Background/Purpose:

Scleroderma renal crisis (SRC), a life-threatening complication of systemic sclerosis (SSc), arises despite therapy combining an angiotensin-converting–enzyme inhibitor (AECI) and/or dialysis. Endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide, has been implicated in SSc pathogenesis. Plasma ET-1 levels are elevated in SSc patients with SRC. Bosentan, a non-selective ET-1–receptor antagonist, was approved to treat pulmonary arterial hypertension and prevent SSc ischemic digital ulcers. Those findings suggested that bosentan could have therapeutic benefits on other vascular manifestations of SSc, particularly SRC. This open-label national prospective study evaluated the efficacy and tolerance of bosentan for 6 months combined with an ACEI and/or dialysis on renal and overall survival of SSc patients with SRC.

Methods:

SRC was defined as rapidly progressive oliguric renal insufficiency and/or rapidly progressive arterial hypertension. All patients received Bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 5 months, in addition to the usual recommended treatments. The primary end-point was kidney survival at 12 months. Secondary endpoints were patient survival and Bosentan side effects at 12 months.

Results:

Between March 2011 and April 2014, 16 patients (10 (62.5%) females; median age 65.3 [range 46.3–71.3] years) were enrolled. Twelve (75%) patients had diffuse SSc, 1 (6.3%) had limited cutaneous SSc and 3 (18.8%) had limited SSc. Four (25%) had pulmonary fibrosis, 3 (18.8%) left ventricular insufficiency and 3 (18.8%) severe bowel involvement. Renal biopsies obtained from 14 patients showed specific vascular SRC lesions. Prior to SRC, 11 (68.8%) patients had taken corticosteroids and 6 (37.5%) were taking an ACEI for hypertension. SRC recurred in 1 patient 2 years after kidney transplantation. Four (25%) patients had normotensive SRC. Seven (43.8%) patients achieved the primary end-point of dialysis-free status. Only 9 (56.3%) patients were alive at 12 months. Seven (43.8%) patients were dialyzed, 6 of them within the first 10 days of inclusion. One patient was dialyzed at month 4 for multivisceral failure and septic shock. No patients on dialysis at baseline came off dialysis. One patient developed an SRC relapse at 6 months. Renal function of dialysis-free survivors did not improve on bosentan, with a mean [range] estimated glomerular filtration rate at entry of 22 [22–49] vs. 16 [11.5–23.5] ml/min/1.73 m² at SRC onset. Seven (43.8%) patients died; 4 (57.1%) of those deaths were not SSc-related. The 3 SSc‐related deaths resulted from severe organ involvement (lung fibrosis, intestinal involvement or associated myositis). No patient suffered serious adverse effects requiring bosentan withdrawal.

Conclusion:

Bosentan does not seem to improve renal outcomes and survival is no better than in historical series¹. However, the high non-SSc–attributable mortality makes drawing any definitive conclusion difficult. Further investigations are needed.

1.Guillevin L et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls. Rehumatology (Oxford). 2012: 460-7

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bosentan-in-scleroderma-renal-crisis-a-national-open-label-prospective-study/