Clinical Rheumatology

Pulmonary artery involvement in Takayasu arteritis: a retrospective study in Chinese

population
--Manuscript Draft--

Manuscript Number: CLRH-D-19-00822R1

Full Title: Pulmonary artery involvement in Takayasu arteritis: a retrospective study in Chinese
population

Article Type: Original Article

Abstract: Background: Takayasu's arteritis (TA) may involve the pulmonary artery, which
signifies a poor prognosis. This study investigated features of TA patients with
pulmonary artery involvement.
Methods: One hundred and twenty-six inpatients diagnosed with TA were
retrospectively studied. The clinical data of TA patients with and without pulmonary
artery involvement were compared. The imaging features of pulmonary artery lesions
in TA patients were evaluated. The treatment responses of pulmonary artery lesions
were described and the drug regimens in different treatment response groups were
compared.
Results: Among the patients with TA, 15.9% showed associated pulmonary artery
involvement. The disease durations were significantly longer in patients with pulmonary
artery involvement than in those without [108.0 (53.5, 222.0) vs. 36.0 (12.0, 120.0)
months, p=0.038]. Hemoptysis was more common in TA patients with pulmonary artery
involvement than in those without (15.0%, 3 cases vs. 0.0%, p< 0.001). TA patients
with disease duration longer than 5 years showed a 3.7-fold higher risk of pulmonary
artery involvement compared to those with a disease duration less than 5 years (odds
ratio: 3.699, p=0.013, 95% confidence interval: 1.316-10.394). The most common
imaging manifestations of pulmonary artery involvement were stenosis and occlusion.
Among the 6 patients who had a good response to treatment of pulmonary artery
lesions, 5 were treated with the interleukin-6 receptor antagonist tocilizumab.
Conclusions: TA patients with pulmonary artery involvement have a longer course of
disease and more symptoms of hemoptysis. TA-related pulmonary artery lesions are
more commonly manifested as stenosis and occlusion. Tocilizumab may be effective
for TA-related pulmonary vascular disease.

Response to Reviewers: Mr./Ms. Editor,

Thank you for your letter and the reviewer’s comments concerning our manuscript
entitled " Pulmonary artery involvement in Takayasu arteritis: a retrospective study of
Chinese population".
The comments are helpful for revising and improving our paper, as well as the
important guiding significance to our researches. We have studied comments carefully
and have made corrections which we hope meet with approval. The main corrections
in the paper and the responds to you and the referee’s comments are as flowing:
Response to Reviewer #2:
- 1. Introduction - the last paragraph of this chapter ("To this end, we compared the
clinical features of TA patients with and without pulmonary artery involvement in our
hospital. The pulmonary artery imaging features of TA patients with pulmonary artery
involvement were described. Moreover, we analyzed the changes in pulmonary artery
lesions after treatment.") pertains to the "Methods" section and is redundant.
Response: Thank you for your suggestion. We have deleted this paragraph from the
introduction in the revision of the manuscript. (Please see section of Introduction)
- 2.4. Statistics:
-- the authors state in the Methods section that they used univariate logistic regression,
but from the 3.2 section of Results the reader can see that the models are multivariate
-- the authors should state briefly why they chose the stepwise method to perform their
regressions
-- regression reporting is incomplete: brief information regarding the chi square of the
models (value, degrees of freedom, p value), a form of R square (e.g. Nagelkerke),
variance
-- it is not "95% confidence index", but "95% confidence interval"
-- the authors should mention the limitation of performing regression on such small
sample size

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 Response:
1.We have corrected the mistake by using the sentence as follow: “Multivariate logistic
regression analysis was used to determine the independent risk factors related to TA
with pulmonary artery involvement.”
2.As TA is a rare clinical disease, the number of cases in this study is small. Stepwise
regression was used to screen statistically significant variables into the regression
equation to identify the risk factors most significantly associated with pulmonary
vascular involvement. Therefore, we add the sentence as follows to explain the reason
why choosing stepwise method to perform our regression: “All baseline variables
associated with TA involvement in pulmonary arteries were analyzed using stepwise
method to create the best performing logistic regression model.”
3.We added the information according to your suggestion except “variance”. All
variables in our regression equation are binary variables, and so this parameter cannot
be obtained. (Please see section of Results)
4.We have corrected the mistake by using the phrase as follow: "95% confidence
interval"(Please see section of Results)
5.We added the limitation of performing regression on such small sample size as
follow: “Lastly, the small sample size may affect the statistical efficiency of the logistic
regression results, and the effect of confounding factors on the results.” (Please see
section of Discussion)

- 2. Methods - brief data about laboratory evaluations are lacking: were lab tests done
by a single laboratory or many, normal ranges in the table etc.
Response:
1.We have added the description about laboratory evaluation as follow: “Lab tests were
done by the laboratory of our hospital.” (Please see section of Methods)
2.We have added the normal ranges, too. (Please see section of Table 2)

Minor comments
- Minor English revision (for example "women under 40 years old")
Response: Thank you for your suggestion. We have corrected the English revision as
follow: “women younger than40 years of age" (Please see section of Introduction). At
the same time, we invited professional companies to revise the language of our
manuscript.
- 1. Introduction: the authors state that "TA is likely to be underestimated" - none and
all diseases are underestimated, maybe the authors meant to characterize TA's
prevalence or incidence
Response: We have corrected the English revision as follow: “prevalence of TA is likely
to be underestimated”
- 1. Introduction: there is no point in abbreviating single words in the article's text, there
is no gain in word count (for example "cyclophosphamide (CTX) and methotrexate
(MTX)")
Response: All such abbreviations have been removed from the text.
- 1. Introduction: "steroid-sparing effects" - the current literature prefers the term
"glucocorticoid-sparing"
Response: We modified the term according your suggestion. Thank you very much.
- 3. Results: for the comparission of hemoptysis the authors report "p = 0.000", which
technically is impossible, maybe "p <0.001" would be more appropriate
Response: We modified it according your suggestion. Thank you.
- Double abbreviations:
-- "erythrocyte sedimentation rate (ESR)" is abbreviated 2 times: once in section 2.1
and once in section 3.2
-- "cyclophosphamide (CTX)", "methotrexate (MTX)" and glucocorticoids (GCS)" are
also abbreviated 2 times
Response: Thank you for your suggestion. We have modified all the abbreviations in
our manuscription.
- Table 1:
-- the authors might take into consideration to report numeric values, except p values,
using a single decimal for easy reading
Response: We have made modifications according to your suggestion. (Please see
section of Table 1 and Table 2)
-- the authors might take into consideration to split Table 1 into 2 tables: one with
demographics, clinics and treatment and the other with the laboratory evaluations
Response: We have made modifications according to your suggestion. (Please see

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 section of Table 1 and Table 2). Thank you very much.
 
Response to Reviewer #3:
This paper uses the retrospective data of 126 patients diagnosed with Takayasu
Arteritis to demonstrate clinical features, imaging characteristics, and treatment options
of pulmonary artery involvement. The topic is very interesting and important to address
as PA involvement in TA is not uncommon.
This paper, however, needs a lot of work.
1.Introduction:
The author states that the lack of specificity of symptoms, laboratory tests, and
biomarkers, many patients cannot be diagnosed in time, hence, TA is likely to be
underestimated. It is a very strong statement for the context, unless backed by proven
studies or reports.
Response: Thank you for your suggestion. This statement in the text is really too
strong. We have deleted the inappropriate statement in the article. (Please see section
of Introduction)
2.Second, Authors have stated no literature available on PA involvement in TA
patients, or available mainly in case reports. Please provide at least 1-2 references of
case reports.
However, I disagree with authors here. References 18-23, which have been cited in the
discussion section clearly indicate that studies are available on this particular topic and
PA involvement in TA has been reported between 7 to 21%. (ref. 18-23). I would
recommend modifying the language with appropriate references.
Response: Thank you for your suggestion. We modified the incorrect statement as
followed: “TA with pulmonary artery involvement has gradually concerned by people.
Pulmonary artery involvement has been mentioned in several studies of TA from
different countries. (1-3) Sharma et al. (4) described the incidence and features of
pulmonary artery involved TA in 1990. In their study, among 42 TA patients, 6 were
confirmed to have pulmonary arterial involvement by intravenous digital subtraction
angiography. Yamada et al. (5) studied the angiographic characteristic of pulmonary
involvement in TA. Recently, Brennan et al. (6) studied cardiopulmonary involvement in
TA, and analyzed some of the characteristics of pulmonary artery involvement in TA. In
the present study, we performed a systematic analysis to investigate the clinical,
imaging, therapeutic, and prognostic characteristics of pulmonary artery involvement in
a large sample of TA patients.” (Please see section of Introduction)
Ref:
1.Bicakcigil M, Aksu K, Kamali S, Ozbalkan Z, Ates A, Karadag O, et al. Takayasu's
arteritis in Turkey - clinical and angiographic features of 248 patients. Clin Exp
Rheumatol 2009;27:S59-64.
2.Arnaud L, Haroche J, Limal N, Toledano D, Gambotti L, Costedoat Chalumeau N, et
al. Takayasu arteritis in France: a single-center retrospective study of 82 cases
comparing white, North African, and black patients. Medicine (Baltimore) 2010;89:1-17.
3.Yang L, Zhang H, Jiang X, Zou Y, Qin F, Song L, et al. Clinical manifestations and
longterm outcome for patients with Takayasu arteritis in China. J Rheumatol
2014;41:2439-2446.
4.Sharma S, Kamalakar T, Rajani M, Talwar KK, Shrivastava S. The incidence and
patterns of pulmonary artery involvement in Takayasu's arteritis. Clin Radiol
1990;42:177-181.
5.Yamada I, Shibuya H, Matsubara O, Umehara I, Makino T, Numano F, et al.
Pulmonary artery disease in Takayasu's arteritis: angiographic findings. AJR Am J
Roentgenol 1992;159:263-269.
6.Brennan DN, Warrington KJ, Crowson CS, Schmidt J, Koster MJ. Cardiopulmonary
involvement in Takayasu's arteritis. Clin Exp Rheumatol 2018;36 Suppl 111:46-50.

