohorts reported from Asia and Mexico. Since 1992, the Cleveland Clinic Center for Vasculitis Care and Research has provided a standardized approach to the diagnosis, followup, and treatment of patients with TA that includes routine imaging of the entire aorta and its branch vessels as dictated by changing disease features, or in cases with no apparent clinical change, vascular imaging has been routinely performed at least every 6–12 months. This approach was derived from previously published longitudinal TA cohort protocols from the National Institutes of Health (NIH). The NIH experience had suggested that TA is a chronic, relapsing illness associated with considerable morbidity and less optimistic outcomes than had been reported from the Far East (3).
We evaluated clinical, laboratory, and radiographic data from patients with TA who received either consultative or continuous care from one physician within our center. We sought to compare features of the disease from our cohort with those from the NIH and ethnically and racially distinct populations from other countries, including Japan, Italy, India, and Mexico.
PATIENTS AND METHODS
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Seventy-five patients with TA were evaluated at the Cleveland Clinic Foundation (CCF) from 1992 to 2004. Patients were identified from a registry maintained by one of the authors (GSH); the registry was checked for completeness by a chart survey that identified prior evaluation within the Center for Vasculitis Care and Research, an International Classification of Diseases, Ninth Revision (ICD-9) code for TA, or imaging studies that included the entire aorta and its primary branches. Patients so identified also had imaging abnormalities, including stenoses and/or aneurysms characteristic of TA, verified by review of radiologic studies. Electronic and paper chart review ensured that potential confounding conditions that could mimic TA (e.g., Cogan's syndrome, sarcoidosis, Kawasaki disease, Behçet's disease, syphilis, tuberculosis, Ehlers-Danlos syndrome, Marfan's syndrome, and neurofibromatosis) were not present.
Only patients meeting the American College of Rheumatology (ACR) criteria for TA (4) and our requirement for imaging abnormalities were included. If ACR criteria were met with the exception of the age requirement (being ≤40 years of age), and if the patients were between the ages of 41 and 50 years without fulfilling ACR criteria for giant cell arteritis (GCA), they were also included because ACR criteria do not classify patients in this age range as having either TA or GCA (4, 5). Disease onset was defined as the initial time at which there was identification of vascular symptoms that were subsequently determined to be compatible with TA and not attributable to comorbid conditions. For the subset of 30 patients who received longitudinal care at our center, we were able to further delineate the effectiveness of medical and surgical interventions and patterns of disease progression.
Criteria for disease activity.
We defined active disease using guidelines from previous NIH studies (3), including onset or worsening of at least 2 of the following disease features: 1) presence of systemic signs or symptoms (e.g., fever, arthralgias) that were not attributable to another condition, 2) elevation of acute-phase reactants (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) in the absence of infection or malignancy, 3) onset of signs or symptoms of vascular insufficiency (unequal or absent pulses or blood pressure, limb claudication), and 4) vascular lesion(s) in previously unaffected vascular territories, detected on serial imaging studies.
Because of the tendency for established vascular abnormalities to progress with regard to further stenosis or dilatation (even in the absence of active disease), for a vascular anatomic change to be considered a measure of active progressive disease, it had to have been entirely absent in prior imaging studies (3). Remission was defined as the resolution of clinical and laboratory features of active disease and the absence of new vascular lesions, as determined by sequential imaging studies. Sustained remission was defined as these conditions having been met for at least 6 months while on a treatment regimen that included <10 mg/day of prednisone.
Initial therapy for active disease generally consisted of prednisone only (1 mg/kg/day) for 1 month, which was then tapered after resolution of symptoms of active disease and normalization of acute-phase reactants. Prednisone dosage was reduced by 5 mg/week until reaching a dosage of 20 mg/day. The taper rate was then reduced to 2.5 mg/week until achieving a dosage of 10 mg/day, and then reductions proceeded by 1 mg/week until prednisone discontinuation or relapse occurred. If relapse occurred, prednisone was increased by 10 mg over the last effective dose, and methotrexate (MTX) therapy was initiated at 15 mg/week (with folic acid 1 mg/day and trimethoprim/sulfamethoxazole double strength 3 times per week for prophylaxis against Pneumocystisjiroveci pneumonia). MTX was increased (maximum 25 mg/week) if necessary to sustain remission.
