Clinical Characteristics and Treatment Outcomes of Patients With Newly Diagnosed Takayasu Arteritis in Japan During the First 2 Years of Treatment　― A Nationwide Retrospective Cohort Study ―

Abstract

Background: This study aimed to clarify recent clinical features and treatment outcomes in Japanese patients with newly diagnosed Takayasu arteritis (TAK) during the first 2 years of treatment.

Methods and Results: A nationwide multicenter retrospective cohort study for TAK was implemented to collect data between 2007 and 2014. The primary outcome of the study was clinical remission at Week 24. Of the 184 participants registered, 129 patients with newly diagnosed TAK were analyzed: 84% were female and the mean age at onset was 35 years. Clinical symptoms at diagnosis were mostly associated with large-vessel lesions. Frequent sites of vascular involvement included the carotid artery, subclavian artery, aortic arch, and descending aorta. The mean initial dose of prednisolone administered was 0.68 mg/kg/day, and 59% and 17% of patients received immunosuppressive drugs and biologics, respectively, by Week 104. Clinical remission at Week 24 and sustained clinical remission with daily prednisolone at ≤10 mg at Week 52 were achieved in 107 (82.9%) and 51 (39.5%) patients, respectively. The presence of signs and symptoms linked to large-vessel lesions was associated with failure to achieve sustained clinical remission at Week 52.

Conclusions: We elucidated the clinical characteristics, treatment outcomes, and factors associated with failure to achieve sustained clinical remission in patients with newly diagnosed TAK in Japan during the first 2 years of treatment.

Takayasu arteritis (TAK) is a rare, idiopathic, large-vessel arteritis that predominantly involves the aorta and its primary branches, and less frequently the coronary and pulmonary arteries.^1,2 The clinical manifestations of TAK may alter with disease course; however, the principal manifestations include systemic inflammation and vascular pain. Vascular injuries, such as wall thickening, stenosis, occlusion, dilatation, and aneurysm, are associated with various signs and symptoms even after achieving clinical remission.^3,4 In addition, TAK may be complicated by symptoms of autoimmune diseases, including inflammatory bowel disease, erythema nodosum, and arthritis.³

TAK is prevalent in Asia, the Middle East, Central and South America, and Africa; however, the clinical disease features vary among races.^3,5,6 Moreover, TAK occurs more frequently in women. The age of onset ranges widely from infancy to middle age and, in some cases, older age. The peak incidence of TAK occurs around 20 years of age.^7,8 The etiology of TAK remains unknown, but genetic background, including human leukocyte antigen (HLA), has been reported to demonstrate a strong association with TAK in Japanese and other populations.^9,10

The development of diagnostic imaging has facilitated earlier and more accurate diagnosis of TAK.^3,11,12 Nevertheless, the clinical manifestation and treatment outcomes of TAK in Japan remain unknown due to the small number of patients. Previously in Japan, a few single-center studies of patients with TAK have been published,^13–15 but only 1 study using a nationwide registration database for TAK has been published.⁸

The first-line therapy for TAK management has been glucocorticoids (GC) for the induction of remission.^3,16 However, GC monotherapy for the management of TAK is frequently associated with adverse events (AEs) with the long-term use of GC, and recurrence often occurs during tapering of the drug.^15,17 Thus, recent guidelines for the management of TAK recommend the use of non-GC immunosuppressive agents with GC as an adjunctive or initial therapy.^3,18–20 However, in Japan, there are few reports of current medication use in patients with TAK.

To provide clinically important evidence on TAK, the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) implemented a nationwide multicenter retrospective cohort study. Here, we report the clinical features of newly diagnosed patients with TAK, the first 2-year treatment outcomes, and factors associated with sustained clinical remission.

Methods

Patients

A total of 26 university hospitals and referral hospitals with sufficient experience to treat vasculitis participated in this study. All investigators were members of the JPVAS. All patients with newly diagnosed or relapsed TAK who started prednisolone at ≥0.5 mg/kg/day or biologics at the study sites between 2007 and 2014 were registered in the JPVAS large-vessel vasculitis retrospective cohort. At each facility, patients were diagnosed with TAK based on the diagnostic criteria of the Japanese Circulation Society 2008 guidelines for the management of vasculitis syndrome.⁷