3.Method:
Number of patients and selected patients for 2 groups (PA vs. non-PA) is confusing.
Total number of patients are 126, and all patients satisfied the modified Ishikawa
criteria. Then authors reported 41 patients underwent pulmonary angiography, and 20
were diagnosed with TA+PA. Then authors reported dividing these patients into two
groups.
From what I understood, group division was done with total of 41 patients who
underwent Pulmonary Angiography, with 20 with PA, and remaining 21 without PA. If
authors want to include all 126 patients in the study, they should clearly indicate
reasons for including 85 TA patients who didn't undergo Pulmonary angiography for

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 diagnosis of PA involvement, and what were the reasons for not performing
angiography in those 85 patients.
If angiography was not performed in those 85 patients, there is a higher possibility of
missing diagnosis in these patients. It this case, the study method is incorrect, and
results are inconclusive.
Again, 10 TA+PA patients underwent re-assessment of PA lesion after treatment.
Response: Thank you for your suggestion. This study does have some limitations. This
is a retrospective study. TA is a rare disease, only a few of TA patients have pulmonary
artery involvement. Assessment of pulmonary artery involvement in TA is not
mentioned in the latest guidelines. (1) In the rheumatology department of our hospital,
all TA patients should be screened for risk of pulmonary artery involvement by two
experienced physicians. TA patients who had respiratory symptom, or imaging clues
(pulmonary hypertension, or abnormal right cardiac structure and function as estimated
by echocardiography or pulmonary artery involvement findings through aortography)
were considered to be at high risk of pulmonary artery involvement and were arranged
further pulmonary angiography. Patients who had pulmonary artery involvement
findings through aortography were also scheduled for pulmonary angiography. We
added this in the section of Methods.
Such an approach does have the possibility of missed diagnosis. However, if only 41
patients with pulmonary angiography were analyzed, there would be a selection bias.
In the future, we will design prospective cohort studies to further study TA with
pulmonary artery involvement to solve such problems.
As this study is a retrospective study, because of economic conditions of our patients
and geographical limitations, most of patients live far from hospital, the imaging follow-
up rate is relative low, and we hope to design perspective studies to solve this problem
in the our future work.
Ref:
1.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 2019;0:1-12.
4.About statistical method: I am not sure what multiple stepwise positive logistic
regression is. I believe it should be just multiple stepwise regression.
Also, looking at the variables the descriptive tables, did you test for multicollinearity?
Response:
1.thanks for pointing out our mistake. We modified the incorrect statement according
your suggestion. (Please see section of Methods)
2.All variables in our regression equation are binary variables, and so test for
multicollineraity cannot be performed.
5.Results:
Table 1 provides onset of age (years) for both TA+PA and TA without PA. Is it for TA
diagnosis only? Or When the PA involvement was diagnoses? Need clarification. It
would be interesting to provide when the PA involvement was diagnoses in TA
patients. It would strengthen your findings to support that PA is late manifestation of
TA.
Response:
1.The onset of age (years) provided in Table 1 is for TA diagnosis only. We modified
the description in Table 1. Please see Table 1.
2.In the group of TA with pulmonary artery involvement, the pulmonary artery
involvement was diagnosed as the same time of diagnosis of TA. 11 had respiratory
symptoms and 9 had Imaging clues of pulmonary artery involvement. Respiratory
symptoms were the initial chief complaints in 7 patients. The other 4 patients
developed respiratory symptoms at 7, 60, 110, and 228 months after onset of TA
symptoms, respectively. We add this in the section of Results. Thank you for your
suggestion.
6.I don't see table for Odds ratio. If not included in main tables, please provide as a
supplement.
Response:
Since only one variable in the regression equation had a statistically significant
correlation with pulmonary artery involvement, we did not present the regression
results in a table. In addition, we re-examined the variables in the regression equation
and found that one of the variables which was not suitable to be a variable in the
equation. Therefore, this variable was removed and regression analysis was performed
again. We present the results in words in our manuscript. (Please see section of
Results and Supplementary Material)

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 7.Discussion:
Please provide reference to any standard guidelines for " Since pulmonary
angiography is not routine for TA patients, screening is usually only considered when
respiratory symptoms are present."
195/5000
Response：Assessment of pulmonary artery involvement in TA is not mentioned in the
latest guideline (1). We modified the incorrect statement in the article "Since pulmonary
angiography is not routinely used for TA patients (1), screening is usually only
considered when respiratory symptoms or imaging clues are present." please see the
Discussion section. (Please see section of Discussion)
Ref:
1.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 2019;0:1-12.
8.Authors have stated that it's a first study to compare symptoms of PA in TA patients.
However, its not true. Please refer to these studies,
1. He, Y., Lv, N., Dang, A., & Cheng, N. (2019). Pulmonary Artery Involvement in
Patients with Takayasu Arteritis. The Journal of Rheumatology, jrheum.190045.
doi:10.3899/jrheum.190045
2. https://www.sciencedirect.com/science/article/pii/S0049017211001521?via%3Dihub
These studies found 20 to 42% of TA+PA cases having hemoptysis. Please cite these
studies and discuss your results.
Response: Thank you for your suggestion. In our study, we found that 3 of the 20
patients with pulmonary artery involvement had hemoptysis (15%). In our study, we
found that 3 of the 20 patients with pulmonary artery involvement had hemoptysis
(15%). This ratio is similar to that in the latest study. He et al. reported that the
proportion of hemoptysis in patients with pulmonary artery involvement was 20.3% (1).
However, in an early literature review, Toledano et al. found that the incidence of
hemoptysis was 42.2% (2). In the past, the diagnosis of TA with pulmonary artery
involvement was more dependent on respiratory symptoms, while increasingly more
patients without respiratory symptoms have received a diagnosis of TA with pulmonary
artery involvement through imaging clues in recent years. This may be the main reason
for the decrease in the incidence of hemoptysis in TA with pulmonary artery
involvement in recent studies. We added this to the discussion section of the article.
Ref:
1.He Y, Lv N, Dang A, Cheng N. Pulmonary Artery Involvement in Patients with
Takayasu Arteritis. J. Rheumatol. 2019. doi:10.3899/jrheum.190045
2.Toledano K, Guralnik L, Lorber A, Ofer A, Yigla M, Rozin A, et al. Pulmonary arteries
involvement in Takayasu's arteritis: two cases and literature review. Semin Arthritis
Rheum 2011;41:461-470.

9.Please elaborate your limitations on retrospective study. It would also be better to

include lost to follow up with Angiography, or treatment. Furthermore, retrospective
data is entered by administrators with possibility of human error. One of the limitations
could be possible method of diagnosis of PA involvement as well.

Response: Thanks for your suggestion. We elaborated the limitations as followed: “In
our study, patients who did not have respiratory symptoms or imaging clues did not
receive pulmonary angiography, which could have resulted in missed diagnosis.
Because of our patients’ economic conditions and geographical limitations, most of
them lived far from our hospital, so the imaging follow-up rate was relatively low.
Another limitation could be possible method of diagnosis of pulmonary artery
involvement. Furthermore, retrospective data were entered by administrators so there
is a possibility of human error. Lastly, the small sample size may affect the statistical
efficiency of the logistic regression results, and the effect of confounding factors on the
results.” (Please see section of Discussion)

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Title Page

Full Title

Pulmonary artery involvement in Takayasu arteritis: a retrospective study in Chinese

population

Authors:

Xin Xi1,2, Juan Du3, Jiayi Liu4, Guangfa Zhu2, Guanming Qi5, Lili Pan3

1. Sleep Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

2. Department of Pulmonary and Critical Care, Beijing Anzhen Hospital, Capital Medical

University, Beijing, China.

3. Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical

University, Beijing, China.

4. Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing,

China.

5. Pulmonary and Critical Care Division, Tufts Medical Center, Boston, MA, USA.

Name and Address for Correspondence

Lili Pan. Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital

Medical University.

Address: 2 Anzhen Road, Chaoyang District, Beijing, China.

E-mail: lilypansxmu@sina.com
Abstract

Background: Takayasu's arteritis (TA) may involve the pulmonary artery, which

signifies a poor prognosis. This study investigated features of TA patients with

pulmonary artery involvement.

Methods: One hundred and twenty-six inpatients diagnosed with TA were

retrospectively studied. The clinical data of TA patients with and without pulmonary

artery involvement were compared. The imaging features of pulmonary artery lesions

in TA patients were evaluated. The treatment responses of pulmonary artery lesions

were described and the drug regimens in different treatment response groups were

compared.

