The Registry Study of Takayasu Arteritis in East China

1. Overview of Takayasu's arteritis.

Takayasu arteritis (TA) is a chronic inflammatory blood vessel that seriously endangers human health, which affects a large variety of blood vessels, characterized by vascular stenosis and occlusion. The clinical manifestations of TA are hypertension, renal failure caused by renal artery stenosis; pulseless, syncope and cerebral infarction caused by carotid vessels stenosis; pulmonary infarction induced by thoracic aorta involvement, etc. The TA usually accompanies high morbidity, high mortality, and poor prognosis. TA is a rare disease which is prone to occur in Asian women, especially in young women (20-40 years old) in the growth period. Currently, the etiology and pathogenesis of TA remain unclear, and the state of the disease is often repeatedly active and continuously progressive. Moreover, non-effective therapy exists for the moment.

2. The diagnosis and activity evaluation of TA

At present, TA is diagnosed according to the American Society of Rheumatology (ACR) classification criteria for Takayasu's arteritis: ① onset at age ≤40 years; ② claudication of an extremity; ③ decreased brachial artery pulse; ④ >10 mm Hg difference in systolic blood pressure between arms; ⑤ a bruit over the subclavian arteries or the aorta; ⑥ and arteriographic evidence of narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities. Participants who meet 3 or more criteria could be diagnosed with this disease posterior to excluding atherosclerosis, congenital muscle fiber dysplasia, etc.

The course of TA is often manifested as chronic, repetitive activity and continuous progression. The evaluation standard proposed by Kerr et al. to monitor TA activity is widely used clinically. Two more new emerging or aggravating clinical manifestations indicates disease Activity: ① systemic symptom, such as fever, bones, muscle symptoms; ② increased erythrocyte sedimentation rate (ESR); ③characteristics of vascular ischemia or inflammation: such as intermittent claudication, pulse weakening or pulseless, vascular bruit, vascular pain, asymmetry blood pressure, etc.; ④ abnormalities in angiography. Although acute phase response protein such as ESR and C-reactive protein (CRP) are non-specific indicators for inflammation, they are still important markers to evaluate the disease activity. Imaging follow-up, primarily based on magnetic resonance imaging (MRI) and color Doppler ultrasound, is critical in assessing TA disease activity. With the help of Pro. Jiang Lin and Dr. Lu Peng, investigators have established an imaging diagnostic team in recent years and proposed the systemic MRI scoring standard in the international firstly. The standard has been applied to quantitatively assess the vascular inflammation prior and posterior to the treatment in participants with TA. Recently, investigators co-operated with the Department of Nuclear Medicine and Radiology to employ the 18F-FDG-PET/CT to evaluate the systemic vascular inflammation and disease activity in participants. Moreover, investigators attempted to use contrast-enhanced ultrasound microbubble imaging to assess the carotid artery inflammation and stenosis. At present, these two technologies are still being explored. Therefore, it is necessary to combine the clinical manifestations, acute phase response proteins (ESR and CRP) and imaging to judge the TA disease activity comprehensively.

3. Treatment of arteritis

The treatment of TA is divided into two phases: remission induction period and maintenance period. The drugs are divided into three categories including glucocorticoids, cytotoxic drugs, and biological agents targeting inflammatory cytokines.

Glucocorticoids are the basic drug for TA treatment. Most TA participants receiving high doses of glucocorticoids treatment could be induced remission quickly, but about 17%-29% of refractory participants treated with standard glucocorticoids strategy could not be alleviated. And the recurrence rate is up to 90% with the single glucocorticoid. About more than 2/3 of participants would be glucocorticoid-dependent, and more than half of the participants need other drugs to maintain remission. Moreover, long-term high-dose glucocorticoids also have many adverse effects.

Recently, targeted biological agents have been attempted to treat refractory, recurrent TA and glucocorticoid-dependent remission induction TA participants. Compared with conventional drugs, targeted biological agents work faster and could bring disease remissions for 70%-90% of refractory participants. However, the long-term use of biological agents would threaten the low-immunity participants with the risk of infections and cancer. Moreover, the effect on the reproductive system is unclear for the moment; in addition, these drugs are expensive and mainly used in refractory and critically ill participants.

The combination of glucocorticoids combining with immunosuppressive agents such as cyclophosphamide, methotrexate, azathioprine, mycophenolate mofetil, etc. are the commonly used remission induction strategy clinically. However, large amounts of clinical evidence demonstrate that TA participants receiving glucocorticoids with the immunosuppressive agents would also face the histopathological activities lesions in the future. In the long-term follow-up, the relapse rate is much higher, and the mortality rate is significantly higher than that of healthy people.

In summary, the current commonly used drugs for TA treatment could not meet the needs of the clinical setting, and TA participants lack a universally effective treatment strategy.

4. Pregnancy of TA participants

TA often occurs in women of childbearing age, so reducing the risk of maternal pregnancy caused by pregnancy in TA participants is one of the investigators' focuses in recent years. At present, there are no relevant guidelines for the pregnancy of TA participants, and doctors instruct them to take pills and monitor disease activity mainly basing on the doctor's clinical experience. Usually, investigators do not recommend the TA participants in active phase to conceive, not only because that the use of hormones and cytotoxic drugs could influence the development of the fetus, but also because that the stenosis or occlusion of the distal artery would increase the cardiac load so as to cause congestive heart failure, pre-eclampsia as well as fetal growth restriction and stillbirth. A case-control study in Brazil recruiting 89 TA and 89 healthy pregnant women discovered that the risk of gestational hypertension and low birth weight was much higher in TA than that in healthy controls. Moreover, the perinatal mortality rate is much higher in TA pregnant participants as well. A retrospective study in France including 96 TA pregnant women, 240 cases of pregnancy events, revealed that TA did not affect the pregnancy outcomes, but increased the risk of complications such as pregnancy hypertension with the elevating of the disease activity. Therefore, there is a lack of large-scale evidence-based medical proof uncovering the relationship between the pregnancy outcome and maternal risk in participants of TA. Here, the present follow-up registration also extends to the service of pregnant TA participants, which is designed to guide the treatment of pregnant participants and monitor maternal safety.

This objective of this study is to record the related materials of the follow-up of TA participants and the pregnancy course, to direct the standardized medication, to monitor the changes of disease conditions, and to provide the better prognosis and pregnancy outcome for TA participants.