In the present study, we enrolled patients with newly diagnosed TAK from the retrospective cohort. Investigators retrospectively evaluated the 2-year medical records of the patients and reported clinical information during treatment initiation (i.e., baseline) and at 4, 8, 24, 52, 76, and 104 weeks after baseline at their facilities using a predefined case report form. The clinical information collected encompassed imaging findings, treatment, date clinical remission was achieved, disease status at the specified time points, and AEs of interest. The definition of clinical remission is provided below (see Outcomes). The AEs of interest in the cohort included serious infections, fractures, cardiovascular lesions requiring hospitalization or prolonged hospitalization, cerebrovascular lesions requiring hospitalization or prolonged hospitalization, gastrointestinal bleeding or perforation requiring hospitalization or prolonged hospitalization, diabetes requiring drug therapy, glaucoma or a cataract requiring drug therapy or eye surgery, psychiatric symptoms requiring drug therapy, and death. In the clinical information, “musculoskeletal disorders” means myalgia, arthralgia, and arthritis; “other systemic symptoms” means general fatigability, easy fatigability, and body weight loss. Signs and symptoms of large-vessel lesions include symptoms of the neck, upper limbs, lower limbs, chest pain, dyspnea, thoraco-abdominal bruit, and renal artery stenosis-associated hypertension.

Ethics Approval

The study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Tokyo Medical and Dental University (No. 2084).

Outcomes

The primary endpoint was the achievement of clinical remission at Week 24. In this analysis, clinical remission was defined as the disappearance of all components of the disease activity domain of the draft core set of remission criteria established by the JPVAS, including systemic symptoms, cranial signs and symptoms, signs and symptoms of 8 core vascular lesions, signs and symptoms of cardiac lesions, inflammatory markers (C-reactive protein [CRP] or erythrocyte sedimentation rate), and imaging findings.²¹ When the signs and symptoms of active disease or the large-vessel lesions persisted without worsening for ≥6 months, these were not considered indicative of clinically active disease status. Specifically, such vascular condition was defined as persistent vascular damage.²¹

Secondary outcomes included sustained clinical remission at Weeks 52 and 104, factors associated with sustained clinical remission at Week 52, vascular imaging assessments, and AEs. Sustained clinical remission at Week 52 was defined as achieving clinical remission by Week 24, maintaining it until Week 52, and daily prednisolone doses ≤10 mg at Week 52.²¹ Sustained clinical remission at Week 104 was defined as achieving sustained clinical remission at Week 52 and maintaining it until Week 104.

Data Collection of Imaging Findings of Large-Vessel Lesions

Site investigators reported imaging findings at 14 anatomical sites of the aorta and its primary branches, including the carotid, vertebral, subclavian, axillary, brachiocephalic, and pulmonary arteries; ascending aorta; aortic arch; descending aorta; abdominal aorta; and renal artery. The imaging findings reported were wall thickening, stenosis, aneurysm, or dissection based on image examination findings of at least one modality, such as computed tomography (CT), CT angiography (CTA), magnetic resonance imaging, magnetic resonance angiography (MRA), ultrasound, digital subtraction angiography or 18-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET), or PET-CT.

Statistical Analysis

Clinical characteristics, results of vascular imaging assessments, treatments, AEs, and vascular damage were analyzed descriptively. Student’s t-test or the Mann-Whitney U test was used to compare continuous variables depending on their distribution. Cumulative rates of clinical remission up to Week 52 were analyzed using the Kaplan-Meier method and the time to clinical remission was compared between groups using log-rank tests. Factors associated with achieving sustained clinical remission at Week 52 were analyzed using a logistic regression model with sex, age at onset, aortic regurgitation on cardiac ultrasound, cranial signs and symptoms, and signs and symptoms associated with large-vessel lesions at baseline as covariates. Statistical significance was set as 2-tailed P<0.05. All analyses were performed using JMP version 13.5 (SAS Institute Inc., Cary, NC, USA).