Results: Among the patients with TA, 15.9% showed associated pulmonary artery

involvement. The disease durations were significantly longer in patients with

pulmonary artery involvement than in those without [108.0 (53.5, 222.0) vs. 36.0

(12.0, 120.0) months, p=0.038]. Hemoptysis was more common in TA patients with

pulmonary artery involvement than in those without (15.0%, 3 cases vs. 0.0%, p<

0.001). TA patients with disease duration longer than 5 years showed a 3.7-fold higher

risk of pulmonary artery involvement compared to those with a disease duration less

than 5 years (odds ratio: 3.699, p=0.013, 95% confidence interval: 1.316-10.394). The

most common imaging manifestations of pulmonary artery involvement were stenosis

and occlusion. Among the 6 patients who had a good response to treatment of

pulmonary artery lesions, 5 were treated with the interleukin-6 receptor antagonist

tocilizumab.
Conclusions: TA patients with pulmonary artery involvement have a longer course of

disease and more symptoms of hemoptysis. TA-related pulmonary artery lesions are

more commonly manifested as stenosis and occlusion. Tocilizumab may be effective

for TA-related pulmonary vascular disease.

Keywords：Takayasu arteritis, pulmonary artery involvement, disease duration, IL-6

receptor antagonist
Highlights

 Disease duration longer than 5 years is an independent risk factor for pulmonary

artery involvement in TA.

 Hemoptysis is a characteristic clinical symptom of TA with pulmonary artery

involvement.

 Tocilizumab may be more effective for pulmonary artery lesions of TA.

1. Introduction

Takayasu arteritis (TA) is a chronic autoimmune arteritis of unknown etiology

that mostly involves the aorta and its main branches. TA usually affects women

younger than 40 years of age(1, 2). It is more prevalent in Asia, although it is present

worldwide. The incidence of TA is estimated to be 40 cases per million in Japan (3)

and 2.6 to 4.7 cases per million in the United States (4) and United Kingdom (5).

Because of the lack of specificity of symptoms, laboratory tests, and biomarkers,

many patients cannot be diagnosed in time. The inflammatory process of TA can lead

to arterial wall thickening, stenosis, and occlusion, resulting in tissue ischemia and

organ failure. This process may also result in lumen dilatation, aneurysm, or aortic

dissection, which may cause vascular rupture and sudden death (6).

Several cytokines have been proved to be involved in the pathophysiological

process of TA, among which interleukin (IL)-6 plays an important role in the process

of inflammation and fibrosis of the vascular wall. IL-6 levels are often found to be

parallel to TA disease activity (7, 8). The first-line strategy for the treatment of TA is

glucocorticoids. Disease-modifying anti-rheumatic drugs such as cyclophosphamide

and methotrexate are also treatment options (9, 10). In recent years, biological agents

including tocilizumab (IL-6 receptor antagonist), have been demonstrated to yield

good clinical responses and glucocorticoid -sparing effects in patients with TA (11, 12).

Pulmonary artery involvement usually occurs in the late stage of TA; the main

clinical manifestations are dyspnea, chest pain, hemoptysis, and cough (13).

Pulmonary artery involvement may cause pulmonary hypertension, leading to right

heart dysfunction, which seriously affects the prognosis of TA patients (6). TA with

pulmonary artery involvement has gradually concerned by people. Pulmonary artery

involvement has been mentioned in several studies of TA from different countries.

(14-16) Sharma et al. (17) described the incidence and features of pulmonary artery

involved TA in 1990. In their study, among 42 TA patients, 6 were confirmed to have

pulmonary arterial involvement by intravenous digital subtraction angiography.

Yamada et al. (18) studied the angiographic characteristic of pulmonary involvement

in TA. Recently, Brennan et al. (19) studied cardiopulmonary involvement in TA, and

analyzed some of the characteristics of pulmonary artery involvement in TA. In the

present study, we performed a systematic analysis to investigate the clinical, imaging,

therapeutic, and prognostic characteristics of pulmonary artery involvement in a large

sample of TA patients.

2. Patients and methods

2.1.Patients

This retrospective study included 126 patients diagnosed with TA in Beijing

Anzhen Hospital from January 2012 to December 2018. All patients were informed of

the terms and conditions of the study; they agreed to participate in the study. Our

study was certified by the hospital ethics committee.

All patients satisfied the modified Ishikawa's diagnostic criteria for TA (20),

fulfilling one or more major criteria and two or more minor criteria. The major criteria

included a left or right mid-subclavian artery lesion, characteristic symptoms and

signs lasting for one month or longer. Minor criteria included elevated erythrocyte

sedimentation rate (ESR), carotid artery tenderness, hypertension, aortic regurgitation

or aortic ring dilation, and lesions in the pulmonary, mid-common carotid artery,

distal brachiocephalic trunk, descending thoracic aorta, abdominal aorta, and coronary

artery.

All TA patients were screened for the risk of pulmonary artery involvement by

two experienced physicians. TA patients who had respiratory symptoms, or

pulmonary hypertension, or abnormal right cardiac structure or function as estimated

by echocardiography were considered to be at high risk of pulmonary artery

involvement and scheduled to undergo further pulmonary angiography. Patients who

had pulmonary artery involvement based on aortography findings were also scheduled

to undergo pulmonary angiography (computed tomography, CT or magnetic

resonance, MR examination).

Of the 41 patients who underwent pulmonary angiography, 20 were diagnosed as

having TA with pulmonary artery involvement. These patients were divided into two

groups according to the presence or absence of pulmonary artery involvement.

Clinical features, laboratory examination, and imaging manifestations of these 2

groups of TA patients were analyzed and recorded. Ten TA patients with pulmonary

artery involvement underwent reassessment of pulmonary artery lesion through

pulmonary angiography (CT or MR examination) after treatment.

2.2.Clinical features and laboratory examination

 We compared demographic characteristics, medical history, clinical

manifestations, laboratory data, angiographic findings, and therapeutic strategies

between the two groups. Lab tests were done by the laboratory of our hospital. The disease

activity was assessed using the modified version of Kerr’s criteria (21) and the Indian

Takayasu Clinical Activity Score (ITAS) (22).

2.3.Imaging examination

We used MR angiography to evaluate the thoracic aorta and its branches and MR

or CT angiography to assess the pulmonary artery involvement. Doppler

ultrasonography and right heart catheterization were used to measure the pulmonary

hypertension. Vascular lesions were classified according to the angiographic

classification described at the 1994 international TAK conference in Tokyo (23). The

detailed classifications were as follows: the distribution of Numano type I (branches

of aortic arch), type IIa (ascending aorta and the aortic arch and its branches), type IIb

(ascending aorta, aortic arch and its branches, and thoracic descending aorta), type III

(thoracic descending aorta and abdominal aorta and/or renal arteries), type IV

(abdominal aorta and/or renal arteries), and type V (combination of the features of

types IIb and IV).

2.4.Statistical analysis

SPSS 20.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical

analysis. The continuous data of normal distribution were expressed as mean ±

standard deviation (SD). The skewed data were expressed as the median and

interquartile range (IQR: 25th and 75th percentiles). Classified data (counts or

frequencies) were expressed as percentages. Student's t-test was used to compare the

mean level of normally distributed variables, and Mann-Whitney U test was used to

compare the non-normally distributed variables. The 2 test was used to assess

qualitative parameters. Multivariate logistic regression analysis was used to determine

the independent risk factors related to TA with pulmonary artery involvement. All

baseline variables associated with TA involvement in the pulmonary arteries were

analyzed using the stepwise method to create the best performing logistic regression-model.

All statistical tests were two-tailed, and p <0.05 was considered statistically

significant.

3. Results

3.1.Comparison of the demographic characteristics, clinical manifestations, and

laboratory parameters between TA patients with and without pulmonary artery

involvement

Among the 126 patients with TA, the average age of onset was 37.4 ± 12.7 years,

and the median duration was 48 (12, 132) months. Pulmonary artery involvement was

present in 20 TA patients (15.9%), including 2 men and 18 women, with a ratio of 1:9.

There was no significant difference in the age of onset between the TA patients

with and without pulmonary artery involvement, but disease duration was

significantly longer in patients with pulmonary artery involvement than in those

without [108.0 (53.5, 222.0) vs 36.0(12.0, 120.0) months, p=0.038].

By comparing the clinical data of the two groups of patients, we found that

hemoptysis was more common in TA patients with pulmonary artery involvement

than in those without (15.0%, 3 cases vs. 0.0%, p <0.001). The incidence of heart

valve involvement and aneurysm formation was higher in patients with pulmonary

artery involvement than in those without (see Table 1).

There was no significant difference in the Numano classification or in the choice

of treatment regimen between the two groups (see Table 1).

Among all the laboratory examination data, the alanine aminotransferase (ALT)

level of TA patients in the pulmonary artery involvement group was significantly

lower than that in the non-pulmonary artery involvement group [10.00 (7.50,11.50),

14.00 (9.00,21.00), p=0.004]; however, the ALT levels of both groups were within

normal range, which means the difference had no clinical significance. Other

laboratory examination data showed no statistically significant difference between the

groups. The disease activity scores (Kerr’s score and ITAS) also showed no

significant difference between groups (see Table 2).

