Hereditary Angioedema (HAE) in China: Advancing Awareness, Access, Advocacy and Alliances From the Greater Bay Area to the Global HAE Community

ABSTRACT

The article offers an overview of the progress in managing Hereditary Angioedema (HAE) in China, with a specific focus on the Greater Bay Area (GBA). Through the ‘4As’ framework—Awareness, Access, Advocacy and Alliance—the article explores the challenges and advancements in HAE care. In terms of collaborative initiatives such as the HAE‐ASIA (Angioedema Screening In Asia) collaboration and the GBA HAE Alliance “Hub‐and‐Spoke model” aim to bridge the gap between East and West, providing optimal patient care and advancing HAE management. By bridging the gap between East and West, the GBA aims to deliver optimal patient care and advance HAE management. Moving forward, it will be essential to persist in nurturing national and international collaborations, not only within China but also extending beyond its borders. These partnerships encourage the exchange of knowledge, research, and best practices, all of which are critical in propelling forward the care of HAE. By uniting as a worldwide community, we can significantly advance efforts to improve the quality of life for those affected by HAE across the globe.

Through the ‘4As’: Awareness, Access, Advocacy, and Alliance, the Greater Bay Area will continue to leverage its unique advantages to confront ongoing challenges such as diagnostic delays and lack of access to diagnosis and hereditary angioedema (HAE)‐specific medications. By uniting a worldwide HAE community, we can advance efforts to improve the quality of life for HAE patients globally.

Summary.

• This review highlights the significant challenges in diagnosing and treating Hereditary Angioedema (HAE) in China.

• The Greater Bay Area is advancing HAE care through improving Awareness, Access, Advocacy and Alliance.

• National and international collaborations will be essential to improve HAE care across China and beyond.

1. Introduction

Hereditary angioedema (HAE) is an uncommon, potentially life‐threatening disease, characterised by recurrent attacks of cutaneous and submucosal swelling [1, 2, 3]. In most patients, HAE is due to C1‐inhibitor (C1INH) deficiency (HAE‐C1INH), characterised by low C1INH levels (HAE‐C1INH‐Type1) or decreased protein function (HAE‐C1INH‐Type2), caused by mutations in the SERPING1, which encodes C1‐INH [2, 4, 5]. International World Allergy Organisation (WAO)/European Academy of Allergy & Clinical Immunology (EAACI) guidelines recommend that the diagnosis of HAE‐C1INH is made by measurements of C4, C1INH level, C1INH function, while genotyping of SERPING1 can be supportive in the diagnostic workup of some patients [2]. Several HAE‐specific medications have now been approved for on‐demand and prophylaxis of angioedema attacks [6]. In the modern era, non‐HAE‐specific medications (such as attenuated androgens, anti‐fibrinolytics and fresh frozen plasma) are no longer favoured or even advocated against by some recommendations [7].

Although the estimated global prevalence of HAE is typically between 1 in 10,000 and 1 in 150,000, the exact prevalence in various regions, particularly in non‐Western countries, remains largely unknown [8]. Moreover, there is also significant heterogeneity in reported prevalence rates in the Asia Pacific region, including China [9]. Within China, there are variations in reported HAE prevalence and access to diagnosis and treatment (Table 1) [9]. Notably, the Guangdong‐Hong Kong‐Macao ‘Greater Bay Area’ (GBA) in China displays a remarkable discrepancy. The reported prevalence of HAE is 15 times higher, compared with Mainland China, (0.60 versus 0.04 per 100,000 population, respectively) [8]. Considering similar genetic and ethnic composition, this disparity may be attributed to differences in medical practices, infrastructures, access to diagnostics and medication [9].

TABLE 1.

Example of reimbursement ratios in different cities in the GBA under the employee's medical insurance policy.

