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Keywords:

  • Takayasu's arteritis;
  • Systemic vasculitis;
  • Rare disease;
  • Italian population;
  • Clinical characteristics

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Objective

Takayasu's arteritis (TA) is a rare vasculitis. The Italian Takayasu's Arteritis study group was established with the aim to describe a large cohort of patients.

Methods

Data were collected by means of an ad hoc form. Demographic information, clinical history, vascular findings, treatment, risk factors, and comorbidities were analyzed.

Results

Data of 104 patients were collected. The median delay in diagnosis was 15.5 months (range 0–325 months). Age at onset <15 years was associated with a higher probability, whereas elevated erythrocyte sedimentation rate with a lower probability, of a delay in diagnosis. The majority of patients experienced nonspecific signs and symptoms indicative of an inflammatory disease in the early phase. Among vascular involvement, stenosis was the most frequent lesion, being present in 93% of patients, followed by occlusion (57%), dilatation (16%), and aneurysm (7%). Glucocorticoids were the mainstay of treatment in our series; however, treatment with cytotoxic agents was required in about half of the patients. Fifty-two patients underwent at least 1 surgical procedure. The main indications for intervention were renal vascular hypertension, cerebral hypoperfusion, and limb claudication.

Conclusion

As with many rare diseases, delay in diagnosis is an important issue for patients with TA. The increasing occurrence of vascular lesions along with the disease progression put to question the long-term effectiveness of contemporary treatment. These data may be helpful in increasing physicians' awareness to prevent diagnosis delay, update guidelines, and plan future research projects.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Takayasu's arteritis (TA) is a granulomatous inflammation of the aorta and its major branches of unknown etiology, usually occurring in patients younger than 50 years (1). The disease is more common in Japan and Southeast Asia than in Europe and North America, although precise data on its prevalence are not available (2, 3). Indeed, most of the information comes from reports on small series of patients, which have helped in profiling the presentation and clinical features of the disease in the West (4–6). As for many rare diseases, the true incidence and prevalence of TA is probably underestimated. Many patients remain undiagnosed or wait a long time before a correct diagnosis is made.

Following the experience in studying other rare conditions, a collaborative group was established (Italian Takayasu's Arteritis [ITAKA] study group) among 17 centers in Italy, with the aim to identify patients with TA and to describe the main characteristics of the disease in the Italian population. This article describes the most important findings of this work.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Centers and patients.

Three independent strategies were applied to identify the Italian centers that have in file ≥1 patient with TA. First we reviewed the administrative data of all hospital discharges that occurred in Italy between January 1, 1995 and December 31, 1997, provided by the Servizio Centrale di Programmazione Sanitaria of the Italian Health Ministry. A total of 181 hospital wards that had discharged ≥1 patient with the diagnosis of Takayasu's arteritis (International Classification of Diseases, Ninth Revision [ICD-9] code 446.7) within that period of time were identified. Apart from this, we retrieved data from the Italian Takayasu Registry (6) and from the Database of the Clinical Research Center for Rare Diseases (7). By merging the 3 sets of data, we were able to identify 404 cases in 201 centers in Italy. Centers were invited to participate in the study by completing a preliminary information form for each patient. After excluding repeated records (108 patients were recorded by >1 center), errors in ICD-9 coding, nonverifiable diagnoses, and dead patients, 75 centers accounting for 192 unique patients remained. Of these centers, 17 agreed to participate in the project and enrolled all their eligible patients, after an informed written consent was obtained. All patients who met the American College of Rheumatology (ACR) 1990 criteria (8) for the classification of TA or had a diagnosis of TA confirmed by histologic findings were considered eligible. Those patients who had not been examined by the physician in charge during the previous 12 months were excluded from the data collection. At last, data for 104 patients were collected.

Data collection.

Data were collected using a form specifically designed and validated for this study. This form collected the following information: demographic information (including racial origin); family history; clinical history of TA, including signs and symptoms (at onset, at time of diagnosis, and during the whole course of the disease); vascular findings, and diagnostic tests used in the followup; risk factors and comorbidities; number and outcome of pregnancies before, during, and after the onset of the disease; and medical and surgical treatment. An evaluation of disease activity at the time of the last examination was also provided. Resolution or stabilization of all clinical features, in the setting of fixed vascular lesions, was classified as “remission” or inactive disease (according to the National Institutes of Health [NIH] criteria) (9) whereas all other cases were considered as “active disease.” Data collection forms were compiled between February 1999 and March 2000.