Results

Baseline Characteristics of Study Patients

Overall, 184 participants were registered in the JPVAS large-vessel vasculitis retrospective cohort for TAK. After excluding 31, 24, and 1 patient due to recurrence, many missing data, and non-Japanese nationality, respectively, 129 patients with newly diagnosed TAK were analyzed (Figure). Clinical characteristics and laboratory data of the patients are presented in Table 1. The mean (±SD) age at onset was 35±18 years. Of the patients, 90 (70%) were diagnosed with the disease at age ≤40 years and 14 (11%) were diagnosed at age <18 years. The male-to-female ratio was approximately 1 : 5. The most frequent symptoms were those associated with large-vessel lesions, followed by systemic symptoms. Laboratory tests represented moderate-to-severe inflammation, with increased white blood cell counts, anemia, hypoalbuminemia, and elevations in CRP levels, the erythrocyte sedimentation rate, and immunoglobulin G. The mean (±SD) CRP level was 6.1±5.4 mg/dL. Among the patients tested for the HLA-B52 allele (n=60), 63% were positive. Ultrasound cardiography was performed in 114 patients; the mean left ventricular ejection fraction was not decreased in these patients, and 34 (30%) had aortic regurgitation. Of the patients included in the study, 27 (21%) had hypertension, 13 (10%) had dyslipidemia, 7 (5%) had diabetes, 7 (5%) had a history of ischemic heart disease, 7 (5%) had a history of stroke, 3 (2%) had chronic lung disease, 3 (2%) had osteoporosis, and 2 (2%) had glaucoma.²²

Figure.

Flowchart of patient follow-up. Of the 184 participants registered in the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) large-vessel vasculitis retrospective cohort for Takayasu arteritis (TAK), 31 and 24 patients were excluded because of recurrence and many missing data respectively. Thus, 129 patients with newly-diagnosed TAK were analyzed in this study. PSL, prednisolone.

Table 1.

Clinical Characteristics and Laboratory Data of Patients With Newly Diagnosed Takayasu Arteritis (n=129)

Age (years)	35.4±18.1
Sex (no. males/females)	21/108
Body mass index (kg/m2)	21.8±4.5
Estimated age at onset
≤20 years	33 (26)
≥21 and ≤30 years	32 (25)
≥31 and ≤40 years	25 (19)
≥41 and ≤50 years	11 (9)
≥51 and ≤70 years	18 (14)
≥71 years	10 (8)
Clinical symptoms
Systemic symptoms
Fever (>38℃)	42 (33)
Other systemic symptomsA	86 (67)
Musculoskeletal disordersB	25 (19)
Cranial signs and symptoms	30 (23)
Headache	18 (14)
Visual disturbance	8 (6)
Visual loss	0 (0)
Others	4 (3)
Jaw claudication	6 (5)
Jaw pain	4 (3)
Signs and symptoms of large-vessel lesion	105 (81)
Symptoms of the neck	61 (47)
Symptoms of the upper limbs	32 (25)
Symptoms of the lower limbs	10 (8)
Chest pain, dyspnea	31 (24)
Thoraco-abdominal bruit	39 (30)
RAS-associated hypertension	7 (5)
Ulcerative colitis	7 (5)
Laboratory tests
WBC (/mm3)	8,935±3,072
Hb (g/dL)	10.9±1.9
Alb (g/dL)	3.5±0.7
Cr (mg/dL)	0.62±0.21
CRP (mg/dL)	6.1±5.4
ESR (mm/h)	76±37
IgG (mg/dL)	1,662±394
HLA-B52 (n=60)	38 (63)
HLA-B67 (n=50)	3 (6)
UCG findings (n=114)
Aortic regurgitation	34 (30)
Right ventricular overload	16 (14)
LV asynergy	10 (9)
LVEF (%)	63.1±9.5

Data are presented as the mean±SD or n (%). ^AOther systemic symptoms include general fatigability, easy fatigability, and body weight loss. ^BMusculoskeletal disorders include myalgia, arthralgia, and arthritis. Alb, albumin; Cr, creatinine; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; HLA, human leukocyte antigen; LV, left ventricular; LVFF, left ventricular ejection fraction; RAS, renal artery stenosis; UCG, ultrasound cardiography; WBC, white blood cells.

Vascular Imaging Assessments and Classification of TAK

Vascular involvement at 14 sites of the aorta and its major branches was evaluated, as described in the Methods, using the findings of imaging studies (Table 2). Wall thickening and stenosis were frequently detected, in 120 (93%) and 77 (60%) patients, respectively. However, aneurysm (10 patients; 8%) and dissection (3 patients; 2%) were rare.²³ Any vascular lesion was seen in the carotid arteries, left subclavian artery, aortic arch, and descending aorta in more than half the patients. Interestingly, lesions in the left subclavian artery were more prevalent than those in the right subclavian artery, consistent with previous reports.²⁴

Table 2.

