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 (IIM), are very rare cause of thrombotic microangiopathies (TMA). 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 C5 cleavage, were observed in the two subgroups at the junction of media and intima of arterioles, co-localizing 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-cells depletion and complement C5 blocking led to one-year survival of 72%, compared to 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 hematological abnormalities in IIM- and SRC-TMA and adding early and aggressive immunosuppressive regimen may improve the survival of IIM-TMA. Underlying chronic vascular and interstitial lesions mitigate renal response in SRC-TMA.