	Reimbursement ratios
	Outpatient service	Inpatient service
Guangzhou	80%	80%
Shenzhen	55%	90%
Dongguan	50%	90%
Zhaoqing	55%	80%
Huizhou	55%	95%
Foshan	40%	85%
Zhongshan	50%	90%
Zhuhai	80%	92%
Jiangmen	70%	83%

Rare diseases have garnered increasing attention and prioritisation from the central government in the past decade, being incorporated into strategic nation‐wide health plans. In 2015, the first National Expert Committee on Diagnosis, Treatment and Insurance of Rare Diseases was formed [10]. Following China's healthy 2030 policy, China has identified rare diseases as a key area of focus and an exponential number of policies, especially in the accessibility of ‘orphan’ drugs, have been made [11, 12]. On May 22, 2018, HAE was officially listed in China's First National List of Rare Diseases [13]. Great strides in the availability and accessibility of HAE‐specific medications were made in recent years with the approval of lanadelumab in 2020 and icatibant in 2021 for prophylaxis in HAE patients 12 years or older and for the treatment of acute attacks in patients 2 years or older, respectively. A year later, both drugs were included onto the National Reimbursement Drug List [14].

1.1. A Brief Overview of the Healthcare System in the Greater‐Bay‐Area: Focus on HAE

The GBA consist of nine cities (Dongguan, Foshan, Guangzhou, Huizhou, Jiangmen, Shenzhen, Zhaoqing, Zhongshan and Zhuhai; with a total population of 87 million) and two Special Administrative Regions (SAR) (Hong Kong and Macau; with populations of 7.3 and 0.7 million, respectively) is one of the most economically developed and densely populated area in China (Figure 1). It is also a strategic initiative by China to stimulate economic growth and development while also serving as a hub for medical research [15]. Hong Kong and Macau operate under the ‘One country, two systems’ principle, exercising a high degree of economic and social independency. Hong Kong and Macau operate under independent medication registration regulations and policies, under the Department of Health and the Health Bureau (Serviços de Saúde), respectively. Mainland China (or hereby referred to as China, or the mainland) is a geopolitical term that refers to the territory under direct administration of the People's Republic of China. In this region, drug regulations are overseen by the National Medical Products Administration (NMPA). Hong Kong operates a mixed medical economy, with 95% of public sector funding sourced from government general tax revenues, with the public fee structure being heavily subsidized [16]. Apart from the two SAR, over 90% of Mainland China population is covered under several universal medical insurance policies with differing co‐insurance reimbursement ratios across different cities, covering both inpatient and outpatient hospital care [17].

FIGURE 1.

Illustrative map of the Greater Bay Area (Guangdong‐Hong Kong‐Macau) and the location of ACARE centres in China. Figures made from mapchart.net and paintmaps.com.

Hong Kong and Macau serve as a unique platform for cross‐border cooperation and international connectivity. As part of China's efforts to encourage innovation in healthcare and streamline processes, the GBA has been granted special privileges in the registration of medications through the ‘Work Plan for the Innovative Development of Drug and Medical Device Supervision in the Guangdong‐Hong Kong‐Macao Greater Bay Area’ [18, 19]. The key task of this Work Plan is to allow urgently needed drugs that have been marketed in Hong Kong and Macao to be approved by the State Council of the Guangdong Provincial Medical Products Administration (GPMPA), instead of the NPMA. This privilege accelerates patients' access to medications, with roll‐out of suitable drugs piloted in designated hospitals and acts as a significant incentive for pharmaceutical companies to invest in the GBA. The aim is to leverage the robust drug regulatory mechanisms of Guangdong, Hong Kong and Macao whilst adhering to the law in ‘one country, two systems’. By 2035, the mission is to establish an effective and mature coordination mechanism to oversee drug rollout in the GBA through this initiative [18].

The unique geopolitical nature of the GBA and China's active and increasing attention on the GBA and rare diseases presents a massive opportunity to improve access to diagnostic services and treatment. Through the ‘4As’ framework—Awareness, Access, Advocacy, and Alliance—the article explores the challenges and advancements in HAE care, with a specific focus on the GBA (Table 2).

TABLE 2.

Summary of initiatives in HAE management in the GBA.