Statistical analysis.

Data are summarized as mean, standard deviation, and median for continuous variables and number of subjects (percent) for categorical variables. Proportional differences between groups were studied using the Mantel-Haenszel chi-square test or Fisher's exact test (when the number of observations was too few).

A logistic regression model was fitted to identify eventual predictors of diagnostic delay. As a dependent variable, we considered the presence of a diagnostic delay of >2 years. The independent variables we tested were as follows: sociodemographic characteristics (sex, marital status, educational and professional status, residence place, birth place), general clinical condition (body mass index, dislipidemia, allergies, presence of comorbidity), and characteristics of the disease at onset (age, signs, and symptoms).

To compare fertility before and after the onset of TA we computed the correspondent incidence rate of pregnancy. Operatively, the numerator was the number of pregnancies occurring in the considered period, and the denominator was the total number of fertile years. The latter was computed by summing up the years of women aged 15–45 years and subtracting 1 year for each pregnancy.

We also analyzed the risk (expressed in terms of cumulative incidence) of receiving a surgical intervention with time through the actuarial method. An event was considered the presence or absence of surgical interventions, and the time to event was fixed from the onset of the disease until the first surgical intervention.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Patients' characteristics.

Data were obtained from 104 patients: 91 women (87.5%) and 13 men (12.5%), whose characteristics are summarized in Table 1. Mean age at disease onset (determined by the occurrence of the earliest specific symptom or a finding attributable to the disease) was 29.4 years in men and 29.1 years in women, a not statistically significant difference. Twenty-five patients (24.0%) met all 6 ACR criteria for TA, whereas 11 patients (10.6%) met all but claudication of extremities and 10 (9.6%) met all but bruit over the subclavian arteries or aorta. The remaining patients fulfilled <5 criteria. Four patients had only 2 diagnostic criteria (age at onset <40 years and typical arteriogram abnormalities). In these cases, TA had been confirmed with histologic findings. Looking at all the possible combinations of 3 diagnostic criteria, the most frequently observed combination was decreased brachial artery pulse, blood pressure difference >10 mm Hg, and typical arteriogram abnormalities (61% of cases). Median diagnostic delay was 15.5 months (range 0–325 months). With the logistic regression model, we were able to identify only 2 variables as predictors of diagnostic delay: age at onset <15 years, which was associated with a higher probability of a delay ≥2 years (odds ratio [OR] 3.9, 95% confidence interval [95% CI] 1.2–12.8), and erythrocyte sedimentation rate (ESR) at onset >30 mm/hour, which was associated with a lower probability of delay (OR 0.35, 95% CI 0.15–0.82).

Table 1. Patients' characteristics (n = 104)
  • *

    Body mass index (BMI) = weight (kg)/height (m2). Underweight BMI <19; ideal BMI = 19–24; overweight BMI = 24–29; obese BMI >29.

  • The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. BP = blood pressure.

  • In the remaining 2 patients (1.9%), typical vascular lesions where documented by nuclear magnetic resonance.

Sex, n (%) 
 Female91 (87.5)
 Male13 (12.5)
Racial background, % 
 White99
 African1
Professional status, % 
 Employed70
 Unemployed30
Age at compilation, years 
 Mean ± SD40.1 ± 15.3
 Range16–79
Age at onset, years, % 
 ≤1514.6
 16–4068.0
 41–506.8
 >5010.7
Range4–74
Duration of disease, years 
 Mean ± SD10.5 ± 7.8
 Range0–32
Delay in diagnosis, months 
 Mean ± SD42.9 ± 64.9
 Median15.5
 Range0–325
Body mass index, %* 
 Underweight6.9
 Ideal51.4
 Overweight30.6
 Obese11.1
Diagnostic criteria, % 
 Age at onset ≤40 years82.7
 Claudication of extremities58.6
 Decreased brachial artery pulse75.0
 BP difference >10 mm Hg68.3
 Bruit over subclavian arteries or aorta70.2
 Arteriogram abnormality98.1

No other vasculitides were reported in the family histories of our patients. Concerning comorbidities, 3 patients had inflammatory bowel disease, 2 had Hashimoto's thyroiditis, and individual patients had systemic lupus erythematosus, relapsing polychondritis, and Hodgkin's lymphoma.

Clinical features and laboratory findings.

