Takayasu arteritis-associated pulmonary hypertension

This editorial refers to ‘Clinical features and survivial in pulmonary Takayasu’s arteritis-associated pulmonary hypertension: a national registry study’, by X. Jiang et al., https://doi.org/10.1093/eurheartj/ehab599. Early diagnosis and early treatment for pulmonary Takayasu arteritis-associated pulmonary hypertension. If patients with Takayasu arteritis have symptoms from elevated pulmonary artery pressure or right ventricular dysfunction, their disease severity, expansion, and organ damage should be evaluated. If pulmonary arteries are involved, cardiac ultrasound should be performed for the screening of pulmonary hypertension. When pulmonary hypertension is suspected, right heart catheterization should be performed to diagnose pulmonary hypertension. After diagnosis of Takayasu arteritis-associated pulmonary hypertension, pateints should be treated as early as possible, for both Takayasu arteritis and pulmonary hypertension. RHF, right heart failure; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography; PA, pulmonary arteries; PTA-PH; pulmonary Takayasu arteritis-associated pulmonary hypertension. Takayasu arteritis, which was first reported by Professor Takayasu in 1908 in the Journal of Japanese Ophthalmological Society, is a systemic vasculitis that affects the aorta and its primary branches, coronary arteries, and pulmonary arteries, also known as pulseless disease.1 The main clinical features are systemic inflammation, pain due to vasculitis, and signs/symptoms of stenosis and occlusion or dilatation of blood vessels.1 It is common in females, and age at onset peaks at ∼20 years old.1 Although the aetiology of Takayasu arteritis is still unknown, environmental factors combined with genetic background may cause vasculitis mainly in the aorta via the autoimmune system, such as the HLA-B52 allele and smoking.2 Takayasu arteritis is classified by angiographic findings; type I (branches of the aortic arch), type IIa (ascending aorta, aortic arch, and its branches), type IIb (IIa lesions with the thoracic descending aorta), type III (thoracic descending aorta, abdominal aorta, and renal arteries), type IV (abdominal aorta and/or renal arteries), and type V (type IIb + IV, ascending aorta, aortic arch, and its branches, and the thoracic descending aorta as well as the abdominal aorta and/or renal arteries).1 The prevalence is reported to be 28% in type I, 16.3% in type IIa, 16.6 in type IIb, 7.3% in type III, 5.9% in type IV, 25.8% in type V, 9.0% in coronary artery involvement, and 8.3% in pulmonary artery involvement,3 indicating that pulmonary artery involvement is not rare in Takayasu arteritis. Actually, a Turkish study indicated that 5.7% of patients with Takayasu arteritis showed pulmonary hypertension (PH), which was also ∼15% in other previous studies.4 However, the prevalence of pulmonary Takayasu arteritis-associated PH (PTA-PH) might be overestimated. Symptomatic patients with PTA-PH can be more easily detected, but it is difficult to perform full screening for PH in all asymptomatic Takayasu arteritis patients during development of the disease. PH has been defined as mean pulmonary arterial pressure (PAP) ≥25 mmHg at rest as assessed by right heart catheterization,5 , 6 while it is proposed in the 6th World Symposium on Pulmonary Hypertension (WSPH)7 that PH should be defined as mean PAP >20 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood Units. In this 6th WSPH, the classification of PH was also updated, where five major categories of the disorder are classified.7 Group 1, pulmonary arterial hypertension (PAH), is characterized by the presence of pre-capillary PH in the absence of other causes of pre-capillary PH, such as PH due to lung diseases, chronic thrombo-embolic PH (CTEPH), or other rare diseases. Pulmonary veno-occlusive diseases and/or pulmonary capillary haemangiomatosis is also included in Group 1.7 Group 2, PH due to left heart disease, is characterized by the passive backward transmission of the pressure elevation (post-capillary PH). There are two types of PH due to left heart disease; one is isolated post-capillary PH, and the other is combined pre- and post-capillary PH.7 Group 3, PH due to lung diseases and/or hypoxia, is caused by hypoxic vasoconstriction as a result of lung diseases, in which PH is generally modest (mean PAP 25–35 mmHg).7 Group 4, PH due to pulmonary artery obstruction, consists of CTEPH and other pulmonary obstructions, including sarcoma or other tumours. CTEPH is caused by