In the group of TA with pulmonary artery involvement, the pulmonary artery

involvement was diagnosed as the same time of diagnosis of TA. Eleven patients had

respiratory symptoms and 9 had imaging clues of pulmonary artery involvement.

Respiratory symptoms were the initial chief complaints in 7 patients. The other 4

patients developed respiratory symptoms at 7, 60, 110, and 228 months after onset of

TA symptoms, respectively.
3.2. Analysis of risk factors for TA with pulmonary artery involvement

We used the stepwise regression method to analyze age at disease onset (older than

40 years), female sex, disease duration longer than 5 years, history of tuberculosis,

ESR, C-reactive protein, Kerr’s score, ITAS, immunoglobulin A, immunoglobulin G.

We found that TA patients with disease duration longer than 5 years had a 3.7-fold

higher risk of pulmonary artery involvement than those with disease duration less than

5 years [odds ratio (OR): 3.699, p=0.013, 95% confidence interval (CI):

1.316-10.394]. The information regarding the chi square of the models including

value 6.735, degrees of freedom 1 and p value 0.009. The R square of Nagelkerke is

0.172.

3.3.Angiographic manifestation of the affected pulmonary arteries

Five main types of pulmonary artery lesions were seen on angiographic (CT or

MR): stenosis, occlusion, arterial wall thickening, arterial dilatation, and in situ

thrombosis. Stenosis was the most common, followed by lumen occlusion (see Table

3). Their incidences in the 20 patients were as follows: 60% (stenosis, 12 cases), 45%

(occlusion, 9 cases), 30% (arterial wall thickening, 6 cases), 5% (in-situ thrombosis, 1

case), and 5% (lumen dilation, 1 case).

We further analyzed the distribution of pulmonary artery lesions in 20 cases of TA

with pulmonary artery involvement, which is summarized in Table 3. Lesions were

seen in the proximal pulmonary artery (main pulmonary artery and left and/or right

pulmonary artery trunk) in 11 cases (55%), including 4 cases (20%) where the main
pulmonary artery was involved and 10 cases (50%) where the left and/or right

pulmonary artery trunk was involved. Of the 10 patients with left and right pulmonary

artery involvement, the left pulmonary trunk was involved in 6 and the right

pulmonary trunk was involved in 8 patients. Among the patients with subsegmental

pulmonary artery involvement, 6 (30%) had bilateral subsegmental pulmonary artery

involvement, 12 (60%) had unilateral subsegmental pulmonary artery involvement,

and 5 (25%) had more than 50% subsegmental pulmonary artery involvement. The

left lung was involved in 8 cases, 5 with left upper lobe involvement and 5 with left

lower lobe involvement. The right lung was involved in 13 cases, 10 with

involvement of the right upper lobe pulmonary artery branches, 6 with involvement of

the right middle lobe pulmonary artery branches, and 8 with involvement of the right

lower lobe pulmonary artery branches.

Among the 126 patients with TA, 6 developed pulmonary hypertension, including 5

with pulmonary artery involvement and 1 without pulmonary artery involvement.

3.4.Treatment options and follow-up results of TA patients with pulmonary artery

involvement

Treatment regimens included cyclophosphamide + glucocorticoids, tocilizumab +

methotrexate + glucocorticoids , methotrexate + mycophenolatemofetil +

glucocorticoids and cyclophosphamide + methotrexate + glucocorticoids. Among the

10 patients with follow-up data, imaging lesions improved in 6 cases, showed no

changes in 3 cases, and progressed in 1 case.

 Among the 5 TA patients with pulmonary artery involvement and pulmonary

hypertension, 4 cases were re-examined with Doppler ultrasonography or right heart

catheterization. The results showed that the pulmonary artery pressure in 2 cases

returned to normal.

We further compared the pulmonary artery involvement in TA patients with and

without amelioration of pulmonary artery lesions. There were no significant

differences in the laboratory indexes and scores related to disease activity between the

two groups. However, the treatment options were markedly different. Tocilizumab

was used in 5 of the 6 patients in whom the pulmonary artery lesions improved, while

it was not used in any of the 4 patients who did not show any improvement (see Table

4).
4. Discussion

TA involvement of pulmonary arteries is rare (13). This study

summarizedinvolvement of pulmonary artery in 126 patients with TA.

In this study, pulmonary artery involvement was found to be 15.8% (20 cases) in

126 TA patients. By comparing the demographic characteristics, clinical

manifestations, imaging manifestations, laboratory indicators, and clinical activity of

TA patients with and without pulmonary artery involvement, it was found that the

symptom of hemoptysis was more common and the disease duration was longer in

patients with pulmonary artery involvement. We propose for the first time that

duration of TA greater than 5 years is an independent risk factor for pulmonary artery

involvement, with a 3.7-fold higher risk. The most common imaging manifestations

of pulmonary artery involvement were stenosis, followed by occlusion and arterial

wall thickening. Among the TA patients with pulmonary artery involvement who

completed the re-examination, the pulmonary artery lesions disappeared or improved

in 60% (6 cases), which included all the patients treated with tocilizumab (5 cases).

The proportion of pulmonary artery involvement in TA has been previously

reported to range from 6.9 to 21% (14-18, 24). The differences between the data in

these studies may be related to different races, sample sizes, and the number of

patients with pulmonary vascular screening. Since pulmonary angiography is not

routinely used for TA patients (25), screening is usually only considered when

respiratory symptoms or imaging clues are present. People with a higher proportion

of respiratory symptoms are more likely to be screened. In the present study, 20 of

 126 (15.9%) TA patients were diagnosed as having pulmonary artery

involvement.Previous literature reported that stenosis was the most common imaging

change seen in pulmonary artery lesions of TA, followed by occlusion. Unilateral

involvement was the most common, and the right lung and upper lobe were the most

common location of pulmonary artery lesions in TA (6, 13, 26). These characteristics

are consistent with our results. The proportion of pulmonary hypertension in TA

patients was 12-17.8% (14, 16). Kohava et al. (13) summarized that 19 of the 45 TA

patients with pulmonary artery involvement had pulmonary arterial hypertension in

previous case reports, but the proportion of pulmonary hypertension in TA patients

with pulmonary artery involvement was rarely reported. In our study, 25% of TA

patients with pulmonary artery involvement developed pulmonary hypertension.

Previous studies have suggested that pulmonary vascular involvement is a late

manifestation of TA (16). Our study also confirmed the same. We found that TA

patients with pulmonary artery involvement had significantly longer disease durations

than patients without pulmonary artery involvement. Further, we found that TA

patients with disease duration longer than 5 years had a 3.7-fold higher risk of

pulmonary artery involvement. Therefore, it is important to evaluate pulmonary artery

involvement in patients with a disease course of more than 5 years. The results

showed that the proportion of hemoptysis in TA patients with pulmonary artery

involvement was significantly higher than that in TA patients without pulmonary

artery involvement. The possible causes of hemoptysis in TA patients were likely

related to pulmonary artery collateral vessel rupture or small aneurysm, or to

pulmonary infarction (6). Although there were relatively few clinical symptoms in our

data, the occurrence of hemoptysis was highly suggestive of the possibility of

pulmonary artery involvement. In our study, we found that 3 of the 20 patients with

pulmonary artery involvement had hemoptysis (15%). This ratio is similar to that in

the latest study. He et al. reported that the proportion of hemoptysis in patients with

pulmonary artery involvement was 20.3% (27). However, in an early literature review,

Toledano et al. found that the incidence of hemoptysis was 42.2% (13). In the past,

the diagnosis of TA with pulmonary artery involvement was more dependent on

respiratory symptoms, while increasingly more patients without respiratory symptoms

have received a diagnosis of TA with pulmonary artery involvement through imaging

clues in recent years. This may be the main reason for the decrease in the incidence of

hemoptysis in TA with pulmonary artery involvement in recent studies.

In this study, we followed up with 10 TA patients with pulmonary artery

involvement for 7.6±2.2 months to evaluate the outcomes of pulmonary artery lesions

after treatment. We found that pulmonary artery lesions improved in 6 of the 10

patients after treatment. There was no significant difference in the index of disease

activity between pulmonary artery involvement TA patients with or without improved

pulmonary artery lesions. In 2016, Ferrante et al. (28) reported a case of effective

treatment of a pulmonary artery involved TA patient with a combination of HAP by

using tocilizumab. In our patients, pulmonary artery lesions improved in 5 TA patients

after treatment with tocilizumab. Figure 1 shows significant improvement of

pulmonary artery lesions in a patient treated with tocilizumab. Previous studies have
confirmed that IL-6 may be involved in the pathophysiological process of TA (7).

Overexpression of IL-6 in lung tissue has been found to cause pulmonary vascular

disease in animal experiments (29). In conclusion, IL-6 directly or indirectly promotes

the proliferation of vascular smooth muscle cells and endothelial cells, and IL-6

receptor antagonists can effectively treat TA patients with pulmonary hypertension. In

this study, follow-up imaging examinations confirmed for the first time that treatment

with tocilizumab can effectively improve pulmonary artery lesions in TA patients.

