Cataland, Spero R

Abstract Complement-mediated thrombotic microangiopathy can be difficult to recognize when it presents in the setting of an apparent clinical trigger, such as pregnancy, severe hypertension, or kidney transplantation. These conditions can each cause endothelial injury directly but may also unmask complement dysregulation in susceptible individuals. In these situations, the critical question is not whether a trigger exists but whether it fully explains the syndrome and whether urgent complement blockade is warranted to prevent irreversible kidney injury. In this How I Treat article, we use 3 real-world cases to illustrate how we approach this decision in practice. We emphasize the bedside features that most influence our threshold to treat, including the pattern and severity of kidney injury, tempo of disease progression, and lack of improvement with supportive or trigger-directed care. We also address the interpretation of complement genetic findings, pregnancy- and transplant-specific risk stratification, and the individualization of treatment duration. Functional assays can support mechanistic assessment in selected cases but remain an adjunct to diagnosis and should not drive management decisions.

Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.