chronic and mechanical obstruction of central and/or distal pulmonary arteries due to thrombo-embolic masses. PH due to arteritis without connective tissue diseases is classified in Group 4.7 Group 5, PH with unclear and/or multifactorial mechanisms, consists of several remaining forms of PH7. During the last several decades, therapeutic strategies have been developed and prognosis has been improved. In Group 1, PAH, specific drug therapies, which consist of prostacyclin and its derivatives, endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and a guanylate cyclase stimulator, have been approved.6 Further, the strategy of combination therapy has been developed,6 which includes sequential (sequential addition of pulmonary vasodilators to achieve the treatment goal) and upfront (use of combined multiple drugs from the early stage of treatment) combination therapies.6 In CTEPH, pulmonary endarterectomy and/or balloon angioplasty8 have been developed, and, in medical therapy, a guanylate cyclase stimulator is approved. Some other pulmonary vasodilators will be available in the near future. Due to these advanced therapies for PH, prognosis has been improved. We have recently reported that 1-, 3-, 5-, 10-, and 15-year survival rates were 95.0, 86.3, 82.1, 73.4, and 59.1%, respectively, in overall pre-capillary PH.9 In PAH, the survival rates were 98.8, 91.9, 88.3, 82.8, and 68.5% respectively, and in CTEPH, they were 100, 88.6, 84.2, 66.5, and 44.3% respectively, in a single centre in Japan.9 The Japan PH Registry (JAPHR) reported that 1-, 2-, and 3-year survival rates were 97.0, 92.6, and 88.2%, respectively, in patients with PAH in Japan.10 It was also reported that the overall survival rates at 1, 3, and 5 years were 81.4, 72.4, and 56.9% in connective tissue disease-associated PH, 75.3, 63.0, and 50.1% in systemic sclerosis (SSc), and 84.7, 77.9, and 58.9% in systemic lupus erythematosus (SLE) in China.11 In SSc-PAH, the survival rates at 1, 2, and 3 years were 86.7, 60, and 53.3%, while they were 96, 92, and 92% in patients with SSc without PH in Brazil.12 In the current issue of the European Heart Journal, Jiang et al.13 have shown the clinical features and long-term prognosis of patients with PTA-PH, based on diagnostic right heart catheterization in a multicentre cohort study with a large enough sample size. In this study, a subset of 92 patients, who completed the first clinical assessments, showed significant improvements in N-terminal probrain natriuretic peptide (NT-proBNP), mean PAP, cardiac index, and pulmonary vascular resistance after medications approved for PAH; however, these patients did not improve their 6 min walking distance and WHO functional class. Patients with PTA-PH had an estimated 3-year survival rate of 83.2%, and most of them died due to right heart failure. Furthermore, the syncope symptoms, NT-proBNP, and mean right atrial pressure were found to be significantly associated with all-cause death. Because it has been reported that the 5- and 10-year survival rates of overall Takayasu arteritis were 92.1% and 96.1%, respectively,14 Takayasu arteritis has a worse prognosis if combined with PH. However, the prognosis of PTA-PH seems to be comparable with overall PH, and might be better than SSc-PH. Further, Jiang et al.13 also showed that patients with a normal range of inflammatory markers had worse pulmonary haemodynamics than those with elevated inflammatory markers, suggesting that they had completed the inflammation in pulmonary arteries, which had led to more severe narrowing of the pulmonary arteries. In order to prevent the development of pulmonary hypertension and to improve the outcome of PTA-PH patients, early detection and early treatment should be considered. First, we should perform image analysis of the aorta and other vessels to evaluate the severity, extension, and damage of the target organs in patients with Takayasu arteritis.15 Next, if the pulmonary arteries are involved, the combination treatment of immunosuppressive therapy for arteritis15 and specific pulmonary vasodilators for PH (although these drugs are not currently approved for PTA-PH) should be considered (Graphical Abstract). According to these findings, we should develop diagnostic and therapeutic strategies for PTA-PH in the near future. Conflict of interest: Y.F. has received research grants and honoraria from Bayer Yakuhin, Ltd, Janssen Pharmaceutical K.K., Nippon Shinyaku Co., Ltd, Mochida Pharmaceutical Co., Ltd, and Pfizer Japan Inc. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.