Vascular Involvement in the Aorta and Its Major Branches

Site of aorta and its primary branches	Any findingA (n=129)	Wall thickening (n=129)	Stenosis (n=129)	Aneurysm (n=129)	Dissection (n=129)	Positive PET-CT (n=53)
Any sites or branches	128 (99)	120 (93)	77 (60)	10 (8)	3 (2)	50 (94)
Left carotid artery	88 (68)	76 (59)	37 (29)	3 (2)	0 (0)	21 (40)
Right carotid artery	81 (63)	68 (53)	33 (26)	2 (2)	0 (0)	27 (51)
Vertebral artery	14 (11)	6 (5)	11 (9)	0 (0)	0 (0)	0 (0)
Left subclavian artery	80 (62)	59 (46)	44 (34)	3 (2)	0 (0)	17 (32)
Right subclavian artery	45 (35)	29 (22)	23 (18)	0 (0)	0 (0)	13 (25)
Left axillary artery	16 (12)	10 (8)	11 (9)	0 (0)	0 (0)	2 (4)
Right axillary artery	9 (7)	4 (3)	6 (5)	0 (0)	0 (0)	2 (4)
Brachiocephalic artery	48 (37)	40 (31)	12 (9)	3 (2)	0 (0)	10 (19)
Pulmonary artery	15 (12)	7 (5)	5 (4)	0 (0)	0 (0)	6 (11)
Ascending aorta	63 (49)	49 (38)	3 (2)	2 (2)	1 (1)	27 (51)
Aortic arch	74 (57)	63 (49)	4 (3)	0 (0)	0 (0)	32 (60)
Descending aorta	68 (53)	56 (43)	13 (10)	3 (2)	0 (0)	23 (43)
Abdominal aorta	57 (44)	47 (36)	10 (8)	1 (1)	2 (2)	17 (32)
Renal artery	23 (18)	16 (12)	18 (14)	0 (0)	1 (1)	2 (4)

Data are presented as n (%). ^AAny finding includes wall thickening, stenosis, aneurysm, and dissection based on imaging studies and positron emission tomography-computed tomography scans.

In each patient, the Numano classification of TAK was evaluated.^8,25,26 In this study, 20 (16%) patients had Type I, 21 (16%) had Type IIa, 26 (20%) had Type IIb, 1 (1%) had Type III, 3 (2%) had Type IV, and 58 (45%) had Type V TAK.

Treatment

GC was administered at baseline to 125 (96.9%) patients (Table 3). The mean (±SD) initial dosage of prednisolone was 35.8±12.8 mg/day or 0.68±0.25 mg/kg/day. During the 2-year observation period, 11 (9%) patients received methylprednisolone pulse therapy. The mean dose of prednisolone decreased to 13.5 mg/day (0.26 mg/kg/day), 10.6 mg/day (0.20 mg/kg/day), and 8.3 mg/day (0.16 mg/kg/day) at Weeks 24, 52, and 104, respectively.

Table 3.

Treatment With Prednisolone and Immunosuppressive Drugs (n=129)

Prednisolone
Initial dose of PSL (n=125)
mg/day	35.8±12.8
mg/kg/day	0.68±0.25
mPSL pulse therapyA	11 (9)
Dose of PSL at Week 24 (n=119)
mg/day	13.5±4.8
mg/kg/day	0.26±0.10
Dose of PSL at Week 52 (n=116)
mg/day	10.6±4.9
mg/kg/day	0.20±0.09
Dose of PSL at Week 104 (n=109)
mg/day	8.3±4.1
mg/kg/day	0.16±0.08
Use of immunosuppressive drugs at baseline	21 (16)
Methotrexate	16 (12)
Azathioprine	3 (2)
Tacrolimus	0 (0)
Cyclosporine A	0 (0)
Cyclophosphamide	2 (2)
Mycophenolate mofetil	0 (0)
Use of biologics at baseline	4 (3)
Infliximab	2 (2)
Tocilizumab	2 (2)
Use of immunosuppressive drugs in the 2 years after baseline	76 (59)
Methotrexate	57 (44)
Azathioprine	26 (20)
Tacrolimus	12 (9)
Cyclosporine A	5 (4)
Cyclophosphamide	4 (3)
Mycophenolate mofetil	2 (2)
Use of biologics in the 2 years after baseline	22 (17)
Infliximab	14 (11)
Tocilizumab	12 (9)

Continuous data are shown as the mean±SD; categorical data are given as n (%). ^AUsed within 2 years after baseline. mPSL, methyl prednisolone; PSL, prednisolone.

