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Complement activation and effect of eculizumab in scleroderma renal crisis.

ABSTRACT: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved.Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the kidney, in the absence of genetic defect of the complement system.Immunofluorescence studies on kidney biopsy showed significant deposits of C1q and C4d in the endothelium of renal arterioles, pointing toward activation of the classical pathway. Because of the dramatic clinical and histological severity, and the lack of response to early treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers and plasma exchange, the patient was treated with the specific C5 blocker eculizumab.Contrarily to conventional treatment, eculizumab efficiently blocked C5b-9 deposition ex vivo and maintained hematological remission. Unfortunately, the patient died from heart failure a few weeks later. Postmortem examination of the heart showed diffuse patchy interstitial fibrosis, the typical lesion of systemic sclerosis-related cardiomyopathy, but normal coronary arteries and myocardial microvasculature.SRC may lead to complement system activation through the classical pathway. Early administration of C5 inhibitor eculizumab may have therapeutic potential in patients with life-threatening SRC refractory to conventional treatment using angiotensin-converting enzyme inhibitors.

SUBMITTER: Devresse A

PROVIDER: S-EPMC5265879 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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Complement activation and effect of eculizumab in scleroderma renal crisis.

Devresse Arnaud A Aydin Selda S Le Quintrec Moglie M Demoulin Nathalie N Stordeur Patrick P Lambert Catherine C Gastoldi Sara S Pirson Yves Y Jadoul Michel M Morelle Johann J

Medicine 20160701 30

<h4>Background</h4>Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved.<h4>Methods</h4>Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the ...[more]

PMID: 27472742

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Project description:Introduction/objectivesScleroderma is a rare complication in taxanes therapy. Although individual cases of taxanes-induced scleroderma have been reported, the clinical manifestation and treatment outcomes were reviewed and summarized rarely. This study reported a patient who developed diffuse scleroderma and possible scleroderma renal crisis after paclitaxel therapy for ureter cancer.MethodA PubMed literature review on published cases of taxanes-induced scleroderma up until April 2022 was included for analysis.ResultsThe search identified 27 patients with adequate information for analysis. Of the 28 patients, including the one presented here, 22 were female. Peripheral edema was the most common symptom in all but one patient, and often accompanied by erythema in 11. Symptoms usually occurred in half of the patients within the 4th course of treatment. Skin lesions gradually progressed to skin fibrosis, and extended proximally. Internal organ involvements were uncommon. Antinuclear antibody tests were positive occasionally, but anti-Scl70 and anti-centromere usually were negative. Taxanes therapy was discontinued, continued and unavailable in 21, 3, and 4 patients, respectively. Corticosteroids for skin lesions with or without immunosuppressive drugs were given to 15 patients. Of 25 patients with available skin outcomes, 19 improved. There was no significant skin improvement between those who did or did not receive skin treatment (62.5% vs. 75.0%, p = 0.37). Skin usually improved after discontinuing taxanes.ConclusionTaxanes-induced scleroderma is different from idiopathic scleroderma. Physicians should be aware of this condition in order to provide early diagnosis and apply appropriate management in order to avoid serious complications from severe skin sclerosis. Key Points • Scleroderma is a rare but unique and serious complication of taxanes therapy • Skin manifestations and distribution are similar to idiopathic scleroderma, but vascular phenomenon, internal organ involvement and scleroderma-associated auto-antibodies are presented rarely. Skin improvement usually occurs shortly after discontinuing taxanes • The role of immunosuppressive therapy in treating taxanes-induced scleroderma is not clear.

Project description:ObjectivesThe objective of this study was to systematically review the mortality and morbidity associated with scleroderma renal crisis and to determine temporal trends.MethodsWe searched MEDLINE, Embase and the Cochrane Database of Systematic Reviews from database inception to 10 February 2020. Bibliographies of selected articles were hand-searched for additional references. Data were extracted using a standardized extraction form. Study quality was assessed using the Newcastle-Ottawa scale. Results were analysed qualitatively.ResultsTwenty studies with 14,059 systemic sclerosis subjects, of which 854 had scleroderma renal crisis and 4095 had systemic sclerosis-associated end-stage renal disease, met inclusion criteria. Study quality was generally moderate. Cumulative mortality in the post-angiotensin-converting enzyme inhibitor era was approximately 20% at 6 months, 30%-36% at 1 year, 19%-40% at 3 years and almost 50% at 10 years from scleroderma renal crisis onset. Although the introduction of angiotensin-converting enzyme inhibitors in the early 1970s resulted in a 50% improvement in scleroderma renal crisis mortality, there was no further improvement thereafter. Scleroderma renal crisis mortality rates were proportionally higher than mortality rates associated with other systemic sclerosis organ involvement. The rate of permanent dialysis after scleroderma renal crisis in the post-angiotensin-converting enzyme inhibitor era ranged from 19%-40%. Three to 17% of systemic sclerosis patients underwent renal transplant. Survival was better in patients post-renal transplant (54%-91%) compared to those on dialysis (31%-56%). Graft survival improved over time and appeared similar to that of patients with other types of end-stage renal disease.ConclusionWhile there has been considerable improvement in scleroderma renal crisis-related outcomes since the introduction of angiotensin-converting enzyme inhibitors, morbidity and mortality remain high for affected patients without convincing evidence of further improvement in the post-angiotensin-converting enzyme inhibitor era. Novel treatments are required to improve outcomes of scleroderma renal crisis.

Dataset Information

Complement activation and effect of eculizumab in scleroderma renal crisis.

Publications

Complement activation and effect of eculizumab in scleroderma renal crisis.

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