The main clinical features and laboratory findings of all 104 patients are shown in Figure 1, by the time of their appearance (onset, diagnosis, and overall disease duration). It is interesting to note that, at the onset, 70.9% of the patients had at least one constitutional or musculoskeletal symptom. In addition to the clinical features shown in Figure 1, 16 patients (15.3%) were diagnosed during the disease course with hypertensive retinopathy and 8 patients, ischemic retinopathy (7.6%).

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Figure 1. Main clinical features and laboratory findings. BP = blood pressure; Hb = hemoglobin; Ht = hematocrit.

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Vascular involvement

Sixty-one patients had a complete angiography study. Stenosis was the most frequent lesion, being present in 57 patients (93%), followed by occlusion (57%), dilatation (16%), and aneurysm (7%). Stenosis was present in 19% of all the examined vessels, whereas the other lesions were less common (occlusion 7%, dilatation 1%, aneurysm 0.5%). The majority of the patients (53%) had lesions above and below the diaphragm; 32% showed isolated supradiaphragmatic disease. Involvement of the abdominal aorta and its branches alone was rarely documented (7%). In 44% of the patients, the subclavian or axillary arteries of both arms were either stenotic or occluded, whereas 2 patients (3%) had such lesions in all the extremities. The distribution of arterial involvement is shown in detail in Table 2.

Table 2. Vascular involvement in patients receiving full aortography
ArteryAny lesion* %Stenosis %Occlusion %Dilatation %Aneurysm %
  • *

    The percentage is not corresponding to the sum of each single lesion percentages because an artery can be affected by more than one lesion.

Left subclavian65.5742.6222.950.001.64
Right subclavian52.4629.5122.950.000.00
Left carotid44.2637.704.920.001.64
Abdominal aorta39.3429.516.563.281.64
Right carotid36.0722.956.563.283.28
Left renal34.4331.153.280.000.00
Left axillary33.3324.079.260.000.00
Superior mesenteric31.5824.567.020.000.00
Right renal29.5122.956.560.000.00
Right axillary25.9312.9612.960.000.00
Celiac trunk21.4317.863.570.000.00
Left iliac19.679.848.201.640.00
Right iliac18.036.569.841.640.00
Left vertebral13.338.335.000.000.00
Right vertebral11.678.331.671.670.00
Thoracic descending aorta11.117.410.001.851.85
Aortic arch10.345.170.005.170.00
Inferior mesenteric9.435.661.891.890.00
Innominate8.778.770.001.750.00

The progressive course of the disease was evaluated considering the last complete vascular examination with angiography or Doppler ultrasonography. The increasing occurrence of the 4 types of vascular lesion with disease duration was documented, as shown in Figure 2. Of note, dilatation and aneurysm became evident only after at least 3 years of disease. Moreover, the number of lesions per patient increased with disease duration (P = 0.04). Comparing patients with a disease course <3 years to those with disease duration >10 years, we observed an increase in the mean number of arterial stenoses per patient (3.50–5.07), occlusion (0.50–2.13), dilatation (0–0.27), and aneurysm (0–0.13). As expected, strong association was observed between site of involved vessels and vascular/neurologic features. Symptoms of limb hypoperfusion (claudication of extremities, Raynaud's phenomenon, distal cutaneous hypothermia) were more frequent in patients with lesions of subclavian or iliac arteries (78.4% versus 40.0%; P = 0.02). Neurologic findings (headache, dizziness, syncopal attacks, convulsions, transient ischemic attacks, stroke) were more frequent in patients with lesions of vertebral or carotid arteries (62.8% versus 22.2%; P = 0.005). Hypertension was more frequent in patients with renal artery stenosis (92.0% versus 30.6%; P < 0.0001). No significant correlation between hypertension and presence of dilatation or aneurysm was found.

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Figure 2. Prevalence of lesions.

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Of all the 104 patients, 60 underwent echocardiography: aortic regurgitation was present in 13 and mixed aortic valvular disease in 1. Twenty-five patients were investigated with coronary angiography because of symptoms of ischemic heart disease. Three patients presented coronary stenosis and 1 coronary occlusion. Among the 9 patients investigated with pulmonary angiography, stenotic lesions and occlusion of pulmonary arteries were detected in 2 and 1 cases, respectively.

Pregnancies.

