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

Abstract

IntroductionConnective 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.MethodsKidney 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.ResultsIIM-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.ConclusionC5 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.