This study has a few limitations. In our study, patients who did not have respiratory

symptoms or imaging clues did not receive pulmonary angiography, which could

have resulted in missed diagnosis. Because of our patients’ economic conditions and

geographical limitations, most of them lived far from our hospital, so the imaging

follow-up rate was relatively low. Another limitation could be possible method of

diagnosis of pulmonary artery involvement. Furthermore, retrospective data were

entered by administrators so there is a possibility of human error. Lastly, the small

sample size may affect the statistical efficiency of the logistic regression results, and the effect of

confounding factors on the results. It is expected that further multi-center prospective

studies will be conducted in the future to further explore the characteristics of TA

cases with pulmonary vascular involvement.

In this study, the clinical characteristics of TA patients with and without pulmonary

artery involvement were compared for the first time. For TA patients with a disease

course of more than 5 years, routine screening of pulmonary angiography should be

performed because of the high risk of pulmonary artery involvement. For TA patients
with pulmonary artery involvement, the Il-6 receptor antagonist tocilizumab is a

relatively effective drug for the control of pulmonary artery lesions. Prospective

randomized controlled studies should be conducted on the treatment of TA pulmonary

artery involvement with tocilizumab.

Declarations

Ethics approval and consent to participate: All subjects provided written informed

consent. The study was conducted in accordance with the ethical principles of the

Declaration of Helsinki and approved by the Clinical Research Ethics Board of

Beijing Anzhen Hospital, Capital Medical University (approval number: 2019009X).

Consent for publication: The authors declare that there are no potential conflicts of

interest with respect to the research, authorship, and/or publication of this article.

Fundings: This project was supported by grants from the National Natural Science

Foundation of China (91739111, 81500037). The sponsors did not have a role in the

study design, data collection and analysis, decision to publish, or manuscript

preparation.

Acknowledgements: None.

Authors' contributions: XX, conceived of the study and drafted the manuscript. JD,
help to collected clinical data. JL, help to collected imaging data. GZ and QG, help
revised the manuscript. LP, guided the design of this study and modified the paper.
All authors read and approved the final manuscript.

Conflict of interest: The authors declared that they have no conflicts of interest to

this work.
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Figure legend

Figure1. Imaging of Pulmonary artery computed tomography angiography (CTA)

in a TA patient. A female patient, 49 years old, was diagnosed with TA. Pulmonary

artery CTA was performed twice with an interval of 1 year. (A) Coronal maximum

intensity projection and (B and C) posterior-anterior volume imaging of pulmonary

artery showed occlusion of right superior lobar artery and fourth-order branch of right

posterior basal segmental artery (white arrow). The patient was reexamined one year

later. (D) Coronal maximum intensity projection and (E and F) posterior-anterior

volume imaging of pulmonary artery showed no significant change in occlusion of

right superior lobar branch. The proximal segmental lumen of fourth-order branch of

right posterior basal segment appeared revascularization (white arrow).

Table 1 Click here to access/download;Table;Table1.docx

Table1. Clinical features and disease activity of TA patients with and without
pulmonary artery involvement

TA with P TA without P p-value

(n=20) (n=106)
Onset of age for TA (years) 27.6±9.1 30.6±12.2 0.32
Age (years) 36.3±9.6 37.6±13.3 0.68
Gender (female) , n(%) 18(90.0) 90(84.9) 0.55
Disease duration (months) 108(53.5, 222.0) 36(12.0,120.0) 0.04
BMI (kg/m2) 22.8±3.9 22.4±3.5 0.62
Hypertension, n(%) 9(45.0) 50(47.2) 0.09
Dyslipidemia, n(%) 4(20.0) 20 (18.9) 0.09
T2DM, n(%) 0(0.0) 6(5.7) 0.28
Arteriosclerosis, n(%) 8(40.0) 52(49.1) 0.46
Smoker, n(%) 1(5.0) 15(14.2) 0.26
Heart failure, n(%) 6(30.0) 15(14.2) 0.08
history of TB, n(%) 5(25.0) 14(13.2) 0.17
Dizziness, n(%) 11(55.0) 52(49.1) 0.68
Headache, n(%) 1(5.0) 22(20.8) 0.09
Pulseless, n(%) 6(30.0) 26(24.5) 0.61
Asymmetry in BP, n(%) 7(35.0) 28(26.4) 0.04
Claudication, n(%) 3(15.0) 12(11.3) 0.64
Fever, n(%) 5(25.0) 15(14.2) 0.22
Fatigue, n(%) 11(55.0) 5(4.7) 0.07
Palpitations, n(%) 3(15.0) 14 (13.2) 0.08
Chest tightness, n(%) 7(35.0) 28(26.4) 0.43
Chest pian, n(%) 4(20.0) 23(21.7) 0.87
Hemoptysis, n(%) 3(15.0) 0(0.0) 0.00
Carotidynia, n(%) 1(5.0) 11(10.4) 0.45
Erythema nodosum, n(%) 0(0.0) 4(3.8) 0.38
Weight loss, n(%) 1(5.0) 5(4.7) 0.96
Cardiac valve involvement , 17(85.0) 61(57.6) 0.02
n(%)
Aneurysm, n(%) 7(35.0) 17(16.0) 0.05
Treatments, n(%) 7(35.0) 17(16.0) 0.05
Treatments, n(%)
Corticosteroids 12(60.0) 61(57.6) 0.84
CTX 9(45.0) 44(41.5) 0.77
MTX 4(20.0) 11(10.4) 0.22
MMF 0(0.0) 14(13.2) 0.09
LEF 0(0.0) 6(5.7) 0.28
HCQ 0(0.0) 8(7.6) 0.20
Numano type
Type I 4(20.0) 22(20.8) 0.94
 Type IIa 1 (5.0) 5(4.7) 0.96
Type IIb 5(25.0) 15(14.2) 0.22
Type III 2(10.0) 7(6.6) 0.59
Type IV 0(0.0) 3(2.8) 0.45
Type V 8(40.0) 54(50.9) 0.37
C+ 5(25.0) 28(26.4) 0.90
Kerr’s Score 2.4±0.5 2.2±0.8 0.31
ITAS 7.6±3.7 6.4±4.0 0.22
Note: P, pulmonary artery involvement; BMI, Body mass index; TB, tuberculosis; TIA, Transitory ischemic attack;
CTX, cyclophosphamide; MTX, methotrexate; MMF, mycophenolate mofetil; LEF, leflunomide; HCQ,
hydroxychloroquine, C+, coronary artery involvement; ITAS, Indian Takayasu Clinical Activity Score
Table 2 Click here to access/download;Table;Table2.docx

Table2. Laboratory parameters of TA patients with and without pulmonary

artery involvement

TA with P TA without P Normal ranges p-value

(n=20) (n=106)
WBC (109/L) 8.2±2.5 7.6±3.1 3.5-9.5 0.46
NE (109/L) 5.2±1.8 5.1±2.9 1.8-6.3 0.84
LY (109/L) 2.3±1.3 2.0±1.7 1.1-3.2 0.20
PLT (109/L) 272.7±85.8 263.2±83.1 125-350 0.66
RBC (1012/L) 4.6±0.6 4.4±0.5 3.8-5.1 0.24
a
Hb (g/L) 126.1±15.7 123.1±18.6 115-150 0.52
130-175 b
ALT (U/L) 10(7.5, 11.5) 14(9.0, 21.0) 7-40 a 0.00
9-60 b
Cr (mol/l) 57.7±8.8 59.8±26.0 41-81 a 0.62
57-111 b
UA (mol/l) 329.5±161.6 292.1±82.5 154.7-357 a 0.14
208.3-428.4 b
GLU (mmol/l) 4.9±0.5 5.0±1.2 3.9-6.1 0.62
HCY (mol/l) 12.2±5.0 14.3±12.6 5-13 a 0.52
6-16 b
BNP (pg/ml) 123.0(54.8, 227.0) 39.0(16.8, 164.8) 0-100 0.08
TNI (ng/ml) 0.01(0, 0.01) 0(0, 0.01) 0-0.04 0.75
IL-6 (pg/ml) 8.3(2.5, 17.4) 5.0(2.8, 15.4) 0-5.9 0.57
TNF- (pg/ml) 13.5(9.4, 72.9) 21.7(7.7, 50.4) 0-8.1 0.84
IgA (g/l) 3.1±2.0 2.5±1.1 1.0-4.2 0.12
IgG (g/l) 12.5±5.0 12.5±4.1 8.4-17.4 0.99
IgM (g/l) 1.3(0.8, 2.2) 1.2(0.9, 1.7) 0.5-2.8 0.63
C3 (g/l) 1.2±0.2 1.2±0.3 0.7-1.4 0.56
C4 (g/l) 0.2±0.1 0.2±0.1 0.1-0.4 0.37
ESR(mm/1h) 14.0(5.3, 37.5) 17.0(6.3, 29.8) 0-20 a 0.73
0-15 b
CRP (mg/l) 7.8(0.4, 22.2) 2.6(0.5, 17.8) 0-8 0.64
Note: P, pulmonary artery involvement; WBC, white blood cell; LY, lymphocyte; NE, neutrophil; PLT, platelet;
RBC, red blood cell; Hb, hemoglobin; ALT, alanine aminotransferase; Cr, creatinine; GLU, Glucose; TG,
triglyceride; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein
cholesterol; HCY, homocysteine BNP, brain natriuretic peptide; TNI, troponin I; IL, interleukin; TNF, tumor
necrosis factor; Ig, immunoglobulin; C3, complement 3; C4, complement 4; ESR, erythrocyte sedimentation rate;
CRP, C-reactive protein; a: normal ranges for women; b: normal ranges for men
Table 3 Click here to access/download;Table;Table3.docx

