Role of C5 inhibition in Idiopathic Inflammatory Myopathies and Scleroderma Renal Crisis–Induced Thrombotic Microangiopathies

Abstract

Introduction Connective tissue diseases, including systemic sclerosis and idiopathic inflammatory myopathies (IIMs), are a very rare cause of thrombotic microangiopathies (TMAs). Whether dysregulation of the complement pathways underlies these secondary forms of TMA and may be targeted by complement blocking agents remains elusive. Methods Kidney pathology and outcomes of 18 critically ill patients with TMA related to inflammatory myopathy flare-up (IIM, n =7) or scleroderma renal crisis (SRC, n =11; biopsy n =9) are assessed. Results IIM-TMA is characterized by acute thrombotic lesions only, whereas SRC-TMA patients also harbored chronic vascular lesions and more interstitial fibrosis. C5b9 deposits, a marker of complement component 5 (C5) cleavage, were observed in the 2 subgroups at the junction of media and intima of arterioles, colocalizing with subendothelial edema. Thus, kidney biopsy distinguished between acute and chronic renal phenotypes that may help to individualize treatment. Treatment of IIM-TMA patients with combined full-code organ support, corticosteroids, B-cell depletion, and complement C5 blocking led to 1-year survival of 72%, compared with 19% in historical cohorts. Treatment of SRC-TMA was more heterogenous and relied on conversion enzyme inhibitor only or with eculizumab ( n =6) and immunosuppressor ( n =5). One-year survival of SRC-TMA patients was 52%, a result similar to historical cohorts. Eculizumab was followed by a rapid dramatic improvement of TMA in all the treated patients. Conclusion C5 blocking may reverse hematologic abnormalities in IIM- and SRC-TMA, and adding an early and aggressive immunosuppressive regimen may improve the survival of IIM-TMA. Underlying chronic vascular and interstitial lesions mitigate renal response in SRC-TMA.

Scleroderma Renal Crisis With Thrombotic Microangiopathy Treated With Eculizumab

“…The renal outcome remained poor (seven patients had to receive renal replacement therapy at the end of follow-up), including in patients receiving eculizumab. The one-year survival of SRC-TMA patients was 52%, which was similar to historical cohorts [ 20 ]. Nonetheless, a proposed algorithm for the management of SRC-TMA, including the use of C5 inhibitors, is shown (Figure 3 ).…”

A glance into the future of myositis therapy

“…Of interest is that in this study the first year survival of IIM-TMA was 72%, compared to other cohort survival in PM/DM-TMA (19%). 23 The results of this study may suggest a role of add-on eculizumab that for management of thrombotic microangiopathy in the setting of IIM.…”

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

“…Eculizumab, a C5 inhibitor, is a complement-targeting approved drug for a variety of vascular disorders and has recently been approved in kidney diseases 55 . Moreover, it has been studied in idiopathic inflammatory myopathies and SSc renal crisis, with promising results 56 , 57 . Our data suggest that C4 genetics in SSc, by affecting expression and C4 protein levels, plays an important role in mediating the genetic association in the MHC locus and might also be involved in the epidemiological sex bias of SSc.…”