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Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

Becker MO, Kill A, Kutsche M, Guenther J, Rose A, Tabeling C, et al. Am J Respir Crit Care Med;190(7):808-817

Background: Pulmonary arterial hypertension (PAH) is a frequent complication of systemic sclerosis (SSc) and early detection is critical for improving outcomes. Biomarkers of PAH in SSc are a promising avenue for screening at-risk patients for pulmonary hypertension. Endothelin-1 (ETAR) and angiotensin II (AT1R) receptors have been implicated in the pathogenesis of PAH, and are linked to risk for vascular complications in SSc.

Methods and Results: Levels of anti-AT1R and anti-ETR were measured using ELISA on serum samples from patients in the following cohorts: SSc-PAH (n=67), SSc no-PAH (n=217), idiopathic PAH (iPAH, n=62), chronic thromboembolic pulmonary hypertension (CTEPH, n=31), congenital heart disease (CHD, n=14), and PAH from unspecified connective tissue diseases (CTD-PAH, n=110).  Levels of anti-AT1R and anti-ETAR were significantly higher in SSc-PAH and CTD-PAH compared to patients with iPAH, CTPEH, or CHD. These levels were slightly higher in the cohort of SSc patients without PAH compared to SSc patients with PAH. Antibody levels did not show any significant correlation with hemodynamic parameters or NT-proBNP; however, there was a strong (r2=0.81) correlation between anti-AT1R and anti-ETAR levels. The sensitivity and specificity of anti-AT1R and anti-ETAR levels to differentiate SSc-PAH from other causes of PAH was 68.8-70.0% and 78.0-82.4%, respectively.

In a prospective follow up study of 253 SSc patients without PAH at baseline (mean observation period=73 months), 36 developed PAH. In a receiver operating characteristics analysis, the area under the curve for predicting PAH development in this cohort was 0.642 for baseline levels of anti-AT1R and 0.633 for anti-ETAR, which was comparable to the predictive ability of NT-proBNP. In a multivariate analysis, systolic pulmonary artery pressure on echo (cut-off=22.5) was the only independent predictor of PAH. In a sub-analysis of 70 prospective patients, patients positive for anti-ETAR were at a higher risk for death compared to those negative for this antibody; anti-AT1R did not show similar predictive characteristics.

 To explore the potential pathogenic effects of these antibodies, IgG from SSc patients induced an increase in endothelial calcium in the rat pulmonary vasculature, which was blocked by valsartan and sitaxsentan. No such increase in calcium occurred in response to IgG from controls.  Using small-vessel myography of rat intralobar pulmonary artery ring segments, anti-AT1R and anti-ETAR antibodies magnified the vasoconstrictive responses to ET-1 and angiotensin II, which were blocked by bosentan and valsartan, respectively. Lastly, IgG from SSc or healthy controls were injected into mice. SSc-IgG increased alpha-smooth muscle actin expression around the walls of small pulmonary vessels after a single injection, and repetitive injections led to obliterative pulmonary arteriopathy. However, pulmonary vascular resistance and right ventricular hypertrophy were not seen after SSc-IgG injections.

Conclusions: Levels of vascular receptor autoantibodies anti-AT1R and anti-ETAR were elevated in SSc-PAH and CTD-PAH compared to other forms of pulmonary hypertension. Autoantibody levels were also elevated in SSc patients without PAH. Baseline levels of these autoantibodies had a fair predictive value for the development of incident PAH in a prospective cohort. In pre-clinical experiments, there is a suggestion that anti-AT1R and anti-ETAR may participate in the pathogenesis of vascular endothelial reactivity and arteriopathy.

Expert Commentary:

Functionally active, stimulatory auto-antibodies are attractive to explain pathophysiological features of autoimmune diseases. In systemic sclerosis (SSc), stimulatory autoantibodies to platelet-derived growth factor receptors (PDGFR) have been described1). These stimulatory antibodies were present in SSc patients, but not in controls including other autoimmune diseases, and induced functional effects such as the production of reactive oxygen species and myofibroblast conversion. However, other studies could not reproduce these findings2-4, showing the challenges in this research area. Possible explanations for the inconsistent results may be the requirement of specific receptor confirmations to allow binding of the agonistic autoantibodies and the presence of a mixture of both agonistic, neutral and antagonistic autoantibodies. This mixture of different functional autoantibodies is also seen in Graves’ disease, which has confirmed stimulatory autoantibodies to the thyroid stimulating hormone receptor (TSHR)5.

