Clinical characteristics and long-term outcome of Takayasu arteritis in Iran: a multicentre study

Background/aim This study aimed to evaluate the demographic, clinical, angiographic and prognostic characteristics of Takayasu arteritis (TA) in Iran. Materials and methods A total of 75 patients with TA based on the American College of Rheumatology 1990 criteria for TA classification referred to the Rheumatology Centres, were followed-up from 1989 to 2019. Demographic, clinical, angiographic and prognostic characteristics were collected at baseline and last visit. Results The mean age was 31.9 ± 9.8 years at the disease onset. Female to male ratio was 14. The median latency in diagnosis was 24 months. Pulse discrepancy in the arms, blood pressure discrepancy in the arms, limb claudication, hypertension and constitutional symptoms were the most common clinical features. The most common angiographic type at the time of diagnosis was Type I (42.7%). The most frequent arterial lesion was stenosis (89.4%). Subclavian, carotid and aortic arteries were the most commonly involved arteries. New lesions developed in 28.6% of patients during the 5.25-year follow-up. Vasculitis-induced chronic damage was observed in all patients. Disease activity decreased and vascular damage remained stable throughout the follow-up period. Conclusions The clinical features and angiographic type of TA in Iran are different from most Asian countries. Differences in angiographic and clinical features may lead to delayed diagnosis. The issue of delay in diagnosis should create awareness among health care providers that TA is not a very rare disease in Iranians and failure to pay attention to warning symptoms may delay the diagnosis.


Introduction
Takayasu arteritis (TA) is a chronic vasculitis of unknown aetiology that affects the large and medium sized arteries, especially the aorta and its major branches. Inflammation of the arterial wall leads to thickening of the wall, stenosis, obstruction and aneurysm of the arteries [1]. These changes are responsible for the clinical manifestations of TA such as reduced blood pressure (BP) in the limbs, claudication, decreased arterial pulses, bruits over arteries, ischemic ulcerations and light-headedness [1]. Acute events like visual loss, myocardial infarction (MI), stroke or transient ischemic attacks (TIA) are other presentations of the disease [1]. Constitutional symptoms including fever, malaise, fatigue, and weight loss are nonspecific findings of TA [1].
TA occurs throughout the world and may have a varying clinical spectrum in different populations [2]. Although TA is a disease of young people that starts most commonly at the ages of 20-30, its maximum prevalence in Sweden and Italy is at 41 [2]. The ratio of women to men is 12:1 in Turkey and 9:1 in Japan, while in India it is 1:1 [2]. Considering the little information about TA in Iran, this multicentre study has been conducted on the demographic, clinical, angiographic and prognosis of TA in Iranians.

Study group
In this cross-sectional multicentre study, the medical records of 92 patients with TA were reviewed, retrospectively. These patients were treated at the following rheumatology centres: Connective Tissue Diseases Research Centre of the Tabriz University of Medical Sciences, the rheumatology clinic in the Isfahan University of Medical Sciences, the rheumatology clinic in the Urmia University of Medical Sciences and the rheumatology clinic in the Army Hospital of Tehran. Rheumatology centres with at least 3 patients with TA were included. After excluding repeated records and patients with incomplete data, 75 patients with clinical and angiographic findings compatible with the TA met the American College of Rheumatology 1990 criteria for TA classification and complete assessment of the arterial tree in the neck, thorax, abdomen and limbs with one of the angiographic methods including computed tomography (CT) angiography, magnetic resonance (MR) angiography or conventional angiography were recruited in the study (Tables 1 and 2) [3]. In patients older than 50, the presence of giant cell arteritis and polymyalgia rheumatica were excluded. Informed consents were taken from the participants in the study and the study protocol was approved by the local ethics committees.

Data collection
A detailed questionnaire containing demographic characteristics: age at the onset of the disease; duration of symptoms before diagnosis; duration of follow-up; clinical  manifestations of the disease; disease activity in the first visit and at the end of follow-up; laboratory findings including blood count, kidney function tests, liver function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP); imaging findings including CT angiography, MR angiography or conventional angiography; the pattern of vascular involvement; treatment modalities including medications and revascularization procedures; morbidity and mortality were applied. Data were collected at the baseline and last visit.

