One possible reason for the attenuated effect of riociguat may be that sGC stimulators rely on haem-bound NO to modulate the cGMP pathway.19 Under hypoxic conditions or oxidative stress, such as in the skin and other fibrotic tissues of patients with SSc, their efficacy may be lower, leading to a reduced cGMP pathway response.19,24 In contrast, sGC activators directly bind to the haem site, independently of haem and NO, thereby stabilising sGC in an active form, allowing cGMP production, even in environments of hypoxia and oxidative stress.19 This evidence concerns the gene SGCB and systemic sclerosis.