At treatment initiation, immunosuppressive drugs and biologics were used in 21 (16%) and 4 (3%) patients, respectively. Two patients each were treated with tocilizumab monotherapy and combination therapy with methotrexate and infliximab. During the 2-year observation period, 76 (59%) patients used immunosuppressive drugs and 22 (17%) used biologics.

Clinical Remission and Sustained Clinical Remission

Of the 129 patients enrolled in this analysis, 113 achieved clinical remission (i.e., the absence of all components of the disease activity domain of the draft core set of remission criteria of the JPVAS) at least once by Week 24, meanwhile 118 achieved remission by Week 52. In all, 48 patients had persistent findings of the disease activity domain without aggravation for 6 months by Week 52 (Supplementary Table 1), which were deemed inactive lesions in this analysis, as mentioned in the Methods section. Using Kaplan-Meier analysis, cumulative clinical remission rates at Weeks 24 and 52 were 88.7% and 92.7%, respectively (Supplementary Figure 1).

At Week 24, 107 (82.9%) patients were in clinical remission; some patients achieved clinical remission before Week 24, but not at Week 24. In all, the absence of all components of the disease activity domain was maintained in 71 (55.0%) patients until Week 52, and 51 (39.5%) patients received daily prednisolone at ≤10 mg, satisfying the criteria of sustained clinical remission at Week 52. At Week 104, 33 (25.6%) patients achieved sustained clinical remission (Figure).

The time to clinical remission by Week 52 was compared between subgroups of patients based on HLA-B52 status, the presence or absence of aortic regurgitation at baseline, Numano classification, the use of immunosuppressive drugs, and age at diagnosis (≤20 and >20 years); however, no significant differences were observed (Supplementary Figure 2). Factors associated with sustained clinical remission at Week 52 were analyzed using a multivariable logistic regression model. Signs and symptoms linked to large-vessel lesion at baseline (symptoms of the neck, upper limbs, and lower limbs, chest pain, dyspnea, thoraco-abdominal bruit, or renal artery stenosis-associated hypertension) were significantly negatively associated with sustained clinical remission at Week 52 (odds ratio 0.24; 95% confidence interval 0.08–0.75) after adjusting for covariates including sex, age at onset, aortic regurgitation on cardiac ultrasound, cranial signs and symptoms, and signs and symptoms associated with large-vessel lesions at baseline (Supplementary Table 2).

By Week 104, only 3 patients had died. The overall survival rate was 97.5% in our study patients with TAK (Supplementary Figure 3).

AEs

During the follow-up periods, 3 patients died: 1 due to intestinal rupture secondary to intestinal obstruction and 2 due to unknown reasons. After treatment initiation, the following AEs of interest were reported: 5 patients with serious infections, including 2 cases of Pneumocystis jirovecii pneumonia, and 1 each of herpes zoster, herpes simplex, and acute colitis; 1 cardiovascular AE requiring hospitalization (i.e., Bentall operation); 2 cerebrovascular AEs requiring hospitalization (i.e., stroke); 5 patients with diabetes requiring drug therapy; and 1 patient with psychiatric symptoms requiring drug therapy (i.e., GC-associated psychosis).

Discussion

In the present study we elucidated the clinical characteristics, treatment response, and associated factors in patients with newly diagnosed TAK in Japan. Most patients with TAK achieved clinical remission by Week 52; however, sustained clinical remission at Week 52 was observed in only 40% of patients. Patients with signs and symptoms associated with large-vessel lesions at baseline were less likely to achieve sustained clinical remission at Week 52.

Some single-center studies^13–15 and 1 study using the database of the Japanese Ministry of Health, Labour, and Welfare for intractable diseases⁸ on TAK have been reported since 2000. The present study is the first in which all data were collected from the leading facilities for the treatment of TAK in Japan. The clinical characteristics in our study cohort corroborate previous studies regarding age of onset and sex ratio. Most of the clinical symptoms at diagnosis were similar to those reported previously, except for the increase in symptoms related to the neck and lungs and the decline in renal artery stenosis-associated hypertension. In the present study, laboratory test results indicated the active disease status of the registered patients. The prevalence of aortic regurgitation detected using cardiac ultrasound was 30%, which is similar to that reported previously.^8,14 Thus, our cohort confirmed the clinical characteristics of patients with TAK at diagnosis in Japan. We further compared the clinical characteristics of TAK patients enrolled in this Japanese study with those in other countries (Supplementary Table 3). TAK patients in the present study had less comorbid hypertension than those in other countries. The prevalence of ischemic symptoms and vascular bruits was comparable between the Japanese patients and those in other countries. Japanese patients more frequently experienced fever and aortic regurgitation than those in other countries.