If a patient was intolerant to or failed to achieve or sustain remission while receiving MTX, azathioprine (AZA) therapy was initiated at 2 mg/kg/day, and if medication intolerance or treatment failure occurred with that agent, mycophenolate mofetil (MMF; 1.5 gm twice daily) was used. In the setting of immediate life-threatening disease (1 patient), daily cyclophosphamide (CYC; 2 mg/kg/day) was used, concurrent with glucocorticoids as initial therapy. After 3 months of CYC therapy, after remission was achieved and sustained, that agent was discontinued and weekly MTX therapy was started. Patients received anti–tumor necrosis factor (anti-TNF) therapy if they were unable to maintain disease remission with these agents.
Assessment of disease activity and acute-phase reactants in the longitudinal cohort.
At each office visit, criteria for disease activity were applied (see above) based on symptom assessment, physical examination, and laboratory studies. Complete aortic and primary branch vessel imaging was performed every 6 months or sooner if there was uncertainty about disease progression.
Statistical analyses were performed using Stata software, version 9.0 (StataCorp, College Station, TX). Categorical data and proportions were compared using the chi-square or Fisher's exact test. P values less than 0.05 were considered significant.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Our experience is derived from the largest US cohort of TA patients studied to date. Our findings are consistent with those reported in the only other large, longitudinal series in the US, that of the NIH. In both studies, young women were affected in ∼90% of cases, patients were usually white (75% and 92%, respectively), and the subclavian artery was the most common site of involvement. Fewer than one-fifth of patients in both series had a self-limiting illness or a course of disease that resolved after a short period of therapy. In nearly all cases, high-dose glucocorticoid therapy resulted in initial disease remission that was followed by relapse after a gradual reduction in the glucocorticoid dose. The addition of other immunosuppressive therapies, especially cytotoxic agents, often allowed for further reductions in the glucocorticoid dose, but was still followed by relapse after additional attempts to discontinue glucocorticoid treatment. At the time of relapse, the average daily dose of prednisone in our longitudinal cohort was 13 mg (median 10 mg/day), a dose well known to produce considerable risk of adverse effects.
Acute-phase reactant values were normal and misleading in approximately one-fifth of patients with active disease, whereas nearly three-fourths of patients with active disease had concordant increases in acute-phase reactants. Therefore, acute-phase reactants are not adequately sensitive to rely on as a definite measure of disease quiescence, but abnormal levels of acute-phase reactants, in the absence of comorbid inflammatory processes, should encourage further investigation to identify additional evidence of disease activity.
In both our experience and that of the NIH, achieving sustained vascular patency by angioplasty was relatively unsuccessful. This observation contrasts with better results that have been reported in Indian patients (7, 12). While this may reflect ethnic or practice differences, it may also relate to median followup periods being relatively brief in the latter studies. Our success (e.g., patency, with no need for further intervention) for arterial bypass/reconstruction was almost 3-fold better (68%), over a 3-year followup period, than that for angioplasty (25%). While both our series and that of the NIH had relatively low mortality rates (NIH 3%, median followup period 5 years; CCF 4%, median followup period 3 years), chronic morbidity and disability were frequent in this relatively young population.
The US experiences are, in certain regards, similar to those in other countries, including Italy, Japan, and Mexico. Each of these TA cohorts had a predominance of female patients, and disease onset was most frequent in the second and third decades of life. Not all large series provided detailed assessments of features at presentation and during followup. The NIH, Italian, and Indian cohorts most clearly outlined manifestations of TA that occurred at disease onset (Figure 4). Longitudinal vascular involvement data were provided in the NIH, Italian, Indian, Japanese, and Mexican cohorts (Figure 5). In all series, aortic arch branch vessels were commonly involved, and the predominant anatomic lesion was stenosis or occlusion. The most frequently affected arch vessel was the subclavian artery. While the thoracic aorta was commonly involved in the US, Mexican, and Japanese series, the abdominal aorta was more frequently affected in Indian and Italian patients. Another important difference was noted concerning renal artery stenosis, which was more frequent in patients in the Mexican and Indian cohorts, in whom hypertension was among the most common presenting features.
