Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension

Abstract

Patients with connective tissue disease-associated pulmonary arterial hypertension (PAH-CTD) have a poor prognosis compared with other aetiologies. The underlying CTD can influence treatment response and outcomes. We characterised the GRIPHON study PAH-CTD subgroup and evaluated response to selexipag.Of 334 patients with PAH-CTD, PAH was associated with systemic sclerosis (PAH-SSc) in 170, systemic lupus erythematosus (PAH-SLE) in 82 and mixed CTD/CTD-other in 82. For the primary composite endpoint of morbidity/mortality, hazard ratios (HR) and 95% CI were calculated using Cox proportional hazard models.Compared with the overall GRIPHON population, the CTD subgroup was slightly older with a greater proportion of females and shorter time since diagnosis. Patients with PAH-SSc appeared to be more impaired at baseline, with a more progressive disease course. The converse was observed for PAH-SLE. Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-CTD by 41% (HR 0.59; 95% CI 0.41–0.85). Treatment effect was consistent irrespective of baseline PAH therapy or CTD subtype (interaction p=0.87 and 0.89, respectively). Adverse events were predominately prostacyclin-related and known for selexipag treatment.GRIPHON has allowed the comprehensive characterisation of patients with PAH-CTD. Selexipag delayed progression of PAH and was well-tolerated among PAH-CTD patients, including those with PAH-SSc and PAH-SLE.

Pulmonary hypertension in systemic sclerosis: different phenotypes

“…Notably, the incidence of post-capillary PH (group 2) was in the same range [12]. Moreover, in the DETECT study, the prevalence of group 2 PH was 6%, as was that of group 3 PH [14], highlighting the importance of properly phenotyping PH in patients with SSc [7,11,12].…”

“…Moreover, SSc-PAH patients are most often less responsive than patients with idiopathic PAH and have a worse prognosis, although they present with milder haemodynamic impairment [2][3][4][5]. However, recent studies have suggested that where aggressive therapy is used, a similar reduction in event rate is achievable in SSc and idiopathic PAH populations [6,7]. The reasons why SSc-PAH patients could exhibit different behaviour than patients with other forms of PAH is still a matter of debate.…”

Pulmonary arterial hypertension associated with connective tissue diseases: A review focusing on distinctive clinical aspects

“…The soluble guanylate cyclase stimulator riociguat has been shown by a recent post hoc analysis from a double‐blinded randomized control trial to be well tolerated and to lead to improvement or stabilization of 6MWD, WHO FC and haemodynamics in 66 SSc‐PAH and 39 other CTD‐PAH patients, although the effect was less pronounced than in the overall study population, particularly in the SSc‐PAH group . In another post hoc analysis with a large number of CTD‐PAH patients including 170 SSc‐PAH, 82 SLE‐PAH, and 82 MCTD or other CTD‐PAH, the prostacyclin receptor agonist selexipag was well tolerated and delayed the progression of PAH irrespective of CTD subtype . AMBITION trial demonstrated the superiority of initial upfront combination therapy with the ERA ambrisentan and the PDE5i tadalafil in terms of lowering the risk of clinical failure events in PAH patients compared to ambrisentan or tadalafil monotherapy.…”

“…42 In another post hoc analysis with a large number of CTD-PAH patients including 170 SSc-PAH, 82 SLE-PAH, and 82 MCTD or other CTD-PAH, the prostacyclin receptor agonist selexipag was well tolerated and delayed the progression of PAH irrespective of CTD subtype. 43 AMBITION trial 44 demonstrated the superiority of initial upfront combination therapy with the ERA ambrisentan and the PDE5i tadalafil in terms of lowering the risk of clinical failure events in PAH patients compared to ambrisentan or tadalafil monotherapy. In a post hoc analysis from the AMBITION trial, SSc-and other CTD-PAH patients have also been shown to benefit from the initial upfront combination therapy, although the eligibility criteria were amended to require more rigorous haemodynamic measurements to exclude patients in whom other forms of PH than PAH were expected to coexist.…”

The Selective Prostacyclin (Ip) Receptor Agonist Selexipag: A Promising Drug in Pediatric Pulmonary Artery Hypertension

“…The underlying CTD is thought to influence treatment response and outcomes. Recently, a subgroup analysis from the GRIPHON trial [4] showed that Selexipag delayed progression of PAH and was well-tolerated among PAH-CTD patients, including those with PAH due to a systemic lupus erythematodes [5]. The efficacy of selexipag was seen by improvements in pulmonary hemodynamics, exercise capacity, and clinical symptoms in a cohort of adult Japanese PAH patients [6].…”