by Dr Sandeep Arora
Hereditary angioedema (HAE) is a rare genetic disorder that affects approximately 1 in 50,000 people worldwide and causes severe swelling in various body parts, including the face, airways, genitals, hands, and feet. It is caused by a deficiency or defective C1 esterase inhibitor (C1-INH) protein, which leads to the overproduction of a chemical called bradykinin that causes leakage of plasma from blood vessels to surrounding tissues. HAE can be self-limited, episodic, and occasionally aggravated by predictable triggers such as emotional stress, physical trauma, or certain drugs. The attacks are often unpredictable, and sometimes life-threatening, especially if swelling develops in the throat region, obstructing breathing and requiring immediate emergency care.
HAE is genetic in nature and root cause is primarily mutations in the SERPING1 gene which encodes for C1-inhibitor (C1-INH) and can be classified into three types: type I, type II, and type III.
Type I HAE is the most common type, accounting for approximately 85% of cases. It is characterized by low levels of C1 inhibitor protein. Type II HAE is caused by normal or elevated levels of dysfunctional C1 inhibitor protein, whereas Type III is not associated with a deficiency of C1-INH but rather mutational changes in multiple other genes.
Life-threatening and Challenging Condition
Cascade of HAE attacks involve the release of excessive bradykinin that results in blood vessel dilation and increased vascular permeability. This leads to the accumulation of fluid in the surrounding tissues, causing swelling and inflammation. The most common sites of swelling are face, hands/feet, extremities, genitalia, and gastrointestinal tract. Typically, the episode can keep progressing over hours or days, leading to major physical dysfunction, pain, and suffering. Throat swelling or laryngeal edema can occur in up to 50% of HAE patients and is potentially life-threatening.
Despite its rarity, HAE can exert a major impact on the quality of life (QoL) of affected persons as the swelling attacks are extremely painful and may end in disfigurement. As a result, it causes physical and emotional distress. Given the above factors, early detection and timely management of HAE are vital in reducing the frequency and severity of HAE incidents.
Diagnosing HAE, however, is challenging, given both the rarity and manifestation of similar symptoms in other ailments. Most of the times, the diagnosis can be made by measuring C1 INH level and function especially during the attacks. However, genetic testing is deemed useful in identifying and differentiating between HAE and other conditions in few cases. Management options include C1 esterase inhibitor replacement therapy (now available in India) and medications suppressing the clinical symptoms, including emergency treatment when the patient presents with life-threatening attack.
The frequency and severity of HAE attacks can be influenced by various factors, including trauma, infections, hormonal changes, emotional stress, and medications that affect the kallikrein-kinin system. Because the attacks are unpredictable, the goal of preventive therapy is focused on reducing the frequency and severity of HAE incidents.
Hence, after a successful diagnosis, the affected persons can be given appropriate therapy together with support to manage symptoms and prevent the recurrence of severe attacks. Through these treatments, the frequency and severity of episodes can be reduced while improving the QoL of affected persons.
In addition to its unpredictable clinical course, HAE is characterised by wide variance in manifestation, response, and treatment tolerance. Keeping the diverse elements in mind, along with the heterogeneous factors affecting disease progression and outcomes, it is necessary to draw up a comprehensive personalised action-cum-management plan in coordination with the treating physicians, patients and their family members or caregivers to meet the needs of HAE patients. Such a plan should aim to engage patients in their therapy while minimising the burden of HAE on both patients and families. Moreover, patients need to be followed up regularly and the management plans updated periodically, depending on their current condition.
Timely Treatment for Productive Outcomes
The management of HAE involves three main strategies: prevention, acute treatment, and long-term prophylaxis. Prevention involves avoiding triggers, such as stress or certain medications, that can lead to HAE attacks. Acute treatment involves administering medications to quickly relieve the symptoms of an HAE attack. Long-term prophylaxis involves regular administration of medication to prevent HAE attacks from occurring. Devising HAE management strategy is important to prevent future attacks and based on improving deficient C1-INH levels to minimize inflammation and swelling.
Despite the availability of effective treatments, there are still significant unmet needs in the management of HAE. The main challenges include the need for frequent administration of acute treatments and the side effects associated with drugs such as attenuated androgens, implying the need for more effective and safer long-term prophylactic options. This includes globally available, based on robust clinical trial program, recently, plasma derived C1 inhibitor protein replacement therapy has been approved for use in HAE patients in India.
With HAE management options available, clinician in charge could develop and optimise the necessary treatment plans while overseeing and coordinating medical care and providing comprehensive education about HAE.
Yet, considering the gaps in the knowledge of physicians regarding HAE and the recent advances in diagnostic work, on-demand therapy as well as short- and long-term prophylactic treatment, clinicians should first be made aware of these facts. Furthermore, teachers, educators and healthcare personnel taking care of children with HAE must be given clear written information about disease characteristics, including information on properly utilising the available treatment modalities in urgent situations, particularly during an airway attack.
Since HAE can manifest throughout a person’s life with significant variables, one should recognise and avoid all the likely triggers. HAE specialists must proactively inquire about any existing comorbidities that require a person to take concomitant treatment. The HAE-linked information should immediately be conveyed to patients, their family members and other healthcare personnel to ascertain adequate provision and coordination of medical care.
Given HAE is genetic or hereditary in nature, in affected HAE family, there should be pre-natal genetic counselling and family members should be screened based on available lab tests in India to diagnose HAE, to help in prevention and early initiation of HAE therapy such as C1-INH replacement medicines. This is crucial since delayed diagnosis can mean a lower QoL due to the late initiation of appropriate therapy and the possibility of increased mortality due to a fatal HAE attack through blocked airways. Besides, it is recommended that all HAE patients undergo at least one annual medical check-up through treating specialist.
In recent years, there has been a spurt in mechanisms for identifying HAE, apart from developing safe, effective, and innovative medications to treat acute manifestations while controlling disease activity through prophylactic therapy. Current research in HAE is focused on identification of new biomarkers for monitoring HAE disease activity and the development of gene therapy approaches for correcting the underlying genetic defects in HAE.
The author is the Head of Medical Affairs and Patient Services at Takeda Biopharmaceuticals India Private Limited (formerly known as Baxalta Bioscience India Private Limited. )
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