Timothy Craig, FAAAAI, DO

2025 American Academy of Allergy, Asthma, & Immunology (AAAAI) 

annual meeting in San Diego from February 28 – March 3, 

 spoke with Timothy Craig, DO, about his session, “Exploring Hereditary Angioedema: Diagnosis, Prophylaxis and Treatment Strategies.”

During the interview, he shared mechanisms behind 

, early recognition of HAE, treatment options, and the importance of cross-specialty care.

Hereditary Angioedema Diagnosis Challenges, with Timothy Craig, DO

 What are the key genetic and inflammatory mechanisms behind HAE, and how do these contribute to the clinical manifestations of the disease?

That’s a really interesting disease, hereditary angioedema. It is genetic. It is a dominant disease, meaning you only have 1 abnormal gene.

If you have that abnormality, you don't make enough C1 inhibitor protein. Without c1 inhibitor protein, there's an activation of factor 12, and then factor 12 activates [kallikrein]. [Kallikrein] causes high molecular weight to fragment [into]… bradykinin [which] binds to the receptor [and] generates cyclic GMP, prostacyclin, and nitric oxide. If you look at the cells [in] the endothelial [lining] in the vessels, you can see the tight junctions between those cells dissolve, and there's little microfilaments of myosin that develop inside the cell, pulling that cell inward, almost like a muscle [does] on your body.

You can see why, then, the fluid would shift from the intravascular space into the interstitial space because of that lack of the tight junction and the cells we treat from each other. It’s a really interesting disease because it's all generated by bradykinin.

The problem, too, is that it takes a long time for that fluid to build up and then also to resolve. Some of these people have 3 days, even 5 days, of swelling. If it's in your stomach, that means you're vomiting. If it's in your hand, maybe you won't be able to type. If it's in your foot, you may not be able to walk. If it's in your neck, you may go to heaven… because asphyxia or upper airway swelling can lead to asphyxia and death.

What are some of the challenges in diagnosing HAE?

One of the major limitations of this disease is recognition. Prior to [diagnosis], it's often [for patients to] receive poor health care. If you go [in] for belly attack, [often] emergency room physicians will think you're seeking narcotics… Some of these people end up getting unnecessary surgery if they get [swelling in] the face. The ER doctors are more likely to say, ‘I know how to treat this. You treat it with antihistamines and steroids and epinephrine,’ but hereditary angioedema swelling is resistant to those

Once the diagnosis occurs, [which] can take up to 3 to 5 doctors in 7 to 10 years… [the patient gets] proper treatment. The doctor understands the disease, [and uses] shared decision-making. It really is a paradigm shift once the diagnosis is made.

Hives usually don't occur in this disease, but you can have hives associated, just like [anyone could]. If you get that swelling without hives, and you have a family history [of] abdominal pain, that makes the diagnosis very likely. You should [assess the] c1 esterase inhibitor level…you rarely ever need genetic testing.

Could you discuss the current treatment strategies for managing HAE?

There has been an evolution of care [with] more people on prophylaxis. The reason is [that] we know that prophylaxis increases quality of life, decreases anxiety, decreases depression.

In research now…we're looking at some [treatments] that may be a pill… instead of…an injection. Some of the other medications we're looking at right now can [be injected] maybe once every six months, so maybe once every three months. We now have some medications that are in research that don't have irritation when they're injected [into] the patient, and so that's good, and they'll probably lead to better compliance.

We’re also looking at prophylactic medications, [which is] one pill a day to keep the symptoms away, and so all that's really important, but those are all for type 1 and type 2, hereditary angioedema. The problem with type 3 hereditary angioedema, which is best to call HAE with normal C1 inhibitor, [is that] in those people, we're not sure what kind of therapy [works]. There are 8 different genetic abnormalities we know that can cause it…. but the problem is, most [cases of] normal, C1 inhibitor HAE [have unidentified genetic abnormalities.

In those cases, we don't know what the best drugs are. I think the best drug for rescue is icatibant because that's at the terminal end where bradykinin binds to the receptor, and that's where icatibant binds. Maybe tranexamic acid…I don't know that's very difficult. Long-term prophylaxis [is] very difficult in these people because they're not homogeneous. It's probably many different types that we haven't discovered yet.

How can healthcare providers collaborate with specialists across different fields to ensure a comprehensive approach to managing the condition?

A lot of doctors know nothing about HAE. We've done well on [educating] allergists [but] most other doctors in the world know little or never even heard of the disease.

As allergists, we have to do a couple things. We have to make sure we educate our emergency room physicians, our primary care physicians. We have to make sure that we give information to the patients that they can share with their physicians. We have to remember to make guidelines so we can help other specialties maybe develop skill sets and hereditary angioedema. We have to make sure we're using therapies correctly, and making sure that the patient understands how to use their therapies so that they can teach their primary care physicians and ER doctors how to use those medications,

There's not enough specialists to really handle all…HAE patients in the country, but I think what you can do is make sure you're available to answer questions [from] doctors around the country. On a regular basis, doctors call me up and say, ‘Hey, what would you do in this case?’ I think that's important if you're calling yourself a specialist in HAE only because [of] the lack of information most doctors have.

Relevant disclosures for Craig include CSL Behring, Takeda Pharmaceuticals USA, Grifols USA, BioCryst Pharmaceuticals, Genentech, BioMarin Pharmaceutical Inc, Blueprint Medicines Corporation, Novartis Pharmaceuticals Corporation, Dermavant Sciences, Amgen Inc, and GlaxoSmithKline.

Giavina-Bianchi P, Craig T, and Zaitoun F. 2306 - Exploring Hereditary Angioedema: Diagnosis, Prophylaxis and Treatment Strategies. Presented at AAAAI 2025 in San Diego on March 1 at 10:45 a.m.

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At AAAAI 2025, HCPLive spoke with Craig about recognizing and treating hereditary angioedemia.