We recorded 92 pregnancies in 39 women before the onset of TA and 24 pregnancies in 18 women after the onset. The yearly incidence of pregnancies in our sample decreased from 8.2 for every 100 fertile women (i.e., 15–45 years old) before the onset of TA to 2.8 after the onset of the disease. We registered a trend toward an increase in the percentage of spontaneous abortions after disease onset (11% versus 21%), but the difference did not reach statistical significance (Fisher exact test 0.012, P = 0.6).

Medical treatment.

At last visit, 69% of the patients were treated with glucocorticoids or cytotoxic agents, 54% of them being in an inactive phase of the disease. Considering the untreated patients (31% at last visit), active disease was present in 10%.

During the overall disease course, glucocorticoids were the most frequently used drugs, being prescribed to 86% of the patients; cytotoxic agents were prescribed to 54% of the patients. Of the 15 patients (14%) who never received steroids, 13 had not received cytotoxic agents either, thus they were left untreated due to inactive disease at diagnosis without relapses during the followup. Eleven of the 13 patients were evaluated for >5 years (median 10 years, interquartile range 6–17 years). Two patients were instead treated with cytotoxic agents as first-line treatment. Antiplatelet agents were used in 84% of the patients at any time of the disease and oral anticoagulants in 16%. Antihypertensive drugs were prescribed in 52% of the patients.

Surgical treatment.

Fifty-two patients underwent ≥1 surgical procedure, the average number of interventions being 2 per patient (SD 0.93). Percutaneous transluminal angioplasty (PTA) of a vessel was performed in 54% of these patients, a bypass in 42%; PTA with stent in 21%, aneurysm repair in 12%, and aortic valve replacement in 8% of the cases. The main indications for intervention were renal vascular hypertension, cerebral hypoperfusion, and limb claudication.

The risk of undergoing a surgical intervention increased during the first phase of the disease (particularly in the first 16 months from the onset) and tended to reach a plateau from 6 years on, as shown in Figure 3. The median followup was 8 years, with 75% of the sample being followed for >6 years.

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Figure 3. Cumulative incidence of undergoing a surgical intervention from the onset of disease.

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Patients with late-onset TA.

Eighteen patients (17.3%) in our series experienced disease onset at age >40 years (range 41–74 years), 11 of them >50 years. In all these patients, the presence of a temporal artery abnormality (tenderness on palpation or decreased or absent pulse), new onset headache, jaw claudication, visual loss, and polymyalgia rheumatica were excluded. In 2 of the 11 patients with onset at age >50 years, temporal artery biopsy had been performed with negative results.

Duration of disease in these patients ranged from 2 to 14 years. All of them had involvement of the aorta and its primary branches, and renal artery stenosis was documented in 3 cases. Surgical procedures were performed for limb claudication in 2 patients and for renal vascular hypertension in 1.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Although TA is most common in Asia, the disease has a worldwide distribution (10). Nonetheless, epidemiology of TA in Western countries is difficult to assess: reports are sparse, often from single centers or concerning few patients, and not representative of a whole country. Indeed, when dealing with rare diseases, it is difficult to assemble a representative sample of patients. Although there are usually few centers that follow a considerable number of subjects, many others provide assistance to only 1 or 2 patients. These smaller centers are rarely involved in research activity, but pooled together, they account for a large number of patients. Thus, to assure a nationwide sample of cases, we made considerable efforts to involve small clinical settings in our study. Increasing the number of patients in studies of rare diseases will subsequently lead to increased power of statistical analyses to detect significant differences. We succeeded in studying a large sample of patients, collected from a good number of centers. To our knowledge, this is the largest series of TA patients ever described in a Western country.

Another problem possibly affecting research on rare diseases is data quality. Prospective unbiased acquisition of information can seldom be applied, and data are usually gathered from a review of medical records. We restricted our analysis to subjects examined by the centers within the previous 12 months so that the data collection, although partially retrospective, was based on an accurate and updated review of clinical forms and patient's visits. This process reduced as much as possible the eventual recall and information bias.

Personal physician opinion can still bias the quality of information, as diagnostic interventions (vascular imaging, clinical and serologic monitoring, etc.) are provided at a varying extent. For this reason, we further restricted the analysis of vascular involvement to the patients who had a complete angiography study.