Table 3. Type, location and treatment respond of pulmonary artery lesion in TA patients with pulmonary artery involvement

NO. Age Sex Disease Type of PA lesion Pulmonary Locations of PA lesions Treatment strategy Vascular
(y) duration hypertension MPA LPA RPA Number of Location of lesion
(m) Subsegmental Subsegmental improvement
PA lesion PA lesion

1 33 F 240 In situ thrombosis, yes no no yes 9 Right lung TCZ+MTX+GCS Yes

Stenosis
2 48 F 3 Stenosis, Occlusion yes no no no 4 Right lung TCZ +MTX+GCS Yes
3 51 F 70 Stenosis yes no no no 3 Left lung CTX+GCS Yes
4 48 F 240 Arterial wall thickening no yes yes yes 1 Right lung TCZ +MTX+GCS Yes
5 42 F 240 Stenosis, Occlusion yes no yes yes 1 Left lung TCZ +MTX+GCS Yes
6 23 F 1 Arterial wall thickening no yes yes yes 0 N/A TCZ +MTX+GCS Yes
7 50 F 240 Occlusion no no no yes 9 Right lung CTX+GCS No
8 44 F 240 Stenosis no no yes no 7 Left lung CTX+GCS No
9 28 F 12 Arterial wall thickening, no no no yes 6 Right lung CTX+GCS No
Occlusion
10 28 F 70 Occlusion no no no no 2 Right lung MTX+MMF+GCS No
11 37 F 48 Stenosis, Occlusion no yes yes yes 16 Bilateral lung CTX+GCS N/A
12 29 F 120 Arterial wall thickening, no no no yes 11 Bilateral lung TCZ+MTX+GCS N/A
Stenosis, Occlusion
13 24 F 168 Stenosis, Occlusion yes no no no 10 Bilateral lung No Treatment N/A
14 26 F 12 Arterial wall thickening no no no no 7 Bilateral lung TCZ+MTX N/A
15 31 F 96 Stenosis no no no no 6 Bilateral lung MTX+MMF+GCS N/A
16 45 M 70 Arterial wall thickening, no no no no 1 Right lung CTX+GCS N/A
Stenosis
 17 31 F 72 Dilatation no yes no no 0 N/A CTX+GCS N/A
18 43 F 120 Stenosis no no yes no 0 Left lung CTX+GCS N/A
19 43 M 156 Occlusion no no no no 3 Bilateral lung MTX+GCS+HCQ N/A
20 28 M 120 Stenosis no no no no 2 Right lung CTX+MTX+GCS N/A
Note: PA, pulmonary artery; MPA, main pulmonary artery; LPA, left pulmonary artery; RPA, right pulmonary artery; TCZ, tocilizumab; MTX, methotrexate; GCS, glucocorticoids; CTX,
cyclophosphamide; MMF, mycophenolatemofetil; HCQ, hydroxychloroquine
Table 4 Click here to access/download;Table;Table4.docx

Table 4. comparison of disease activity and treatment regimens of TA patients

with pulmonary artery involvement in different treatment response groups

PA lesions improved (n=6) PA lesions non-improved (n=4) p-value

ESR 13.00(5.75,43.25) 29.50(11.00,75.00) 0.522
CRP 4.91(0.12,21.89) 22.49(3.84,38.42) 0.201
Kerr’s Score 2.50±0.55 2.75±0.50 0.486
ITAS 21.89(9.5,43.25) 8.5(5.00,10.50) 0.828
TCZ+MTX+GCS 5, 83.3% - -
CTX+GCS 1, 16.7% 3, 75.0% -
MMF+MTX+GCS - 1, 25.0% -
Note: PA, pulmonary artery; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; ITAS, Indian
Takayasu Clinical Activity Score; TCZ, tocilizumab; MTX, methotrexate; GCS, glucocorticoids; CTX,
cyclophosphamide; MMF, mycophenolatemofetil;
Supplementary Material Click here to access/download;Supplementary
Material;Supplementary Material.docx

95% C.I. for Exp (B)

B S.E. Wals df Sig. Exp (B) Lower Upper

Step 1# More than 5 y 1.476 0.562 6.896 1 0.009 4.373 1.454 13.155
ESR -0.092 0.256 0.131 1 0.718 0.912 0.553 1.505

CRP 0.698 0.595 1.376 1 0.718 0.912 0.553 1.505

ITAS 1.294 1.108 1.364 1 0.241 3.646 0.416 31.969

IgA 0.521 0.732 0.508 1 0.476 1.684 0.402 7.066

IgG -0.708 0.814 0.756 1 0.385 0.493 0.100 2.431

Older than 40 -0.265 0.749 0.028 1 0.867 0.882 0.203 3.830

TB 0.802 0.650 1.524 1 0.217 2.231 0.624 7.977

female -0.125 0.749 0.028 1 0.867 0.882 0.203 3.830

Constant -3.836 1.309 8.584 1 0.003 0.022
Manuscript With Tracked Changes Click here to access/download;Manuscript With Tracked
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Title Page

Full Title

Pulmonary artery involvement in Takayasu arteritis: a retrospective study in Chinese

population

Authors:

Xin Xi1,2, Juan Du3, Jiayi Liu4, Guangfa Zhu2, Guanming Qi5, Lili Pan3

1. Sleep Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

2. Department of Pulmonary and Critical Care, Beijing Anzhen Hospital, Capital Medical

University, Beijing, China.

3. Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical

University, Beijing, China.

4. Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing,

China.

5. Pulmonary and Critical Care Division, Tufts Medical Center, Boston, MA, USA.

Name and Address for Correspondence

Lili Pan. Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital

Medical University.

Address: 2 Anzhen Road, Chaoyang District, Beijing, China.

E-mail: lilypansxmu@sina.com
Abstract

Background: Takayasu's arteritis (TA) may involve the pulmonary artery, which

signifies a poor prognosis. This study investigated features of TA patients with

pulmonary artery involvement.

Methods: One hundred and twenty-six inpatients diagnosed with TA were

retrospectively studied. The clinical data of TA patients with and without pulmonary

artery involvement were compared. The imaging features of pulmonary artery lesions

in TA patients were evaluated. The treatment responses of pulmonary artery lesions

were described and the drug regimens in different treatment response groups were

compared.

Results: Among the patients with TA, 15.9% showed associated pulmonary artery

involvement. The disease durations were significantly longer in patients with

pulmonary artery involvement than in those without [108.0 (53.5, 222.0) vs. 36.0

(12.0, 120.0) months, p=0.038]. Hemoptysis was more common in TA patients with

pulmonary artery involvement than in those without (15.0%, 3 cases vs. 0.0%, p<

0.001). TA patients with disease duration longer than 5 years showed a 3.7-fold higher

risk of pulmonary artery involvement compared to those with a disease duration less

than 5 years (odds ratio: 3.699, p=0.013, 95% confidence interval: 1.316-10.394). The

most common imaging manifestations of pulmonary artery involvement were stenosis

and occlusion. Among the 6 patients who had a good response to treatment of

pulmonary artery lesions, 5 were treated with the interleukin-6 receptor antagonist

tocilizumab.
Conclusions: TA patients with pulmonary artery involvement have a longer course of

disease and more symptoms of hemoptysis. TA-related pulmonary artery lesions are

more commonly manifested as stenosis and occlusion. Tocilizumab may be effective

for TA-related pulmonary vascular disease.

Keywords：Takayasu arteritis, pulmonary artery involvement, disease duration, IL-6

receptor antagonist
Highlights

 Disease duration longer than 5 years is an independent risk factor for pulmonary

artery involvement in TA.

 Hemoptysis is a characteristic clinical symptom of TA with pulmonary artery

involvement.

 Tocilizumab may be more effective for pulmonary artery lesions of TA.

1. Introduction

Takayasu arteritis (TA) is a chronic autoimmune arteritis of unknown etiology

that mostly involves the aorta and its main branches. TA usually affects women

younger than 40 years of age(1, 2). It is more prevalent in Asia, although it is present

worldwide. The incidence of TA is estimated to be 40 cases per million in Japan (3)

and 2.6 to 4.7 cases per million in the United States (4) and United Kingdom (5).

Because of the lack of specificity of symptoms, laboratory tests, and biomarkers,

many patients cannot be diagnosed in time. The inflammatory process of TA can lead

to arterial wall thickening, stenosis, and occlusion, resulting in tissue ischemia and

organ failure. This process may also result in lumen dilatation, aneurysm, or aortic

dissection, which may cause vascular rupture and sudden death (6).

Several cytokines have been proved to be involved in the pathophysiological

process of TA, among which interleukin (IL)-6 plays an important role in the process

of inflammation and fibrosis of the vascular wall. IL-6 levels are often found to be

parallel to TA disease activity (7, 8). The first-line strategy for the treatment of TA is

glucocorticoids. Disease-modifying anti-rheumatic drugs such as cyclophosphamide

and methotrexate are also treatment options (9, 10). In recent years, biological agents

including tocilizumab (IL-6 receptor antagonist), have been demonstrated to yield

good clinical responses and glucocorticoid -sparing effects in patients with TA (11, 12).

