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Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility.
QJM. 2013 Sep; 106(9):839-48.QJM

Abstract

BACKGROUND

We have studied endothelin-1 (ET-1) levels and ET-1 ligand and receptor tissue expression in scleroderma renal crisis (SRC) and undertaken a pilot open label safety study of bosentan, a non-selective ET-1 receptor antagonist, in SRC [Bosentan in Renal Disease-1 (BIRD-1)].

METHODS

Serum levels of ET-1 were measured in healthy controls (n = 20) or systemic sclerosis (SSc) (n = 80) with or without SRC, including cases of pulmonary arterial hypertension (PAH). Renal biopsies (n = 27) from patients with SRC were stained for endothelin ligand and receptors. Six cases of SRC received 6 months bosentan. Outcome measures were compared with SRC cases managed at our centre from 2000 to 2004 (n = 49).

RESULTS

Serum ET-1 was elevated in SRC but less than in PAH. ET-1 and both endothelin A and endothelin B receptor expression was increased in SRC biopsies in glomeruli, interstitium and hallmark vascular lesions of SRC. In the BIRD-1 cohort, serum ET-1 was elevated in all cases at SRC (median healthy controls 0.50 pg/ml; SRC 1.48 pg/ml; P < 0.0005), and increased further with bosentan therapy (1.46 vs. 3.05 pg/ml; t-test P < 0.05). Bosentan was well tolerated with no significant drug-related serious adverse events and long-term outcomes were favourable compared with historic cases. Three patients developed rebound hypertension on withdrawal of bosentan and one appeared to further benefit from maintenance therapy.

CONCLUSION

Upregulation of ET-1 ligand axis suggests that ET-1 receptor blockade is logical and treatment with bosentan appears to be safe in SRC. Future studies to assess therapeutic benefit and compare selective or non-selective receptor antagonists are justified.

Authors+Show Affiliations

Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital and UCL Medical School, Pond Street, London NW3 2QG, UK. c.denton@ucl.ac.uk.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23696678

Citation

Penn, H, et al. "Targeting the Endothelin Axis in Scleroderma Renal Crisis: Rationale and Feasibility." QJM : Monthly Journal of the Association of Physicians, vol. 106, no. 9, 2013, pp. 839-48.
Penn H, Quillinan N, Khan K, et al. Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility. QJM. 2013;106(9):839-48.
Penn, H., Quillinan, N., Khan, K., Chakravarty, K., Ong, V. H., Burns, A., & Denton, C. P. (2013). Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility. QJM : Monthly Journal of the Association of Physicians, 106(9), 839-48. https://doi.org/10.1093/qjmed/hct111
Penn H, et al. Targeting the Endothelin Axis in Scleroderma Renal Crisis: Rationale and Feasibility. QJM. 2013;106(9):839-48. PubMed PMID: 23696678.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility. AU - Penn,H, AU - Quillinan,N, AU - Khan,K, AU - Chakravarty,K, AU - Ong,V H, AU - Burns,A, AU - Denton,C P, Y1 - 2013/05/21/ PY - 2013/5/23/entrez PY - 2013/5/23/pubmed PY - 2014/9/4/medline SP - 839 EP - 48 JF - QJM : monthly journal of the Association of Physicians JO - QJM VL - 106 IS - 9 N2 - BACKGROUND: We have studied endothelin-1 (ET-1) levels and ET-1 ligand and receptor tissue expression in scleroderma renal crisis (SRC) and undertaken a pilot open label safety study of bosentan, a non-selective ET-1 receptor antagonist, in SRC [Bosentan in Renal Disease-1 (BIRD-1)]. METHODS: Serum levels of ET-1 were measured in healthy controls (n = 20) or systemic sclerosis (SSc) (n = 80) with or without SRC, including cases of pulmonary arterial hypertension (PAH). Renal biopsies (n = 27) from patients with SRC were stained for endothelin ligand and receptors. Six cases of SRC received 6 months bosentan. Outcome measures were compared with SRC cases managed at our centre from 2000 to 2004 (n = 49). RESULTS: Serum ET-1 was elevated in SRC but less than in PAH. ET-1 and both endothelin A and endothelin B receptor expression was increased in SRC biopsies in glomeruli, interstitium and hallmark vascular lesions of SRC. In the BIRD-1 cohort, serum ET-1 was elevated in all cases at SRC (median healthy controls 0.50 pg/ml; SRC 1.48 pg/ml; P < 0.0005), and increased further with bosentan therapy (1.46 vs. 3.05 pg/ml; t-test P < 0.05). Bosentan was well tolerated with no significant drug-related serious adverse events and long-term outcomes were favourable compared with historic cases. Three patients developed rebound hypertension on withdrawal of bosentan and one appeared to further benefit from maintenance therapy. CONCLUSION: Upregulation of ET-1 ligand axis suggests that ET-1 receptor blockade is logical and treatment with bosentan appears to be safe in SRC. Future studies to assess therapeutic benefit and compare selective or non-selective receptor antagonists are justified. SN - 1460-2393 UR - https://www.unboundmedicine.com/medline/citation/23696678/Targeting_the_endothelin_axis_in_scleroderma_renal_crisis:_rationale_and_feasibility_ L2 - https://academic.oup.com/qjmed/article-lookup/doi/10.1093/qjmed/hct111 DB - PRIME DP - Unbound Medicine ER -