TAK diagnosis and evaluation require blood vessel imaging.³ Recent developments in imaging modalities can provide precise information on arterial trees in patients with TAK. In addition to CTA, MRA, and ultrasound, ¹⁸FDG-PET has been added to the set of imaging modalities.^11,12 In our study, ¹⁸FDG-PET was conducted in approximately half the patients to evaluate disease activity. The proportions of patients with lesions of the carotid artery and descending and abdominal aorta were higher than those reported by the Diagnostic and Classification Criteria in Vasculitis (DCVAS) cohort and a North American cohort.²⁴ These results may demonstrate differences in the distribution of affected arteries between Japanese and other populations. In terms of Numano’s classification, less than 20% of the Japanese patients with TAK in our cohort had Type III+IV, compared with approximately 20–25% of patients with TAK in other countries (Supplementary Table 4). Conversely, both TAK cohorts in Japan (present study; Supplementary Table 4) had more than 30% Type IIa+IIb TAK, which was more than in any other country.

In the present study, the proportion of patients with Numano Type V TAK was higher than reported in previous studies in Japan,^3,8,14,15 which could be attributed to changes in the distribution of arterial involvement in patients with TAK in recent years or the progress in imaging modalities, including PET-CT, to detect lesions of the abdominal aorta or renal arteries. A future study to confirm this trend is warranted.

The treatment goal of TAK is to control vascular inflammation and prevent irreversible organ damage. In our study, the cumulative clinical remission rate at Weeks 24 and 52 was 88.7% and 92.7%, respectively. In an Indian study, 85.3% of adult TAK patients achieved clinical remission within an average observation period of 27 months.²⁷ In a Turkish study, 80.7% of adult TAK patients achieved clinical remission.²⁸ Thus, the clinical remission rate in our study was comparable to those of other countries.

To achieve a favorable outcome, early diagnosis and treatment of TAK are crucial. Oral GCs have been most frequently used as the initial treatment for TAK.^3,19,20 In the present study, moderate doses of prednisolone were administered orally as an initial treatment. However, prednisolone monotherapy often failed to maintain clinical remission during tapering or induced prednisolone-associated AEs.^16,29 Thus, the use of non-GC immunosuppressive agents for TAK has gained widespread attention.^30,31 In recent guidelines for TAK, immunosuppressants and biologics are recommended as adjunctive or initial therapy with GC.^3,19,20 The optimal timing for administering non-GC immunosuppressive agents remains to be determined. In our study, only one-sixth of the patients were administered an immunosuppressant within 2 weeks of treatment initiation; however, the use of these drugs had minimal effects on the achievement of clinical remission. Further studies are required to evaluate the efficacy and safety of these secondary agents and to determine the appropriate timing for their addition.

During their clinical course, patients with TAK are prone to relapse. Comarmond et al.²² analyzed 318 patients with TAK and reported a 58.6% relapse-free survival rate at the 5-year follow-up. Male sex, elevated CRP levels, and carotidynia were associated with relapse-free survival. In an Indian study, the cumulative relapse-free survival at 1, 3, 5, and 10 years was 93%, 73%, 66%, and 52%, respectively.²³ Baseline CRP levels, disease extent index for TAK, and Numano Type IV were independently associated with sustained inactive disease.²³ In the present study, signs and symptoms linked to large-vessel lesions at baseline were significantly negatively associated with sustained clinical remission at Week 52. A possible reason for the higher relapse rate in patients exhibiting signs and symptoms linked to large-vessel lesions could be the association of such symptoms with high disease activity. The high disease activity may contribute to a shorter treatment response and an increased risk of relapse. However, our present analysis failed to find an association between inflammatory markers and relapse. Our results indicate the need for intensive treatments and meticulous vascular imaging follow-up in such patients.

This study has several limitations. First, selection biases should be considered due to the retrospective study design. Second, the number of study patients was small because TAK is a rare disease. Third, patients who were newly diagnosed and started treatment between 2007 and 2014 were enrolled in this study. At that time, PET-CT was not covered by health insurance for the evaluation of the disease activity of TAK in Japan. Thus, the vascular involvement in the present study could be underestimated. Fourth, because this was an observational study, imaging tests were not routinely performed by the attending physician during the follow-up periods, leading to a possible underscoring of vascular damage.

