About the Disease
Hereditary Angioedema (HAE) is considered an orphan disease, meaning that very few people in the world suffer from this disease. Estimates range from 6,000-10,000 affected individuals in the United States and 12,000-20,000 individuals in Europe. This disease is different from idiopathic angioedema and urticaria because HAE is a bradykinin disease. Bradykinin causes leakage from small blood vessels, like the capillaries.
HAE vs Idiopathic Angioedema
If you find yourself with any swelling, it could be histamine driven. The use of antihistamines such as Claritin, Benadryl, Allegra or Zyrtec should improve these symptoms. In more severe cases, the use of steroids and/or epinephrine may be needed to abate the swelling. In patients with HAE, antihistamines, steroids and epinephrine have no effect on the swelling as the swelling is caused by overproduction of bradykinin.
The Role of Bradykinin and C1-Esterase Inhibitor in HAE
Bradykinin is a protein that causes the dilatation of blood vessels and leakage from small blood vessels, particularly capillaries. In the case of HAE there is an overproduction and excess presence of bradykinin. C1-Esterase Inhibitor (C1-INH) interacts in the body to reduce the overproduction of bradykinin, so patients lacking C1-INH tend to have more swelling episodes.
Presentation of the Disease
Imagine a sheet of paper that has a top and a bottom, so it must have a middle. Within the middle of our sheet of paper the capillaries would be found. And if the capillaries start to leak plasma, then that piece of paper will start to swell from the inside out. That shredding and expansion is very painful and will cause the appearance typical of hereditary angioedema. So individuals with this disease will suffer with occasional or frequent swelling of their face, tongue, larynx, arms, legs and abdomen. The swelling can be painful, disfiguring and affect your daily life. Triggers for these attacks are anxiety, physical trauma, estrogen and infections such as viruses and pneumonias.
Hereditary Angioedema can be categorized into various types based on blood tests and symptom presentation. In the past, we felt there was a Type I and a Type II only. Type I HAE is diagnosed in patients with low to absent levels of C1-INH. In Type II HAE, the C-1 esterase inhibitor level is low or normal but is non-functional. There is another type of HAE that involves a factor XII deficiency. With accumulating patient histories and diagnoses, there is HAE with C-1 Esterase Inhibitor at normal levels, occasionally called HAE Type III. To determine Type I or Type II, a blood test can be ordered by a physician to test the levels of C1-INH, levels of functional C1-INH and C4 (a complement protein).
Treatment is differentiated into prophylactics to prevent the attacks and abortive to stop an attack. Prophylactics include: Takhzyro®, Cinryze®, Haegarda®. Abortives include: Ruconest®, Kalbitor®, Firazyr®, Berinert®. If no medications are available to you in your area, fresh frozen plasma (FFP) which contains active C1-INH can be administered to patients via IV. If a patient is Type III, the FFP helps in a manner which is unknown at this time. Researchers are actively looking into data to help determine more about diagnosis and treatment of Type III HAE.
The majority of our patients that were frequently attacking have found great relief by taking a prophylactic. Since the launch of Takhzyro®, we have seen a tremendous benefit in the majority of our patients. Unfortunately, there are a few patients where the Takhzyro® has provided little benefit. They will experience frequent attacking. In these patients, we turn to Haegarda®, Cinryze® and Ruconest®. Not FDA approved, some patients are using multiple treatments of Haegarda®, Cinryze® and Ruconest often throughout the week, and not just every three days. These individuals, as well as our Takhzyro® individuals, also add a diuretic on a daily basis or a few times a week to eliminate the extra fluid that is associated with HAE.
If you find yourself in the emergency room with swelling, the cause needs to be determined to be either histamine or bradykinin. To begin, the ER should administer antihistamines, steroids orally or intravenous (IV) or intramuscular (IM), and/or epinephrine. If the swelling does not improve half an hour another round of treatment should be administered. If the second round of medications does not improve the swelling, the use of HAE abortive medication should be administered. If the hospital does not have access to these medications, patients should request FFP. Each unit of FFP should run over an hour to hour and a half. Many patients need antihistamines and diuretics, such as Lasix, in addition to the FFP to eliminate adverse reactions.
HAE in Our Practice
We currently manage about 30 patients with HAE in our practice. Two of which are Type I and the rest are HAE with normal C1-INH levels (Type III). In our practice we currently have three sets of families where it is mothers and daughters suffering with this. Of our 30 patients, only two are males and the rest are females. This disease is very rare and individuals can go undiagnosed for long periods of time. We assess each of our patients to determine the proper HAE Diagnosis for each specific individual to determine the best plan of treatment. Because this disease can be genetic, many of our patients have found that their close relatives have been experiencing similar symptoms and can finally find treatment and relief after years of abnormal swelling and pain.
We welcome any patient that has failed on any treatments as we are constantly in contact with manufacturers for upcoming treatment options and clinical trials, especially for patients with Type III HAE.
After years of only being told that one aunt was said to have had “elephantiasis,” cause unknown, the patient was recently told that two paternal aunts have had symptoms like hers their entire lives. They describe having experienced many tongue, throat and feet swelling events, and one of them said, “We just start looking like monsters and there is nothing you can do about it.” For some reason, they had never really confided this to anyone but each other. The patient’s oldest son has had experiences of severe facial swelling when he was younger, while her other son has not had symptoms. This patient’s experiences highlight the importance of communicating with one’s loved ones. This patient has tried numerous doses of Cinryze® and Firazyr,® with minimal improvement.
She feels that Firazyr has helped her, but only works for her if she catches the attack as it begins, and the effect only lasts about 24 hours. Therefore, she usually has to use something else to prevent a full attack. She felt that Cinryze helped her for the two weeks that she used it. She notes that she was not seeing results from Takhzyro and Haegarda as many patients do. She now has a port installed, and administers Ruconest, which seems to be working, as long as she can get the medication consistently, which is sometimes difficult.
She reports the best improvement with multiple infusions of FFP, which unfortunately requires frequent hospitalizations, during which it can be very difficult to receive enough FFP to stop her HAE attacks. HAE constantly interferes with her daily life, and caused her a lot of pain that often bring her to her knees. We continue to evaluate her symptom presentation and treatment plan to improve her quality of life.