Pulmonary artery involvement usually occurs in the late stage of TA; the main

clinical manifestations are dyspnea, chest pain, hemoptysis, and cough (13).

Pulmonary artery involvement may cause pulmonary hypertension, leading to right

heart dysfunction, which seriously affects the prognosis of TA patients (6). TA with

pulmonary artery involvement has gradually concerned by people. Pulmonary artery

involvement has been mentioned in several studies of TA from different countries.

(14-16) Sharma et al. (17) described the incidence and features of pulmonary artery

involved TA in 1990. In their study, among 42 TA patients, 6 were confirmed to have

pulmonary arterial involvement by intravenous digital subtraction angiography.

Yamada et al. (18) studied the angiographic characteristic of pulmonary involvement

in TA. Recently, Brennan et al. (19) studied cardiopulmonary involvement in TA, and

analyzed some of the characteristics of pulmonary artery involvement in TA. In the

present study, we performed a systematic analysis to investigate the clinical, imaging,

therapeutic, and prognostic characteristics of pulmonary artery involvement in a large

sample of TA patients.

2. Patients and methods

2.1.Patients

This retrospective study included 126 patients diagnosed with TA in Beijing

Anzhen Hospital from January 2012 to December 2018. All patients were informed of

the terms and conditions of the study; they agreed to participate in the study. Our

study was certified by the hospital ethics committee.

All patients satisfied the modified Ishikawa's diagnostic criteria for TA (20),

fulfilling one or more major criteria and two or more minor criteria. The major criteria

included a left or right mid-subclavian artery lesion, characteristic symptoms and

signs lasting for one month or longer. Minor criteria included elevated erythrocyte

sedimentation rate (ESR), carotid artery tenderness, hypertension, aortic regurgitation

or aortic ring dilation, and lesions in the pulmonary, mid-common carotid artery,

distal brachiocephalic trunk, descending thoracic aorta, abdominal aorta, and coronary

artery.

All TA patients were screened for the risk of pulmonary artery involvement by

two experienced physicians. TA patients who had respiratory symptoms, or

pulmonary hypertension, or abnormal right cardiac structure or function as estimated

by echocardiography were considered to be at high risk of pulmonary artery

involvement and scheduled to undergo further pulmonary angiography. Patients who

had pulmonary artery involvement based on aortography findings were also scheduled

to undergo pulmonary angiography (computed tomography, CT or magnetic

resonance, MR examination).

Of the 41 patients who underwent pulmonary angiography, 20 were diagnosed as

having TA with pulmonary artery involvement. These patients were divided into two

groups according to the presence or absence of pulmonary artery involvement.

Clinical features, laboratory examination, and imaging manifestations of these 2

groups of TA patients were analyzed and recorded. Ten TA patients with pulmonary

artery involvement underwent reassessment of pulmonary artery lesion through

pulmonary angiography (CT or MR examination) after treatment.

2.2.Clinical features and laboratory examination

 We compared demographic characteristics, medical history, clinical

manifestations, laboratory data, angiographic findings, and therapeutic strategies

between the two groups. Lab tests were done by the laboratory of our hospital. The disease

activity was assessed using the modified version of Kerr’s criteria (21) and the Indian

Takayasu Clinical Activity Score (ITAS) (22).

2.3.Imaging examination

We used MR angiography to evaluate the thoracic aorta and its branches and MR

or CT angiography to assess the pulmonary artery involvement. Doppler

ultrasonography and right heart catheterization were used to measure the pulmonary

hypertension. Vascular lesions were classified according to the angiographic

classification described at the 1994 international TAK conference in Tokyo (23). The

detailed classifications were as follows: the distribution of Numano type I (branches

of aortic arch), type IIa (ascending aorta and the aortic arch and its branches), type IIb

(ascending aorta, aortic arch and its branches, and thoracic descending aorta), type III

(thoracic descending aorta and abdominal aorta and/or renal arteries), type IV

(abdominal aorta and/or renal arteries), and type V (combination of the features of

types IIb and IV).

2.4.Statistical analysis

SPSS 20.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical

analysis. The continuous data of normal distribution were expressed as mean ±

standard deviation (SD). The skewed data were expressed as the median and

interquartile range (IQR: 25th and 75th percentiles). Classified data (counts or

frequencies) were expressed as percentages. Student's t-test was used to compare the

mean level of normally distributed variables, and Mann-Whitney U test was used to

compare the non-normally distributed variables. The 2 test was used to assess

qualitative parameters. Multivariate logistic regression analysis was used to determine

the independent risk factors related to TA with pulmonary artery involvement. All

baseline variables associated with TA involvement in the pulmonary arteries were

analyzed using the stepwise method to create the best performing logistic regression-model.

All statistical tests were two-tailed, and p <0.05 was considered statistically

significant.

3. Results

3.1.Comparison of the demographic characteristics, clinical manifestations, and

laboratory parameters between TA patients with and without pulmonary artery

involvement

Among the 126 patients with TA, the average age of onset was 37.4 ± 12.7 years,

and the median duration was 48 (12, 132) months. Pulmonary artery involvement was

present in 20 TA patients (15.9%), including 2 men and 18 women, with a ratio of 1:9.

There was no significant difference in the age of onset between the TA patients

with and without pulmonary artery involvement, but disease duration was

significantly longer in patients with pulmonary artery involvement than in those

without [108.0 (53.5, 222.0) vs 36.0(12.0, 120.0) months, p=0.038].

By comparing the clinical data of the two groups of patients, we found that

hemoptysis was more common in TA patients with pulmonary artery involvement

than in those without (15.0%, 3 cases vs. 0.0%, p <0.001). The incidence of heart

valve involvement and aneurysm formation was higher in patients with pulmonary

artery involvement than in those without (see Table 1).

There was no significant difference in the Numano classification or in the choice

of treatment regimen between the two groups (see Table 1).

Among all the laboratory examination data, the alanine aminotransferase (ALT)

level of TA patients in the pulmonary artery involvement group was significantly

lower than that in the non-pulmonary artery involvement group [10.00 (7.50,11.50),

14.00 (9.00,21.00), p=0.004]; however, the ALT levels of both groups were within

normal range, which means the difference had no clinical significance. Other

laboratory examination data showed no statistically significant difference between the

groups. The disease activity scores (Kerr’s score and ITAS) also showed no

significant difference between groups (see Table 2).

In the group of TA with pulmonary artery involvement, the pulmonary artery

involvement was diagnosed as the same time of diagnosis of TA. Eleven patients had

respiratory symptoms and 9 had imaging clues of pulmonary artery involvement.

Respiratory symptoms were the initial chief complaints in 7 patients. The other 4

patients developed respiratory symptoms at 7, 60, 110, and 228 months after onset of

TA symptoms, respectively.
3.2. Analysis of risk factors for TA with pulmonary artery involvement

We used the stepwise regression method to analyze age at disease onset (older than

40 years), female sex, disease duration longer than 5 years, history of tuberculosis,

ESR, C-reactive protein, Kerr’s score, ITAS, immunoglobulin A, immunoglobulin G.

We found that TA patients with disease duration longer than 5 years had a 3.7-fold

higher risk of pulmonary artery involvement than those with disease duration less than

5 years [odds ratio (OR): 3.699, p=0.013, 95% confidence interval (CI):

1.316-10.394]. The information regarding the chi square of the models including

value 6.735, degrees of freedom 1 and p value 0.009. The R square of Nagelkerke is

0.172.

3.3.Angiographic manifestation of the affected pulmonary arteries

Five main types of pulmonary artery lesions were seen on angiographic (CT or

MR): stenosis, occlusion, arterial wall thickening, arterial dilatation, and in situ

thrombosis. Stenosis was the most common, followed by lumen occlusion (see Table

3). Their incidences in the 20 patients were as follows: 60% (stenosis, 12 cases), 45%

(occlusion, 9 cases), 30% (arterial wall thickening, 6 cases), 5% (in-situ thrombosis, 1

case), and 5% (lumen dilation, 1 case).

We further analyzed the distribution of pulmonary artery lesions in 20 cases of TA

with pulmonary artery involvement, which is summarized in Table 3. Lesions were

seen in the proximal pulmonary artery (main pulmonary artery and left and/or right

pulmonary artery trunk) in 11 cases (55%), including 4 cases (20%) where the main
pulmonary artery was involved and 10 cases (50%) where the left and/or right

pulmonary artery trunk was involved. Of the 10 patients with left and right pulmonary

artery involvement, the left pulmonary trunk was involved in 6 and the right

pulmonary trunk was involved in 8 patients. Among the patients with subsegmental

pulmonary artery involvement, 6 (30%) had bilateral subsegmental pulmonary artery

involvement, 12 (60%) had unilateral subsegmental pulmonary artery involvement,

and 5 (25%) had more than 50% subsegmental pulmonary artery involvement. The

left lung was involved in 8 cases, 5 with left upper lobe involvement and 5 with left

lower lobe involvement. The right lung was involved in 13 cases, 10 with

involvement of the right upper lobe pulmonary artery branches, 6 with involvement of

the right middle lobe pulmonary artery branches, and 8 with involvement of the right

lower lobe pulmonary artery branches.