On the whole, the main sociodemographic and clinical characteristics of our sample resemble those described in a Japanese nationwide survey (11). This contradicts the idea that the female:male ratio decreases, from the 9:1 of Japan, as one moves toward the west (12). The mean age at onset of 29.2 years, with a range of 4–74 years, strengthens the concept that TA can also be diagnosed in older people. Thus the problem arises of differential diagnosis with giant-cell (temporal) arteritis. As demonstrated by a comparative study (13), these 2 conditions can be considered as separate disorders, even when the typical age criterion of 40 years at onset of disease is ruled out. Even though we cannot absolutely rule out that some of our oldest patients had indeed atypical giant-cell (temporal) arteritis, disease duration and clinical characteristics make this diagnosis unlikely.

In our series, the delay between onset of symptoms and diagnosis was longer than that previously reported (15.5 versus 10 months) (9). To evaluate the contributing factors, we performed a multivariate analysis. We found 2 independent risk factors associated with a higher probability of a diagnosis delay of ≥2 years: age <15 years and an ESR <30 at onset. The greater delay in diagnosis in our pediatric patients compared with adults, already described in Western hemisphere (9), suggests that a better sensitization of pediatricians toward TA is needed.

An elevated ESR is a strong indicator of an underlying inflammatory process, such as vasculitis; therefore, it is not surprising that this laboratory finding shortened the diagnostic delay of TA. However, an ESR value within the normal range should not rule out the possibility of TA, since vascular damage can progress even in the absence of systemic inflammatory alterations (14).

Nonspecific signs and symptoms indicative of an inflammatory disease were more frequent at the onset of the disease than at diagnosis, as were raised ESR, anemia, and leukocytosis. On the contrary, cardiovascular and central nervous system symptoms increased in time, parallel to the prevalence of arterial lesions. These findings confirm that the early phase of the disease is often characterized by general symptoms of systemic inflammation, whereas the subsequent, evolutive course of TA is dominated by the consequences of vascular inflammation or fibrosis.

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. Taking into account the literature and our experience, 2 types of presentation should alert the clinician to the possibility of TA: 1) a systemically ill patient with nonspecific laboratory findings indicative of an inflammatory disease and 2) cardiovascular features, such as claudication of extremities, hypertension, arterial pain, and distal cutaneous hypothermia, particularly in a young patient or a patient without risk factors for atherosclerosis. A high index of suspicion, proper evaluation of the patient's history, meticulous 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.

Sixty-one patients in our series had a complete aortographic study. Most of the patients had extensive disease of aorta and its branches above and below the diaphragm. The involvement of the abdominal aorta and its branches alone was less frequent. Similar angiographic features have been reported in Japanese (15) and North American subjects (9, 16), whereas in India, China, and Thailand (17–19), subdiaphragmatic involvement prevails. The high prevalence of the involvement of the left aortic arch branches is in agreement with the hypothesis of Ishikawa (20) that in TA the arterial lesions begin in the left subclavian artery and subsequently extend to other sites.

Overall, stenosis was the most common lesion, and aneurisms were less frequent than in other series (9, 17, 19). The association between aneurisms or dilatation and hypertension has been previously reported (21). The lack of such association in our data could be justified by either a possible underestimation of the lesions, due to the retrospective nature of the study, or a better control of hypertension and vascular inflammation than in the past.

On the other hand, we must also consider the possibility of a misdiagnosed hypertension in some patients. Stenosis and occlusion are widely diffused lesions, often involving the subclavian, iliac, and femoral vessels. Patients with systemic hypertension in a setting of 4-limb ischemia cannot be adequately monitored using conventional noninvasive blood pressure cuffs. Accurate evaluation by central arterial pressure monitoring is not feasible in everyday clinical practice. Physicians must therefore be aware of this limitation. Not knowing that severe central hypertension is present could lead to inadequate treatment and premature morbidity and mortality due to hypertensive cerebrovascular, cardiovascular, or renovascular complications.

The observation that hypertension is most often associated with renal artery stenosis is supported by past observations. Hypertensive patients without evidence of renal artery stenosis represent a relevant subset (30%) in our series. In such patients, other mechanisms are to be considered. Middle aortic syndrome causing acquired atypical coarctation and hypertension have been described (22). Arterial baroreceptor abnormalities can be hypothesized considering the high frequency of carotid arteries and aortic arch involvement. Such medications as prednisone or long-term nonsteroidal antiinflammatory drugs may also contribute to secondary hypertension.

As far as pulmonary artery involvement, pulmonary angiography was abnormal in 3 of the 9 patients who underwent the procedure. However, a frequency of 30% pulmonary involvement probably underestimates the real figure. Indeed, the procedure had been performed only when clinically needed. Moreover, using ventilation-perfusion lung scan, unmatched segmental perfusion defects were shown in 76% of Japanese patients (23) and in 60% of Italian asymptomatic patients (24).

