<p>When educating patients with paroxysmal nocturnal hemoglobinuria (PNH) about their disease and treatment options, it is important to distinguish between the hemolytic complications of the disease and those that can result from the use of complement inhibitor therapy. Doing so can help patients gain a greater appreciation of the role that complement inhibitors play in the management of PNH.</p>

When I educate patients with PNH about their disease and its available treatment options, I make sure to explain the difference between disease-related intravascular or breakthrough hemolysis and what I call “iatrogenic anemia,” which is related to ongoing therapy with C5 inhibitors. In addition, I discuss the consequences of disease-related intravascular hemolysis, which include trouble swallowing, chest pain, abdominal pain, erectile dysfunction, and hemoglobinuria, as well as more serious complications such as propensity for thrombosis, anemia, pulmonary hypertension, chronic kidney disease, kidney failure, and Budd-Chiari syndrome.

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Treatment with complement inhibitors, initially in the form of C5 inhibitors, has changed the way we think about and treat PNH and, most importantly, it has changed the lives of patients with this disease. Not only did these agents control intravascular hemolysis, reduce the rate of transfusions and thrombotic events, and improve quality of life for patients with PNH but they also resulted in improved survival. However, a subset of patients receiving therapy with C5 inhibitors continue to have breakthrough hemolysis, require an occasional transfusion, or develop transfusion-dependent anemia. Moreover, it has become evident that extravascular hemolysis is the likely etiology for the anemia described in treated patients, which may have been unmasked by C5 inhibitor therapy.

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Extravascular hemolysis has been described to occur in up to 20% of patients treated with C5 inhibitors, and it can lead to symptomatic anemia or transfusion dependency. So, this certainly needed to be improved upon, and this is why the idea of developing proximal complement inhibitors became important. In a phase 3 trial of pegcetacoplan, it was clear that the drug was superior to eculizumab in a patient population with anemia and evidence of extravascular hemolysis. The improvement in hemoglobin levels was significant, and fewer patients receiving pegcetacoplan vs eculizumab required transfusion. Two other alternative complement pathway inhibitors have been developed. You have danicopan, which is an add-on therapy to C5 inhibitors, for the control of extravascular hemolysis–related anemia, and then you also have iptacopan, which is an oral factor B inhibitor, for the control of both extravascular and intravascular hemolysis.

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So now, there are multiple complement inhibitors for us to consider for our patients with PNH. When selecting therapy, I start by thinking about patients with newly diagnosed PNH vs those who may have been previously treated. How do we go about approaching the issue of treatment selection for a particular patient? That depends on many factors related to the patient and the disease, including the severity of the extravascular hemolysis–associated anemia, the frequency of breakthrough hemolysis, and the degree of anemia. I like to think about this on a patient-by-patient basis.