Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Abstract

Pulmonary arterial hypertension (PAH) is a serious complication of connective tissue disorders (CTDs), and CTD-PAH is the second cause of PAH after the idiopathic form. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which can lead to right heart failure and death. About 90% of CTD-PAH cases are associated with systemic sclerosis (SSc, 74%), mixed connective tissue disease (MCTD, 8%) or systemic lupus erythematosus (SLE, 8%). CTD-PAH has also been reported, albeit rarely, in Sjögren syndrome, inflammatory idiopathic myopathies and rheumatoid arthritis. As for idiopathic PAH, the impaired production of vasoactive mediators such as nitric oxide and prostacyclin, and the increased production of vasoconstrictors and proliferative mediators such as endothelin-1, affect the vascular tone and promote vascular remodeling. Moreover, there is growing evidence suggesting that inflammation and autoimmunity may contribute to the genesis and progression of CTD-PAH, especially in SLE and MCTD patients who require an early administration of corticosteroids and immunosuppressants in order to avoid irreversible pathologic changes in pulmonary vessels. Conversely, immunosuppressive agents are ineffective in SSc-PAH, which requires a timely and aggressive treatment with specific PAH therapies (combination therapy). In this review, we summarized the current data on the pathophysiology and treatment of CTD-PAH. Impact statement Our article focuses on the pathogenesis and treatment of CTD-PAH. In the latest ESC/ESR guidelines for PAH, the authors underline that although CTD-PAH should follow the same treatment protocol as idiopathic PAH, the therapeutic approach is more complex and difficult in the former. This review throws light on several peculiar aspects of CTD-PAH and the latest findings in the pathogenesis, namely, the role of inflammation in the maladaptive right ventricle remodeling in SSc-PAH where immunosuppressants are classically believed to be ineffective. Furthermore, we discuss the major critical points in the therapy of CTD-PAH which is one of the strengths of our article. To the best of our knowledge, there are no other reviews that exclusively focus on the pathogenesis and treatment of CTD-PAH patients, with an emphasis on the more critical issues. Thus, it is our contention that our work would be of interest to the readers.

Role of Gas6 and TAM Receptors in the Identification of Cardiopulmonary Involvement in Systemic Sclerosis and Scleroderma Spectrum Disorders

“…In our population, sMER concentration in plasma was increased in CTD-PAH, while neither that of Gas6 nor of sAxl was different according to this complication. Endothelial dysfunction is known to be a key impairment of CTD-PAH sustained by a mismatch of mediators acting as vasodilators in favour of vasoconstrictors; this process evolves with the activation of vascular remodelling towards an increase of vascular tone mediated by the endothelium and vascular smooth muscle cell (VSMC) activation [35]. Gas6/TAM interplay is known to be involved in vessel wall homeostasis: Gas6 was isolated from aortic endothelial cells, and it has a trophic effect on vessel walls; additionally, the Gas6/TAM system is activated in case of vessel damage or in human atherosclerotic plaque formation [14,36].…”

“…Possibly, sMER increase in these patients could be an expression of endothelial stress and dysfunction, typical of PAH. One additional possible explanation comes from the other mainstay of the pathogenesis of CTD-PAH, the presence of persistent inflammation of pulmonary vessel walls [35]. TAM receptors, indeed, are involved in regulation of innate immunity, being upregulated in activated antigen-presenting cells (APCs) through type I interferon (IFN) signalling that determines the activation of suppressor of cytokine signalling proteins (SOCS1 and SOCS3) which, in turn, dampens the inflammatory response [37,38].…”

Controversies and advances in connective tissue disease‐related pulmonary arterial hypertension

“…The remaining cases of CTD-PAH are typically associated with primary Sjögren's syndrome (pSS), idiopathic inflammatory myopathies (IIM) and rheumatoid arthritis (RA). 2,3 In contrast to above prevalence reports which largely consist of Caucasian populations, a large Chinese study identified SLE as the predominant cause of CTD-PAH, accounting for 58.4%, while SSc accounted for only 26.3% of cases. 4 In SSc, PAH occurs with a prevalence of 8%-12% and is the leading cause of mortality, accounting for 25%-40% of SSc-related deaths.…”

“…4 In SSc, PAH occurs with a prevalence of 8%-12% and is the leading cause of mortality, accounting for 25%-40% of SSc-related deaths. 2,5 In SLE, the prevalence of PAH ranges 1%-5% 6 depending on the ethnicity of the population studied, with a recent Chinese study reporting a prevalence of SLE-PAH as high as 12.8%. 6 Similar to SSc, the presence of PAH in SLE is an independent predictor of mortality.…”

The dynamics of endothelial dysfunction markers among patients with pulmonary hypertension on the background of chronic obstructive pulmonary disease under the influence of treatment

“…Стійка вазоконстрикція, порушення балансу між вазодилатуючими і вазоконстрикторними речовинами, звуження просвіту спричиняє потовщення легеневої артерії, що, у свою чергу, призводить до стійкого підвищення тиску в ній. Цей судинозвужувальний ефект посилюється за рахунок зниження судинорозширювальної здатності дистального відділу легеневої артерії [10,11]. Ураження ендотелію можна розглядати як інтегративний концентратор, що запускає множинні патофізіологічні шляхи розвитку легеневої гіпертензії у хворих на ХОЗЛ.…”