Making the complicated simple is a specialty for Professor Marc Riedl, but even he had to admit that HAE with normal C1 is difficult. He told the packed conference that ‘HAE with normal C1 (HAE-nC1INH) is a hot topic because it’s difficult.’

Nevertheless, he accepted the challenge of explaining the progress made to date in understanding, diagnosing, and treating HAE-nC1INH.

Starting with all angioedema, Prof. Riedl could quickly describe and categorize non-allergic angioedemas, of which HAE is one. If these angioedemas ‘hit the airway,’ he said, they’re much more dangerous. They can be highly debilitating. Prof. Riedl noted that we understand HAE Type I, Type II, and acquired angioedema pretty well. Using a traffic light system, he classified these forms of HAE with a green ‘go’ light.

The traffic light changed to yellow ‘caution’ regarding HAE-nC1INH. We proceed cautiously, Prof. Riedl told the audience, ‘We understand a little bit, but there’s still lots of questions.’

Finally, with HAE unknown (sometimes called idiopathic angioedema), Prof. Riedl said the traffic light goes red. ‘We don’t understand this condition well at all. Sometimes we don’t even know what’s the underlying cause’.

Very importantly, Prof. Riedl stressed the need to ask specific questions. HAE is known to last longer and doesn’t have hives or itching. There can be specific triggers such as medicines, stress, or trauma. Also, the patient should be asked if allergy medicines work at all. And especially with HAE-nC1INH, familial and genetic elements are important. Prof. Riedl said all this and more helps guide clinicians to a diagnosis. Prof. Riedl stressed that after decades of study, we know HAE is caused by missing or ineffective C1 inhibitor, leading to too much bradykinin, making blood vessels leak and causing swelling. The test rightly, therefore, focuses on levels of C1 and C4 as these can reliably diagnose this HAE.

Around the turn of the millennium, any confidence clinicians felt about their knowledge of HAE was shaken. Families were identified as having all the symptoms of HAE, but the tests showed normal levels of C1 inhibitor. ‘These people weren’t following the rules,’ Prof. Riedl quipped.

Quoting the famous American writer Mark Twain, Prof. Riedl said: ‘It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.’ There is so much unknown or unclear that it is important to proceed thoughtfully.

‘It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.’

– Mark Twain

Complicated genetic testing has identified eight genetic mutations that cause HAE-nC1INH, but these versions of HAE often appear with troublingly different symptoms. As Prof. Riedl put it, ‘People with HAE don’t get hives. Well, now there’s this form; maybe they get hives.’ One of the significant questions is how many people have HAE-nC1INH. In one study, Prof. Riedl highlighted that HAE-nC1INH accounted for 20% of the people studied, so it is rare, but as he put it: ‘it’s not minuscule.’

Returning to patient care, Prof. Riedl made it clear that when he’s sitting with a patient or a family with angioedema, he’s got to help them. Understanding cause and genetics is ultimately vital, but right now, what can be done to manage the condition?

Sadly, Prof. Riedl mentioned that there has only been one controlled clinical trial, which hasn’t been published yet. All the available evidence is reports from centers or something that worked well for one patient or a group. There is some data on the benefits of tranexamic acid, Prof. Riedl suggested, along with medications like landelumab, berotralstat, icatibant, etc.

‘So how do I manage it?’ Prof. Riedl asked rhetorically. There’s no substitute for sitting down with the patient and their family and asking about the symptoms. Questions might include:

• How many times do you have attacks?
• What are those attacks like?
• How long do they last?
• Do you get hives or itching?
• Does your throat swell?
• Do you get abdominal pain?
• What have you taken before that did or didn’t work?

The best diagnostic test, he said, is still face-to-face history taking. Although even that can be pretty unreliable, he cautioned. Some people don’t know their family history; perhaps they’re adopted or estranged. There can also be what he called ‘variable penetrance,’ where some people have the mutation but have no symptoms. Or, in 25% of people with HAE Type I or Type II, it’s a ‘de novo’ mutation, which Prof. Riedl explained means, ‘You’re the first person in your family to have that mutation.’

Without any abnormal tests, Prof. Riedl suggested that the first treatment for an unknown HAE or HAE-nC1INH is antihistamines, steroids, or preventative medicines such as omalizumab. These are, of course, treatments for allergies, but as Prof. Riedl put it, that’s the most common type of angioedema. Start there and move on to HAE medications if allergy treatment offers nothing. If people use an HAE medication and get better within a couple of hours after an attack, it can help clinicians understand the mechanism.

Prof. Riedl concluded by acknowledging how troubling, disabling, and scary HAE is for people living with it. ‘We know there’s a lot of depression and anxiety associated with recurrent angioedema,’ he said.

He left the audience with another Mark Twain quote: ‘Continuous improvement is better than delayed perfection,’ and a nod to the memory of Prof. Marcus Maurer in his commitment to continuing to fight the good fight.