Figure 4. Manifestations of Takayasu arteritis at the time of disease onset in the American, Italian, and Indian cohorts. Instances in which data were not provided for a cohort are indicated by the absence of a comparison bar. HA = headache; sx = symptoms; BP = blood pressure; Dim = diminished; HTN = hypertension; TIA = transient ischemic attack; CVA = cerebrovascular accident; CHF = congestive heart failure; CCF = Cleveland Clinic Foundation; NIH = National Institutes of Health.
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Figure 5. Frequency of vascular involvement during the course of disease. Instances in which data were not provided for a cohort are indicated by the absence of a comparison bar. CCF = Cleveland Clinic Foundation; NIH = National Institutes of Health.
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Because it was not customary to use antiinflammatory/immunosuppressive agents in India or Mexico, and detailed information about efficacy was not available from the Japanese series, comparisons of specific treatment outcomes are only available from the CCF and the NIH series. However, it was generally noted across cohorts that many patients improved with glucocorticoid therapy, but relapsed after glucocorticoids were tapered, leading to repeated courses of treatment or the addition of other immunosuppressive agents. Additionally, it was only in the 2 US cohorts that routine sequential imaging was used to assess the effectiveness of therapy in arresting anatomic progression in all patients. In both studies, glucocorticoids and adjunctive immunosuppressive therapies were shown to control disease in most patients, but not to sustain remission when glucocorticoids were tapered toward discontinuation. Relapse and anatomic progression were seen in the majority of patients.
Procedures to restore vascular patency or to repair aneurysmal disease were performed in approximately one-half of US and Italian patients. These interventions were used considerably less often in Japanese, Indian, and Mexican patients. The higher mortality rates in the Indian and Mexican cohorts could have several explanations, including ethnic differences that influence disease phenotypes and severity of disease expression, differences in medical therapy (e.g., less frequent use of glucocorticoids and cytotoxic agents), and variations in access to medical and surgical therapy. The lack of data does not allow for an analysis of these factors.
Our study has several important limitations. We were unable to collect complete longitudinal data on patients who were seen only on an intermittent consultative basis. This is a problem that is intrinsic to most tertiary referral centers, where patients often travel from other regions or countries for single or infrequent visits. Furthermore, our analysis was performed as a retrospective review of a cohort acquired at various periods in the course of their disease. Prospective enrollment and data collection from the time of diagnosis would be ideal, but is more difficult to achieve with rare diseases.
The strengths of our study include evaluation by a single provider, a comprehensive standardized approach to collection of historic data, complete and at least yearly vascular imaging, and routine collection of laboratory data in all patients to assess disease status and progression. Each visit specifically addressed elements of the disease state, e.g., the absence or presence of disease activity, relapses, or sustained remission.
Medical treatments for TA are severely flawed. While symptomatic improvement usually follows high-dose therapy with glucocorticoids, at least three-fourths of patients receiving close followup care have numerous relapses with dosage reduction. Relapses remain common despite the use of adjunctive immunosuppressive therapies. These results are supported by longitudinal data from 2 large US series. The relatively low rate of disease relapse that we have reported in patients receiving anti-TNF therapy is noteworthy (13). However, confirmation of these observations in rigorous randomized controlled studies is needed. The failure of conventional medical therapy for TA has led to vascular surgery being a common salvage procedure. At least half of these relatively young patients will eventually develop ischemic symptoms or aneurysms that require one or more surgical interventions. The frequency of significant morbidity and disability among affected patients with TA in the US speaks to their unmet medical and surgical needs.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Maksimowicz-McKinnon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Maksimowicz-McKinnon, Hoffman.
Acquisition of data. Maksimowicz-McKinnon, Clark, Hoffman.
Analysis and interpretation of data. Maksimowicz-McKinnon, Hoffman.
Manuscript preparation. Maksimowicz-McKinnon, Hoffman.
Statistical analysis. Maksimowicz-McKinnon.