Behind the scenes of a scientific push to improve care for those with HAE with normal C1 Inhibitor

Thirty-one authors from 16 countries. 140 separate references. Four rounds of review. Just under 2 years from the first meeting to official publication. These are a few of the statistics from a new consensus paper on HAE with normal C1 inhibitor (HAE-nC1INH), published in March 2025. They show what a marathon effort it was to distill scientific discussion, debate, and decision into 24 pages.

Considering the detail in the paper, all authors appreciated the positive feedback from the peer review process, which reflected the value of the work. Within the author team, the mood was captured by comments like: “Big congratulations on an important paper which many have been anticipating” and “This is great news, and I think this paper will be extremely useful.”

To understand why HAEi and the US HAEA supported this initiative from first thought to last word, and why the clinical community was motivated to work so long and so hard, we need to start with HAE-nC1INH. What is it, and what has life been like for people with the condition?

HAE-nC1INH is rarer even than HAE Type-I and Type-II, and was identified only in the early years of the 21st century. Initially called HAE Type-III, people with the condition suffered from recurrent episodes of swelling without hives, but existing diagnostic tests indicated normal levels and function of the C1 inhibitor protein, which made effective diagnosis and management of the condition very difficult. With the advent of detailed genetic testing, the condition began to be better understood and was eventually renamed HAE-nC1INH. As diagnosis rates increased, the US HAEA, in particular, began hearing from people with the condition, but had no way to answer the many questions asked. Driven by the US HAEA, the last expert consensus review of the science was published in 2012.

The US HAEA and HAEi understood the need to advocate for this underserved group of patients and, in early 2023, enlisted a group of global HAE experts to synthesize the current knowledge in the area. Anthony J. Castaldo, HAEi Chief Executive Officer and Chairman of the Board, said: “There was no one source of truth in an emerging and highly complex form of HAE. We needed this paper to give practical support to a group of patients who really needed better care.”

The experts presented their preliminary findings, sharing a best practice approach to the diagnosis and management of HAE-nC1INH at an HAEi/US HAEA-supported symposium held on 1 September 2023 in Germany, ahead of the first 2023 HAEi Regional Conference EMEA. HAEi and the US HAEA represented the patient throughout and worked with the co-chairs to ensure the work reflected the patient’s needs.

The efforts culminated in a new and comprehensive review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH.

What’s the consensus?

>> Click here for the full paper

Here are some of the key points that people with HAE should know:

  • Three critical areas of science were covered:
    • Clinical features, diagnosis, and differential diagnosis
    • Genomics, biomarkers, and pathophysiology
    • Management and treatment
  • C1 tests are normal, so doctors may hesitate to initiate treatment for patients with HAE-nC1INH as they don’t have a test to confirm the diagnosis. Genetic testing to identify a mutation would then confirm the diagnosis, but this isn’t available to everyone. In the meantime, patients are not being treated and living with attacks.
  • In response to this, the paper states:
    • Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality.
    • Proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important.
    • Even without an identified mutation, a presumptive diagnosis of HAE-nC1INH made by an expert physician is sufficient. Since these patients are at risk, treatment needs to be available even for a presumptive diagnosis of HAE-nC1INH.
  • In the absence of robust clinical data on treatment, the authors were surveyed to pull together real-world evidence of treatment outcomes from 594 patients in 15 countries.

The science didn’t stop with this publication either. A further publication, in a Japanese journal, is also planned to bring the consensus paper to a broader audience there. And part of the survey data has subsequently been used in a scientific paper on the management of idiopathic non-mast cell angioedema (INMA).

Deborah Corcoran, HAEi’s Director, Research, 1 of the combined HAEi and US HAEA team supporting the expert publication, commented: “We are grateful to everyone who contributed to making this publication possible. There was a single-minded focus on practical ways to improve the lives of people with HAE-nC1INH, and we hope to see this translate from the page to improved care very soon.”

HAEi and the US HAEA extend heartfelt thanks to all the experts involved in this vital publication, in particular Prof Bruce Zuraw, Prof Konrad Bork, and the much-missed Prof Marcus Maurer, who were Co-Chairs for this mammoth project.