We collected data on fertility and parity in TA patients. The finding of reduced female fertility has been never reported, although this study was not intended to specifically address the reproductive history of the patients. Of course, direct comparison of these results are impossible without further analyses aimed at eliminating the confounding effect of age and other important factors, such as the disease itself, treatment, and personal reproductive preferences. It is an interesting observation, however, that calls for further specific investigations.

This retrospective data collection shows that, even in absence of evidence of their prophylactic efficacy in TA, antiplatelet agents were very frequently prescribed. On the contrary, oral anticoagulants were used only in patients who underwent major surgical procedures. Glucocorticoids were the mainstay of active disease treatment in our series. However, in about half of the patients treatment with cytotoxic agents was required. Evaluation of the disease activity at the time of the last examination was based on NIH criteria (9), largely employed to manage the amount and duration of immunosuppressive therapy in clinical practice. It is, however, important to emphasize the current limitations in monitoring disease activity and underline that such criteria, although useful, may underestimate the percentage of patients with active disease (25).

According to other reports (26–28), main indications for surgical interventions were 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.

In summary, the work of the ITAKA group allows a quite close picture of patient and disease characteristics in the Italian population, previously not available to this extent. These data may be helpful in increasing physician's awareness to prevent delay in diagnosis, update guidelines, and plan future research projects. The implementation of an international registry of Takayasu arteritis patients will allow for more powerful clinical studies leading to increases in the knowledge of etiology, pathogenesis, treatment, and prognosis, as well as the quality of life of patients with this rare disease.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

We thank Dr. Rumen Stefanov for helpful discussion. The Authors are indebted to Manuela Passera, who helped prepare the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

APPENDIX A

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

THE ITALIAN TAKAYASU'S ARTERITIS (ITAKA) STUDY GROUP

Coordinating Center

Mario Negri Institute for Pharmacological Research—Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Villa Camozzi, Ranica, Bergamo, Italy: G. Bertolini, MD, E. Daina, MD (study coordination); G. Bertolini, MD, C. Rossi, Stat Sci (data management and analysis); A. Ricotta, RN (monitoring and data entry); S. Gamba, RN (organizing secretariat)

Participating Centers and Investigators

IRCCS Ospedale Maggiore, Milano, Italy: M. Vanoli, MD, G. Bacchiani, MD (current address: Istituti Clinici di Perfezionamento Hospital, Milano, Italy), M. Caronni, MD

Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Bergamo, Italy: E. Daina, MD, A. Schieppati, MD, S. Bruno, MD

S. Raffaele Hospital, Milano, Italy: M. G. Sabbadini, MD, E. Baldissera, MD, E. Bozzolo, MD

S. Orsola Malpighi Hospital, Bologna, Italy: E. Conti, MD, C. Pili, MD

Torrette Regional Hospital, Ancona, Italy: G. Malcangi, MD, P. Fraticelli, MD

Spedali Civili Hospital, Brescia, Italy: A. Zambruni

University Hospital A. Gemelli, Roma, Italy: R. Manna, MD

Policlinic Hospital, Bari, Italy: R. Rizzi, MD

Ospedali Riuniti, Trieste, Italy: E. Alberti, MD

CMID, Luigi Einaudi Hospital, Torino, Italy: M. Alpa, MD

Arcispedale S. Maria Nuova, Reggio Emilia, Italy: C. Salvarani, MD

S. Antonio Hospital, S. Daniele del Friuli (Udine), Italy: C. Volpe, MD

Santa Croce e Carle Hospital, Cuneo, Italy: G. Canepari, MD

Bianchi Melacrino Morelli Hospital, Reggio Calabria, Italy: M. Garozzo, MD

S. Camillo de Lellis Hospital, Schio (Vicenza), Italy: M. Lagni, MD

University Hospital S. Matteo, Pavia, Italy: C. M. Montecucco, MD

Casa di Cura Eretenia, Vicenza, Italy: N. Santipolo, MD

Contributing Correspondence

S. Raffaele Hospital, Milano, Italy: E. Angeli, MD

Alessandro Manzoni Hospital, Lecco, Italy: G. Lorenzi, MD

Spedali Civili Hospital, Brescia, Italy: G. Balestrieri, MD

S. Anna Hospital, Como, Italy: E. D'Ingianna, MD