Anatomic classification
TA was classified into 6 groups using the Hata's angiographic classification [4] as the following: Types I, IIa, IIb, III, IV, and V. The patterns of vascular involvement were assessed by angiography, including occlusion (a total occlusion of the lumen), stenosis (a narrowing of more than 70% in the lumen) and aneurysm.

Pulmonary artery hypertension (PAH)
We used transthoracic echocardiography for the assessment of pulmonary artery (PA) pressure. PAH was defined as PA systolic pressure higher than 30 mmHg.

Assessment of disease activity and course
Disease activity was measured using national institutes of health (NIH) criteria for active disease [5], Birmingham Vasculitis Activity Score (BVAS) version 3 [6] and Indian Takayasu Clinical Activity Score (ITAS) [7]. Patients were categorized according to the disease activity in the last 6 months of the follow-up: active disease, disease in remission, or death. We defined active disease using NIH criteria. Sustained remission was applied to cases that had NIH criteria for at least 6 months. Vasculitis Damage Index (VDI) at the time of diagnosis and last visit were used for quantifying damage [8,9].

Statistical analysis
For statistical analysis, we used SPSS 16 software (SPSS Inc., Chicago, IL, USA). Categorical variables were expressed as number and percentage. Continuous variables were reported as mean ± SD and for out of range data by median. Continuous variables were compared using parametric test (independent sample t-test) and/or nonparametric test (Mann-Whitney U test). Chi-squared test was used for the comparison of categorical variables. Factors correlated with delay in diagnosis of TA or remission were subjected to univariate regression analysis and were expressed as odds ratio (OR) and 95% confidence interval (95% CI). All factors with P-values less than 0.20 were assessed using multivariate regression analysis. P-values of < 0.05 were considered statistically significant.

Demographic, clinical and laboratory characteristics
The study included 75 patients with TA followed between 1989 and 2019. Demographic characteristics of patients are summarized in Table 1. Mean duration of follow-up was 5.25 (min: 0.5, max: 30) years. Female to male ratio was 14. The onset of the disease in 13 (17.3%) patients was after 40 years of age. The median latency in diagnosis was 24 months. Using regression analysis, we were not able to identify variables as predictors of latency in diagnosis ( Table 3). The clinical features of the studied patients are shown in Figure 1. Pulse discrepancy in the arms, BP discrepancy in the arms, limb claudication, hypertension and constitutional symptoms were the most common features. Laboratory findings are evident in Figure 2. In 54 (72%) patients at least one of the laboratory tests (ESR, CRP, and CBC) was abnormal.

Angiographic findings
CT angiography was performed in 73 (97.3%) patients. In 2 patients, MR angiography was performed for imaging. Patients were classified according to the angiographic findings at the time of diagnosis (Table 2). Type I was the most common type. No case of Type III was observed.
Arterial stenosis was the most frequent arterial lesion (89.4%). Dilatation or aneurysm (11.1%) and finally occlusion (7.2%) were less frequent. Patients with Type I were significantly older than the patients in other types ( Table 2). No significant association was observed between other demographic characteristics, the outcome and angiographic types of the disease ( Table 2). The distribution of arterial involvement is shown in Table 4. Subclavian and carotid arteries and aortic arc were the most commonly involved arteries. During the follow-up imaging, studies were repeated in 28 patients. New lesions developed in 8 patients (28.6%).

