POS-053 Type I Beta Interferon Induced Thrombotic Microangiopathy – Could the Alternative Pathway of the Complement Be Implicated?

IntroductionThrombotic microangiopathy (TMA) is a rare systemic microvascular disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ischemic damage in different organs. Beta-interferon (β-IFN), an immune-modulating agent widely used as a first line treatment for relapsing–remitting multiple sclerosis (RRMS), has been associated with TMA in several reports but the underlying mechanisms are still controversial. Treatment is mainly based on plasma exchanges, corticosteroids but the renal prognosis is poor.MethodsWe report the case of a 48-year-old male patient, with a 13-years history of RRMS, treated weekly with 132 µg of a type I Beta-Interferon (βI-IFN) and admitted for focal seizure. Initial investigations revealed classical laboratory features of TMA and a severe acute kidney injury requiring renal replacement therapy. Renal biopsy was performed and showed severe TMA lesions. Thrombotic thrombocytopenic purpura and typical hemolytic uremic syndrome were ruled out. Laboratory findings interestingly suggested a possible involvement of the alternative pathway of the complement (APC) with CFB: 32,5 mg/dl (normal value: 11-22 mg/dl), FBb: 0,258 mg/dl (normal value <0,153 mg/dl) and SC5b-9: 822 ng/ml (normal value <314 ng/ml). Genetic workup did not find a mutation for regulators of the APC, and the search for anti-factor H antibodies was negative. The withdrawal of βI-IFN resulted in the rapid resolution of hemolytic microangiopathic anemia and thrombocytopenia, but with delayed improvement of the renal function. No plasma exchange was required and no eculizumab was administered because of the absence of reimbursement procedure available in our country in case of secondary TMA.ResultsTMA is a rare complication of βI-IFN treatment. Recent experimental data suggest a causal relationship. Kavanagh et al. showed that βI-IFN was responsible for a direct dose-dependent TMA in a rodent model, and that TMA was absent in type I-IFN receptor (IFNAR) knock-out mice. Jia et al. showed that βI-IFN could interfere with endothelial cell by inhibiting fibrinolysis and VEGF-dependent angiogenesis. Furthermore, eculizumab, an anti-C5 antibody blocking complement terminal activation, has been reported to significantly improve renal prognosis in case series even in the absence of mutation of the APC. These data suggest that 1) TMA may occur as a second hit in patients with yet undiscovered mutations of the APC; or 2) IFN could activate complement cascade in patients without mutations of the APC. Indeed, some data suggest a direct activation of the complement cascade by type-I IFN, but an indirect link can also be hypothesized. For example, antiphospholipid antibodies have been associated with βI-IFN treatment and are known to activate complement pathway and to be associated with TMA. Figure 1. summarizes the pathophysiological hypotheses of βI-IFN mediated TMA. Blue lines represent data from the literature, whereas green arrows represent pathophysiological hypotheses. The red arrow represents lacking data up to now.ConclusionsβI-IFN mediated TMA is a rare but well-known complication. βI-IFN has a direct toxic effect on endothelial cells and can also act as a trigger in the setting of APC regulation deficiency. Eculizumab seems to be effective, even in the absence of mutations for regulators of the APC suggesting a potential activation of the complement cascade by IFN.No conflict of interest IntroductionThrombotic microangiopathy (TMA) is a rare systemic microvascular disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ischemic damage in different organs. Beta-interferon (β-IFN), an immune-modulating agent widely used as a first line treatment for relapsing–remitting multiple sclerosis (RRMS), has been associated with TMA in several reports but the underlying mechanisms are still controversial. Treatment is mainly based on plasma exchanges, corticosteroids but the renal prognosis is poor.