Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

Abstract

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg−1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Macrophage–NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension

“…It is noteworthy that the drug was given one week after MCT injection to Wister rats, a week earlier than given in our study, which might increase its opportunity to improve PAH by preventing (rather than regressing) adverse pulmonary vascular remodeling. Toshner et al reported that tocilizumab (an IL-6 specific antibody) did not significantly alter PAH severity in human PAH 48 .…”

Vascular Remodeling in Pulmonary Arterial Hypertension: The Potential Involvement of Innate and Adaptive Immunity

“…In SSc, the paradigm vasculopathic disease for PAH, IL-6 serum levels were also increased when compared to healthy controls and correlated with disease severity ( 78 ). Nevertheless, due to the exclusion criteria, the major etiology of CTD-aPAH in the study of Toshner et al was SSc ( 70 ). This study showed that more patients with CTD-aPAH had a >15% reduction in PVR after 6 months of tocilizumab treatment, in comparison to IPAH/HPAH patients.…”

“…This makes IL-6 an interesting potential therapeutic target. The use of tocilizumab (anti-IL-6-receptor blocker) has been investigated for itsefficacy in PAH, in a randomized phase 2 clinical trial ( www.clinicaltrials.gov NCT02676947) ( 69 , 70 ). Six months of treatment with tocilizumab, in this selection of patients, showed no significant improvement of PVR.…”

“…Tocilizumab may therefore not be the drug of choice in patients without supportive evidence for underlying IL-6 mediated pathology. This randomized controlled trial (RCT) included world health organization (WHO) type 1 PAH patients, though CTD-aPAH patients with underlying disease like mixed connective tissue disease (MCTD), SLE and, especially, rheumatoid arthritis (RA) were excluded ( 69 , 70 ). Toshner et al argued that PAH in these patients may be rare and that they, in many cases, already used immunosuppression.…”

Smouldering fire or conflagration? An illustrated update on the concept of inflammation in pulmonary arterial hypertension

“…A potential improvement was noted in the small subgroup of patients with CTD-associated PAH. This raises the possibility that disease is driven by inflammation in only a subset of patients [47]. Other cytokines represent relevant therapeutic targets like tumour necrosis factor (TNF).…”