In this paper by Becker et al, the authors provide exciting clinical and preclinical results supporting a role for stimulating autoantibodies targeting and activating endothelin receptor type A (ETAR) and Angiotensin receptor type-1 (AT1R) in the pathogenesis of SSc-PAH. This study follows other publications showing additional associations of these antibodies with lung fibrosis, digital ulcers and overall survival6-7. Furthermore, pathophysiological effects favoring the pathogenesis of SSc were analyzed using microvascular endothelial cells, fibroblasts, peripheral blood mononuclear cells and IgG transfer into naïve C57BL/6J mice8-9. These circumstantial data open new perspectives for the pathophysiology and possibly also for the treatment of SSc patients.

As with every novel pathophysiological pathway, further work will have to address additional aspects of these stimulating autoantibodies. For example, considering the experience with the stimulatory PDGFR antibodies and the fact that a recent smaller study could in part not reproduce the findings10, confirmation in additional cohorts will be important. Do the stimulatory antibodies require specific receptor confirmations? Are there both agonistic and antagonistic antibodies as in Graves' disease that could explain different findings? In light of the overlap of SSc patients with and without PAH, with other autoimmune diseases and with IPAH, are there subtypes of stimulatory antibodies that might be more important than others or are there subgroups of patients in which these specific subtypes of antibodies might play a more prominent role?  As the in vivo mice experiments were able to reproduce some, but not all patho-anatomical features of SSc vasculopathy, what could be the other factors that synergize with the stimulating ETAR and AT1R antibodies to cause the full phenotype? Can the role of these autoantibodies also be confirmed in other animal models of SSc? These and other future experiments should provide additional support for a role of stimulating ETAR and AT1R antibodies in SSc.

Article summary by: Matthew Lammi, MD; Assistant Professor of Clinical Medicine, Louisiana State University Health Sciences Center

Expert commentary by: Oliver Distler, MD, Professor of Inflammatory Rheumatology, Division of Rheumatology, University Hospital Zurich, Switzerland


  1. Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, et al. Stimulatory autoantibodies to the PDGF receptor in system Loizos N, LaRiccia L, Weiner J, Griffith H, Boin F, Hummers L, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor  in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 2009;60:1145–51.

  2. Classen JF, Henrohn D, Rorsman F, Lennartsson J, Lauwerys BR, Wikstrom G, et al. Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum 2009;60:1137–44.

  3. Balada E, Simeon-Aznar CP, Ordi-Ros J, Rosa-Leyva M, Selva-O’Callaghan A, Pardos-Gea J, et al. Anti-PDGFR- antibodies measured by non-bioactivity assays are not specific for systemic sclerosis. Ann Rheum Dis 2008;67:1027–9.

  4. Loizos N, LaRiccia L, Weiner J, Griffith H, Boin F, Hummers L, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor  in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 2009;60:1145–51.

  5. Dragun D, Distler JH, Riemekasten G, Distler O. Stimulatory autoantibodies to platelet-derived growth factor receptors in systemic sclerosis: what functional autoimmunity could learn from receptor biology. Arthritis Rheum. 2009 Apr;60(4):907-11. doi: 10.1002/art.24364.

  6. Riemekasten G, Philippe A, Näther M, Slowinski T, Müller DN, Heidecke H, Matucci-Cerinic M, Czirják L, Lukitsch I, Becker M, Kill A, van Laar JM, Catar R, Luft FC, Burmester GR, Hegner B, Dragun D. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis. 2011 Mar;70(3):530-6.

  7. Avouac J, Riemekasten G, Meune C, Ruiz B, Kahan A, Allanore Y. Autoantibodies against Endothelin 1 Type A Receptor Are Strong Predictors of Digital Ulcers in Systemic Sclerosis. J Rheumatol. 2015 Aug 1. pii: jrheum.150061. [Epub ahead of print].

  8. Günther J, Kill A, Becker MO, Heidecke H, Rademacher J, Siegert E, Radić M, Burmester GR, Dragun D, Riemekasten G. Angiotensin receptor type 1 and endothelin receptor type A on immune cells mediate migration and the expression of IL-8 and CCL18 when stimulated by autoantibodies from systemic sclerosis patients. Arthritis Res Ther. 2014 Mar 11;16(2):R65.

  9. Kill A, Tabeling C, Undeutsch R, Kühl AA, Günther J, Radic M, Becker MO, Heidecke H, Worm M, Witzenrath M, Burmester GR, Dragun D, Riemekasten G. Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. Arthritis Res Ther. 2014 Jan 28;16(1):R29.

  10. Becker MO1, Riemekasten G. Reply: vascular receptor autoantibodies in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015 Mar 1;191(5):602-3. doi: 10.1164/rccm.201412-2322LE.

Last Reviewed: September 2016