Disease activity, treatment and outcome
Disease was active in 62 (82.7%) patients at the time of diagnosis. Treatment with prednisolone was started in 66 (88%) patients. In 47 (62.7%) patients at least one disease modifying antirheumatic drug (DMARD) was added to the treatment regime (Table 5). During the follow-up period disease activity (ITAS and BVAS) decreased, and vascular damage remained stable (Table 5). In 54 (72%) patients the disease was in sustained remission at the end of the follow-up. Apart from the age of the patients at disease presentation, less latency in diagnosis and higher ITAS at the baseline, no significant differences were observed between TA patients with disease in remission and active disease (Table 6). However, using regression analysis, we were not able to identify variables as predictors of remission in TA patients (

Discussion
In this study, we presented demographic, clinical and imaging features, disease activity and outcomes of 75 Iranian patients with TA. Clinical manifestations, angiographic findings and outcomes in patients with TA vary in different geographic regions. We compared demographic characteristics, clinical features and outcomes of patients in our study with studies from other countries (Table 8)

Demographic characteristics
In studied patients, the mean age at onset of TA was 32 years, similar to the age of the onset in Asia, Europe, and North and South America (Table 8). Female predominance was highest in our patients after Japan (Table 8). TA was introduced as a disease present in patients below 40. This study showed that TA in 17% of Iranian patients started after the age 40, whilst this figure was 14% in Turkish, 17.5% in Italian, 26% in Norwegian, and 32.0% in French patients [11,14,16,18,19]. There was a 51-months delay between disease presentation and diagnosis of TA in Iran. The interval from the initial symptoms of TA until the time of the diagnosis in other series was 14-91 months ( Table 8). None of the demographic, clinical and laboratory parameters were predictors of delay in diagnosis in the studied patients. In a report by Karageorgaki et al., delay in diagnosis of TA was 24 months and fatigue at the time of diagnosis was associated with an increased risk for delay in diagnosis. Vanoli et al. reported the age < 15 years and an ESR < 30 at disease onset as risk factors associated with a diagnosis delay ≥ 2 years [16].

Angiographic findings
The most common angiographic type in the studied patients was Type I, whereas in countries with high  prevalence of TA (Japan, India and China) and in most European countries and USA, the most common type was V ( Table 8). The distribution of the vascular stenosis in our study is consistent with those in other studies, which means that the most commonly involved arteries are subclavian and carotid.

Treatment and outcome
Glucocorticoids (GCs) are the mainstay of TA treatment. However, in 63% of our patients DMARDs were used in order to get remission or decreasing GC dose. The figure varies from 4%-98% in different countries (Table 8).
Although remission occurred in the majority of TA patients, 52% of them experienced at least one of the morbidities of the disease and more than 20% of the patients underwent interventional or surgical procedures. During 5.2 years of follow-up, disease stayed in remission in 72% of the patients. In our study, the survival rate was 90%, 10 years after the diagnosis. Studies from other countries reported a rate ranged from 46%-94% for remission and 73%-98% for 10-year survival (Table 8). In our study, younger age of patients at disease presentation and more diagnosis delay were associated with sustained remission. The association between diagnosis delay and remission rate may be related to a   milder nature of the disease compared to the patients who were diagnosed with more delay. In Schmidt et al. study no association was found between sex, ESR, CRP level, or angiographic classification with risk of relapse or remission [20]. Older age at diagnosis was associated with an increased likelihood of sustained remission (hazard ratio of 1.89 per 10-year increase in age) [20]. We did not find any association between angiographic type and remission rate. However, in Goel et al. study, low CRP and angiographic type 4 were associated with a low remission rate in TA [13].
Our study had some important limitations: i) retrospective design of the study; ii) heterogeneous treatment regimens and the treatment durations present a risk of bias when evaluating the effects of the therapy on progression of vascular lesions; iii) existing serious complications before starting treatment in almost all the patients.
In conclusion, this multicentre study provides novel data on the demographic and clinical characteristics, angiographic findings, treatment and outcome of TA in Iran. The clinical features and angiographic type of TA in Iran are different from most Asian countries and similar to the North European countries. Angiographic Type 1 is the most common type in Iranians. The delay in diagnosis is high in Iran. Differences in angiographic and clinical features may lead to delayed diagnosis. The issue of delay in diagnosis should create awareness among health care providers that TA is not a very rare disease in Iranians and failure to pay attention to warning symptoms may delay the diagnosis. Earlier diagnosis and treatment of TA may improve prognosis of this disease.