IPIG 2025 | Adverse events associated with proximal and terminal complement inhibitors in PNH treatment

So in terms of adverse effects of complement inhibitors, not necessarily a common adverse effect, but one that I always counsel patients about and it’s essential to counsel patients about, is the increased risk of infections, and this is particularly bacterial infections with encapsulated organisms. This is because the complement system is really essential in the immune system’s response to these sorts of pathogens. And so we know the relative risk is significantly increased compared to the general population in patients on complement inhibitors. So this includes especially Neisseria meningitidis infections and so this is why it’s required that individuals who are on complement inhibitors are vaccinated against Neisseria meningitidis for the available serotypes. But this doesn’t entirely mitigate the risk. So it’s very important to counsel patients that they remain at increased risk of infections and that there should be a low threshold for starting antibiotics at any sign of infection. Patients should be counseled on symptoms to look out for and healthcare professionals really need to be aware of this risk in our patients too. 

To the question about the differences between proximal and terminal complement inhibition. We heard actually this morning about differences. One of the big differences is in how the phenomenon of breakthrough hemolysis may manifest in these different patient populations. We know that all patients with PNH on complement inhibitors are susceptible to some forms of breakthrough hemolysis. This can include, we heard about pharmacokinetic breakthrough hemolysis, pharmacodynamic breakthrough hemolysis is one that’s especially challenging to manage and this is when there’s some sort of complement activating condition that’s able to overcome the complement inhibition that’s from the drug. In proximal complement inhibition there’s some clinical experience and evidence that the breakthrough hemolysis can be particularly severe and particularly precipitous in these individuals and there’s mechanistic reasoning for this in the sense that these individuals may have longer survival of their PNH red blood cells. Also there may be amplification steps in the complement cascade that aren’t as effectively blocked by these therapies. And so it’s really important that patients are educated about this, that healthcare professionals are also aware of the increased risk or of the severity of breakthrough hemolysis that can happen on these treatments. And this is another area where we need more evidence on how to best manage these. Right now strategies include increasing the doses of the medications as well as rescue doses of terminal complement inhibitors and of course supportive management and treating the underlying condition which can include infection or other complement activating conditions.

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