Vascular receptor autoantibodies implicated in SSc-PAH

By Laura Cowen, medwireNews Reporter

Autoantibodies to endothelin receptor type A (ET_AR) and angiotensin receptor type-1 (AT₁R) predict the development of, and mortality from, systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH), research suggests.

Furthermore, serum levels of the two vascular receptor autoantibodies were significantly higher among patients with SSc-PAH (n=81) and connective tissue disease (CTD)-associated PAH (n=110) than among those with other forms of PAH or pulmonary hypertension (n=106), report Gabriela Riemekasten (Charité University Hospital, Berlin, Germany) and colleagues.

These data “indicate that the anti-AT₁R and anti-ET_AR [antibodies] may have a role in risk stratification of SSc-PAH”, say the researchers.

Indeed, the majority of the patients with SSc-PAH (69.1%) and CTD-PAH (62.7%) were positive for anti-AT₁R antibodies, compared with one-fifth of those with idiopathic PAH (21.0%) or coronary heart disease (21.4%) and just 8% of those with chronic thromboembolic pulmonary hypertension. A similar pattern was observed for anti-ET_AR antibodies.

During a prospective 73-month follow-up of 253 patients with SSc, 36 were diagnosed with PAH. Statistical analyses showed that the presence of either autoantibody, at levels above 19 units for anti-AT₁R and 23 units for anti-ET_AR, significantly predicted the development of PAH in the SSc patients, at hazard ratios of 4.3 and 3.5, respectively.

In addition, AT₁R and ET_AR levels above 16 and 18 units, respectively, predicted SSc-PAH mortality, with a sensitivity of 68.2% for each and respective specificities of 62.2% and 71.1%. Furthermore, patients with raised anti-ET_AR antibody levels had a 2.7-fold higher risk for death than those whose levels were below the 18-unit cut-off, but there was no significant association for the anti-AT₁R antibodies in this cohort.

The researchers also found that the autoantibodies’ ability to predict PAH and its mortality was comparable to or better than that of known haemodynamic risk factors.

To investigate the contribution of anti-AT₁R and ET_AR antibodies to the pathogenesis of SSc-PAH, Riemekasten and team carried out imaging experiments in lungs isolated from rats, and antibody transfer experiments in mice.

They found that both receptor autoantibodies induced endothelial cell activation in isolated rat lungs, which could be blocked by respective specific receptor antagonists, and augmented vasoconstriction in response to natural ligands in rat pulmonary resistance vessels.

Furthermore, passive transfer of anti-AT₁R and anti-ET_AR antibody–positive human SSc-IgG increased airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy in mice.

Taken together, these findings “unify autoimmune receptor activation processes with increased vascular reactivity and vascular remodeling”, say the researchers.

Writing in the American Journal of Respiratory and Critical Care Medicine, Riemekasten and co-authors conclude: “Although therapeutic implications of our findings remain to be established, the current study implies a contribution of functional autoimmunity to the development of PAH-associated vasculopathy.”

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