In conclusion, we elucidated the clinical characteristics and responses to treatment in patients with TAK in Japan between 2007 and 2014. Patients with signs and symptoms linked to large-vessel lesions at baseline were less likely to achieve sustained clinical remission at Week 52.

Acknowledgments

The authors acknowledge all the investigators in the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS). In addition to the authors, the following investigators and institutions participated in this study: Hiroshi Akazawa and Issei Komuro (Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine); Tetsuya Horita (Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine); Shunsuke Furuta (Department of Allergy and Clinical Immunology, Chiba University Hospital); Atsushi Kawakami (Department of Immunology and Rheumatology, Clinical Neuroscience and Neurology, Endocrinology, and Metabolism, Nagasaki University Graduate School of Biomedical Sciences); Takashi Wada at Division of Nephrology, Department of Laboratory Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Faculty of Medicine, Kanazawa University); Yasuhiro Katsumata (Department of Rheumatology, School of Medicine, Tokyo Women’s Medical University); Satoshi Ito (Niigata Rheumatic Center); and Shinichi Takeda (Kurobe City Hospital).

Sources of Funding

This work was supported by grants from the Ministry of Health, Labour, and Welfare, Japan (H29-nanchitou (nan)-ippan-018 and 23FC1019) and the Japan Agency for Medical Research and Development (AMED; JP17ek0109121).

Disclosures

H.A.U. belongs to the Department of Chronic Kidney Disease and Cardiovascular Disease which is endowed by Olba Healthcare Holdings, Boehringer Ingelheim, and Terumo Corporation. T.S. has received research grants from AsahiKASEI Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo., and Ono Pharmaceutical. H.Y. has received speaker honoraria from Chugai and consultancy fees from Janssen. Y. Murakawa has received research grants from Taisho Pharmaceutical Co., and honoraria from Astellas Pharma Inc., Eisai Co., UCB Japan Co., and MSD. M.H. has received research grants from AbbVie Japan GK, Chugai Pharmaceutical Co., Mitsubishi Tanabe Pharma Co., and Pfizer Japan Inc. The remaining authors have no conflicts of interest to declare.

IRB Information

The study was approved by the Ethics Committee of Tokyo Medical and Dental University (No. 2084).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0178