Among the 126 patients with TA, 6 developed pulmonary hypertension, including 5

with pulmonary artery involvement and 1 without pulmonary artery involvement.

3.4.Treatment options and follow-up results of TA patients with pulmonary artery

involvement

Treatment regimens included cyclophosphamide + glucocorticoids, tocilizumab +

methotrexate + glucocorticoids , methotrexate + mycophenolatemofetil +

glucocorticoids and cyclophosphamide + methotrexate + glucocorticoids. Among the

10 patients with follow-up data, imaging lesions improved in 6 cases, showed no

changes in 3 cases, and progressed in 1 case.

 Among the 5 TA patients with pulmonary artery involvement and pulmonary

hypertension, 4 cases were re-examined with Doppler ultrasonography or right heart

catheterization. The results showed that the pulmonary artery pressure in 2 cases

returned to normal.

We further compared the pulmonary artery involvement in TA patients with and

without amelioration of pulmonary artery lesions. There were no significant

differences in the laboratory indexes and scores related to disease activity between the

two groups. However, the treatment options were markedly different. Tocilizumab

was used in 5 of the 6 patients in whom the pulmonary artery lesions improved, while

it was not used in any of the 4 patients who did not show any improvement (see Table

4).
4. Discussion

TA involvement of pulmonary arteries is rare (13). This study

summarizedinvolvement of pulmonary artery in 126 patients with TA.

In this study, pulmonary artery involvement was found to be 15.8% (20 cases) in

126 TA patients. By comparing the demographic characteristics, clinical

manifestations, imaging manifestations, laboratory indicators, and clinical activity of

TA patients with and without pulmonary artery involvement, it was found that the

symptom of hemoptysis was more common and the disease duration was longer in

patients with pulmonary artery involvement. We propose for the first time that

duration of TA greater than 5 years is an independent risk factor for pulmonary artery

involvement, with a 3.7-fold higher risk. The most common imaging manifestations

of pulmonary artery involvement were stenosis, followed by occlusion and arterial

wall thickening. Among the TA patients with pulmonary artery involvement who

completed the re-examination, the pulmonary artery lesions disappeared or improved

in 60% (6 cases), which included all the patients treated with tocilizumab (5 cases).

The proportion of pulmonary artery involvement in TA has been previously

reported to range from 6.9 to 21% (14-18, 24). The differences between the data in

these studies may be related to different races, sample sizes, and the number of

patients with pulmonary vascular screening. Since pulmonary angiography is not

routinely used for TA patients (25), screening is usually only considered when

respiratory symptoms or imaging clues are present. People with a higher proportion

of respiratory symptoms are more likely to be screened. In the present study, 20 of

 126 (15.9%) TA patients were diagnosed as having pulmonary artery

involvement.Previous literature reported that stenosis was the most common imaging

change seen in pulmonary artery lesions of TA, followed by occlusion. Unilateral

involvement was the most common, and the right lung and upper lobe were the most

common location of pulmonary artery lesions in TA (6, 13, 26). These characteristics

are consistent with our results. The proportion of pulmonary hypertension in TA

patients was 12-17.8% (14, 16). Kohava et al. (13) summarized that 19 of the 45 TA

patients with pulmonary artery involvement had pulmonary arterial hypertension in

previous case reports, but the proportion of pulmonary hypertension in TA patients

with pulmonary artery involvement was rarely reported. In our study, 25% of TA

patients with pulmonary artery involvement developed pulmonary hypertension.

Previous studies have suggested that pulmonary vascular involvement is a late

manifestation of TA (16). Our study also confirmed the same. We found that TA

patients with pulmonary artery involvement had significantly longer disease durations

than patients without pulmonary artery involvement. Further, we found that TA

patients with disease duration longer than 5 years had a 3.7-fold higher risk of

pulmonary artery involvement. Therefore, it is important to evaluate pulmonary artery

involvement in patients with a disease course of more than 5 years. The results

showed that the proportion of hemoptysis in TA patients with pulmonary artery

involvement was significantly higher than that in TA patients without pulmonary

artery involvement. The possible causes of hemoptysis in TA patients were likely

related to pulmonary artery collateral vessel rupture or small aneurysm, or to

pulmonary infarction (6). Although there were relatively few clinical symptoms in our

data, the occurrence of hemoptysis was highly suggestive of the possibility of

pulmonary artery involvement. In our study, we found that 3 of the 20 patients with

pulmonary artery involvement had hemoptysis (15%). This ratio is similar to that in

the latest study. He et al. reported that the proportion of hemoptysis in patients with

pulmonary artery involvement was 20.3% (27). However, in an early literature review,

Toledano et al. found that the incidence of hemoptysis was 42.2% (13). In the past,

the diagnosis of TA with pulmonary artery involvement was more dependent on

respiratory symptoms, while increasingly more patients without respiratory symptoms

have received a diagnosis of TA with pulmonary artery involvement through imaging

clues in recent years. This may be the main reason for the decrease in the incidence of

hemoptysis in TA with pulmonary artery involvement in recent studies.

In this study, we followed up with 10 TA patients with pulmonary artery

involvement for 7.6±2.2 months to evaluate the outcomes of pulmonary artery lesions

after treatment. We found that pulmonary artery lesions improved in 6 of the 10

patients after treatment. There was no significant difference in the index of disease

activity between pulmonary artery involvement TA patients with or without improved

pulmonary artery lesions. In 2016, Ferrante et al. (28) reported a case of effective

treatment of a pulmonary artery involved TA patient with a combination of HAP by

using tocilizumab. In our patients, pulmonary artery lesions improved in 5 TA patients

after treatment with tocilizumab. Figure 1 shows significant improvement of

pulmonary artery lesions in a patient treated with tocilizumab. Previous studies have
confirmed that IL-6 may be involved in the pathophysiological process of TA (7).

Overexpression of IL-6 in lung tissue has been found to cause pulmonary vascular

disease in animal experiments (29). In conclusion, IL-6 directly or indirectly promotes

the proliferation of vascular smooth muscle cells and endothelial cells, and IL-6

receptor antagonists can effectively treat TA patients with pulmonary hypertension. In

this study, follow-up imaging examinations confirmed for the first time that treatment

with tocilizumab can effectively improve pulmonary artery lesions in TA patients.

This study has a few limitations. In our study, patients who did not have respiratory

symptoms or imaging clues did not receive pulmonary angiography, which could

have resulted in missed diagnosis. Because of our patients’ economic conditions and

geographical limitations, most of them lived far from our hospital, so the imaging

follow-up rate was relatively low. Another limitation could be possible method of

diagnosis of pulmonary artery involvement. Furthermore, retrospective data were

entered by administrators so there is a possibility of human error. Lastly, the small

sample size may affect the statistical efficiency of the logistic regression results, and the effect of

confounding factors on the results. It is expected that further multi-center prospective

studies will be conducted in the future to further explore the characteristics of TA

cases with pulmonary vascular involvement.

In this study, the clinical characteristics of TA patients with and without pulmonary

artery involvement were compared for the first time. For TA patients with a disease

course of more than 5 years, routine screening of pulmonary angiography should be

performed because of the high risk of pulmonary artery involvement. For TA patients
with pulmonary artery involvement, the Il-6 receptor antagonist tocilizumab is a

relatively effective drug for the control of pulmonary artery lesions. Prospective

randomized controlled studies should be conducted on the treatment of TA pulmonary

artery involvement with tocilizumab.

Declarations

Ethics approval and consent to participate: All subjects provided written informed

consent. The study was conducted in accordance with the ethical principles of the

Declaration of Helsinki and approved by the Clinical Research Ethics Board of

Beijing Anzhen Hospital, Capital Medical University (approval number: 2019009X).

Consent for publication: The authors declare that there are no potential conflicts of

interest with respect to the research, authorship, and/or publication of this article.

Fundings: This project was supported by grants from the National Natural Science

Foundation of China (91739111, 81500037). The sponsors did not have a role in the

study design, data collection and analysis, decision to publish, or manuscript

preparation.

Acknowledgements: None.

Authors' contributions: XX, conceived of the study and drafted the manuscript. JD,
help to collected clinical data. JL, help to collected imaging data. GZ and QG, help
revised the manuscript. LP, guided the design of this study and modified the paper.
All authors read and approved the final manuscript.

Conflict of interest: The authors declared that they have no conflicts of interest to

this work.
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Figure legend

Figure1. Imaging of Pulmonary artery computed tomography angiography (CTA)

in a TA patient. A female patient, 49 years old, was diagnosed with TA. Pulmonary

artery CTA was performed twice with an interval of 1 year. (A) Coronal maximum

intensity projection and (B and C) posterior-anterior volume imaging of pulmonary

artery showed occlusion of right superior lobar artery and fourth-order branch of right

posterior basal segmental artery (white arrow). The patient was reexamined one year

later. (D) Coronal maximum intensity projection and (E and F) posterior-anterior

volume imaging of pulmonary artery showed no significant change in occlusion of

right superior lobar branch. The proximal segmental lumen of fourth-order branch of

right posterior basal segment appeared revascularization (white arrow).