Quick response to Ruconest may indicate rare form of HAE
HAE-nl-C1INH diagnosis difficult due to lack of criteria, varied symptoms
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A rapid response to Ruconest (recombinant C1 esterase inhibitor) may support an otherwise difficult diagnosis of a rare form of hereditary angioedema (HAE) marked by normal levels of C1-inhibitor (C1-INH) protein, a study suggested.
This form of the disease, HAE-nl-C1INH, is challenging to diagnose because there are no standardized diagnostic criteria or reliable biomarkers, and patients often present with a wide range of angioedema symptoms without a clear family history of swelling attacks.
“These results suggest that it may be worthwhile to consider whether responsiveness to HAE-specific therapy should play a more prominent role in diagnosis (eg, rather than merely supportive),” the researchers wrote.
The study, “C1 esterase inhibitor (C1-INH) response as a supportive diagnostic criterion for patients with suspected hereditary angioedema with normal C1-INH,” was published in the World Allergy Organization Journal. Pharming Healthcare, which markets Ruconest, provided funding solely for the preparation of the manuscript.
Many wait years for diagnosis
Most HAE patients carry mutations in the SERPING1 gene, resulting in a deficiency or dysfunction of the C1-INH protein. Without sufficient C1-INH activity, the proteins kallikrein and factor XII become overactive, stimulating the production of excessive amounts of the pro-inflammatory molecule called bradykinin, which triggers episodes of swelling.
Some people with HAE, however, do not carry SERPING1 mutations and have normal levels of C1-INH. This rare form of the disease has been associated with mutations in several other genes, including the F12 gene, which encodes factor XII.
HAE-nl-C1-INH is challenging to diagnose due to the absence of standardized diagnostic criteria and reliable laboratory biomarkers, as well as a wide variation in symptoms. Patients often wait years for a correct diagnosis.
Doctors rely on clinical criteria, including recurrent swelling attacks and normal levels of C1-INH and C4, an immune protein that’s abnormally low during a swelling episode. Relevant mutations or a family history of similar angioedema, or a poor response to high-dose antihistamines, can also suggest this type of HAE.
An HAE diagnosis is often supported by a patient’s rapid response to medications that suppress bradykinin production, including C1-INH replacement therapies. So a team of U.S.-based researchers investigated whether a response to Ruconest — a lab-made C1-INH replacement therapy — can also support a diagnosis of HAE-nl-C1INH.
From a review of medical records, the team identified 31 people with HAE-nl-C1INH, aged 16-74, primarily women (87.1%), from six centers across the U.S.
All patients experienced recurrent swelling attacks and had near-normal to normal C1-INH levels, as well as normal C4 levels, all assessed during a time without attacks. They also failed to respond to at least one antihistamine and a therapy that targets immune mast cells. Of the nine patients who underwent genetic testing, none carried a known HAE-related mutation.
Clinicians confirmed a HAE-nl-C1INH diagnosis in all 31 patients because they responded favorably to Ruconest at the recommended dosage during a swelling attack — defined by fewer or no symptoms within four hours of treatment.
All patients continued to do well, with fewer or less severe attacks following preventive or on-demand treatment with HAE-specific medications.
Of the 30 patients assessed, 30% had a documented family history of recurrent angioedema or HAE. After three patients were diagnosed, eight other family members also received an HAE-nl-C1INH diagnosis.
“These descriptive data highlight the potential use of C1-INH administration as a diagnostic tool for HAE-nl-C1INH,” the researchers wrote. “This is important, given the lack of biomarkers and standardized diagnostic criteria.”