References

• 1.   Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, et al. Takayasu arteritis. Ann Intern Med 1994; 120: 919–929.
• 2.   Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 2013; 65: 1–11.
• 3.   Isobe M, Amano K, Arimura Y, Ishizu A, Ito S, Kaname S, et al. JCS 2017 guideline on management of vasculitis syndrome: Digest version. Circ J 2020; 84: 299–359.
• 4.   Mason JC. Takayasu arteritis--advances in diagnosis and management. Nat Rev Rheumatol 2010; 6: 406–415.
• 5.   Watts R, Al-Taiar A, Mooney J, Scott D, Macgregor A. The epidemiology of Takayasu arteritis in the UK. Rheumatology (Oxford) 2009; 48: 1008–1011.
• 6.   Russo RAG, Katsicas MM. Takayasu arteritis. Front Pediatr 2018; 6: 265.
• 7.   JCS Joint Working Group. Guideline for management of vasculitis syndrome (JCS 2008). Circ J 2011; 75: 474–503.
• 8.   Watanabe Y, Miyata T, Tanemoto K. Current clinical features of new patients with Takayasu arteritis observed from cross-country research in Japan: Age and sex specificity. Circulation 2015; 132: 1701–1709.
• 9.   Terao C, Yoshifuji H, Kimura A, Matsumura T, Ohmura K, Takahashi M, et al. Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population. Am J Hum Genet 2013; 93: 289–297.
• 10.   Soto ME, Vargas-Alarcón G, Cicero-Sabido R, Ramírez E, Alvarez-León E, Reyes PA. Comparison distribution of HLA-B alleles in Mexican patients with Takayasu arteritis and tuberculosis. Hum Immunol 2007; 68: 449–453.
• 11.   Isobe M. Takayasu arteritis revisited: Current diagnosis and treatment. Int J Cardiol 2013; 168: 3–10.
• 12.   Tezuka D, Haraguchi G, Ishihara T, Ohigashi H, Inagaki H, Suzuki J, et al. Role of FDG PET-CT in Takayasu arteritis: Sensitive detection of recurrences. JACC Cardiovasc Imaging 2012; 5: 422–429.
• 13.   Yoshida M, Watanabe R, Ishii T, Machiyama T, Akita K, Fujita Y, et al. Retrospective analysis of 95 patients with large vessel vasculitis: A single center experience. Int J Rheum Dis 2016; 19: 87–94.
• 14.   Fukui S, Iwamoto N, Shimizu T, Umeda M, Nishino A, Koga T, et al. Fewer subsequent relapses and lower levels of IL-17 in Takayasu arteritis developed after the age of 40 years. Arthritis Res Ther 2016; 18: 293.
• 15.   Ohigashi H, Haraguchi G, Konishi M, Tezuka D, Kamiishi T, Ishihara T, et al. Improved prognosis of Takayasu arteritis over the past decade: Comprehensive analysis of 106 patients. Circ J 2012; 76: 1004–1011.
• 16.   Misra DP, Rathore U, Patro P, Agarwal V, Sharma A. Corticosteroid monotherapy for the management of Takayasu arteritis: A systematic review and meta-analysis. Rheumatol Int 2021; 41: 1729–1742.
• 17.   Kim ESH, Beckman J. Takayasu arteritis: Challenges in diagnosis and management. Heart 2018; 104: 558–565.
• 18.   Keser G, Direskeneli H, Aksu K. Management of Takayasu arteritis: A systematic review. Rheumatology (Oxford) 2014; 53: 793–801.
• 19.   Hellmich B, Agueda A, Monti S, Buttgereit F, de Boysson H, Brouwer E, et al. 2018 update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2020; 79: 19–30.
• 20.   Maz M, Chung SA, Abril A, Langford CA, Gorelik M, Guyatt G, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of giant cell arteritis and Takayasu arteritis. Arthritis Rheumatol 2021; 73: 1349–1365.
• 21.   Sugihara T, Nakaoka Y, Uchida HA, Yoshifuji H, Maejima Y, Watanabe Y, et al. Establishing clinical remission criteria and the framework of a treat-to-target algorithm for Takayasu arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour and Welfare for intractable vasculitis. Mod Rheumatol 2022; 32: 930–937.
• 22.   Comarmond C, Biard L, Lambert M, Mekinian A, Ferfar Y, Kahn JE, et al. Long-term outcomes and prognostic factors of complications in Takayasu arteritis: A multicenter study of 318 patients. Circulation 2017; 136: 1114–1122.
• 23.   Goel R, Danda D, Joseph G, Ravindran R, Kumar S, Jayaseelan V, et al. Long-term outcome of 251 patients with Takayasu arteritis on combination immunosuppressant therapy: Single centre experience from a large tertiary care teaching hospital in southern India. Semin Arthritis Rheum 2018; 47: 718–726.
• 24.   Gribbons KB, Ponte C, Carette S, Craven A, Cuthbertson D, Hoffman GS, et al. Patterns of arterial disease in Takayasu arteritis and giant cell arteritis. Arthritis Care Res (Hoboken) 2020; 72: 1615–1624.
• 25.   Hata A, Noda M, Moriwaki R, Numano F. Angiographic findings of Takayasu arteritis: New classification. Int J Cardiol 1996; 54(Suppl): S155–S163.
• 26.   Isohisa I, Numano F, Maezawa H, Sasazuki T. HLA-Bw52 in Takayasu disease. Tissue Antigens 1978; 12: 246–248.
• 27.   Danda D, Goel R, Joseph G, Kumar ST, Nair A, Ravindran R, et al. Clinical course of 602 patients with Takayasu’s arteritis: Comparison between childhood-onset versus adult onset disease. Rheumatology (Oxford) 2021; 60: 2246–2255.
• 28.   Karabacak M, Kaymaz-Tahra S, Şahin S, Yıldız M, Adroviç A, Barut K, et al. Childhood-onset versus adult-onset Takayasu arteritis: A study of 141 patients from Turkey. Semin Arthritis Rheum 2021; 51: 192–197.
• 29.   Mutoh T, Shirai T, Fujii H, Ishii T, Harigae H. Insufficient use of corticosteroids without immunosuppressants results in higher relapse rates in Takayasu arteritis. J Rheumatol 2020; 47: 255–263.
• 30.   Barra L, Yang G, Pagnoux C; Canadian Vasculitis Network (CanVasc). Non-glucocorticoid drugs for the treatment of Takayasu’s arteritis: A systematic review and meta-analysis. Autoimmun Rev 2018; 17: 683–693.
• 31.   Ohigashi H, Tamura N, Ebana Y, Harigai M, Maejima Y, Ashikaga T, et al. Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment. J Cardiol 2017; 69: 774–778.