Awareness

Improving awareness among physicians Interdepartmental/multidisciplinary collaborations between various specialties (gastroenterologist, emergency physicians, allergist, immunologist) to establish referral, diagnostic and treatment pathways for HAE. Cross‐regional referral pathway: Hong Kong‐Macau Severe Hives and Angioedema Referral Pathway (SHARP) Advancing post‐graduate education and establishing robust post‐graduate specialty training programmes. Improving awareness among patients Cascade Screening and Evaluation of Hereditary Angioedema (CaSE‐HAE) programme: promote family screening and diagnosis Internet mobile platform, featuring a ‘one‐click help’ function, provide smart and timely recommendations for patients experiencing acute attacks

Access

Access to diagnostics ‘Poor man's C1INH function’—utilising the diagnostic sensitivity of a low C4 and raised C1INH level to diagnose HAE‐C1INH‐Type2, when C1INH function is not available. Dried blood spot testing for C4, C1INH level and function and genetics in (i) family screening and (ii) screening and diagnosis of HAE Providing complimentary screening and diagnostic services in severe manifestations of HAE (i.e., patients with previously unexplained recurrent abdominal pain or laryngeal oedema) Access to treatment Granting access to C1INH replacement in the GBA through the Work Plan for the Innovative Development of Drug and Medical Device Supervision in the Guangdong‐Hong Kong‐Macao Greater Bay Area Access to novel medications through international clinical trials (also discussed in the ‘alliance’ section)

Advocacy

Patient advocacy groups used news outlets and audiovisual platforms to highlight drug costs and raise awareness of rare diseases, urging government action. Generating patient data using PROMs and utilising patient diaries to record disease activity and control (‘HAE passports’)

Alliance

Joining internationally recognised Centers of Excellence, such as the ACARE network: foster opportunities for collaborative research In collaboration with ACARE and patient support groups: organise educational activities—including regional preceptorship courses, regional patient meetings, webinars, and HAE masterclasses Creating the Greater‐Bay‐Area Hereditary Angioedema (GBA HAE) Alliance: promote multidisciplinary, cross‐regional alliances Engaging in collaborative research in basic science, exemplified by the joint venture between HKU and Cambridge University using stem cell platforms Collaboration with pharmaceutical industries to join global clinical trials to recruit Chinese patients, facilitating the early application for registration of new drugs

2. Awareness

Bibliometric analysis of HAE publications worldwide showed progressive increase around 2008 when the first HAE‐specific drug, C1INH concentrate, was approved by the Food and Drug Administration in the United States (Figure 2). Although HAE publications in China demonstrates modest growth in the past 5 years, perhaps owing to various factors such as Angioedema Centers of Excellence (ACARE) center accreditation, drug registration and establishment of patient advocacy groups, there has been significant lag in publications compared to the West. This is perhaps due to the lack of disease awareness, expertise, diagnostic and treatment availability [20]. Hopefully, with volume and experience with newer HAE medications, with lanadelumab and icatibant, awareness will continue to rise [21, 22].

FIGURE 2.

Bibliometric analysis of all HAE‐related publications from China and comparator country, indexed on MEDLINE between 1987 and 2024.

Awareness of HAE could perhaps be observed in the change in HAE presentations of various cohorts throughout the years. Prior to the availability of HAE‐specific medications in China, unfortunate research on the “natural course” of HAE among Chinese (i.e., without medications) found an alarmingly high mortality rate of 13% from laryngeal oedema and median age of death of just 46 years [23]. Significant diagnostic delays also likely contributed to the high mortality and morbidity rates, with a case report highlighting a delay of more than 40 years [24]. A large HAE cohort from Beijing reported HAE among Chinese patients have later onset of symptoms and lower frequency of abdominal attacks compared to Western literature (gastrointestinal: 34% vs. laryngeal involvement 59%) [25]. In 2019 and 2021, the same group reported more gastrointestinal involvement (around 70%) and less laryngeal oedema (33%) [26, 27]. The report highlights the high rate of misdiagnosis of abdominal HAE attacks, attributing 35% and 10% to gastroenteritis and appendicitis, respectively. Alarmingly, one in four of these patients even underwent unnecessary appendectomy or laparotomy. Improvement in the time taken for diagnosis could also be observed throughout the decades. Delay in diagnosis was significantly longer if onset of symptoms occurred before 1999 compared with symptom onset occurring between 2000 and 2017 (19.75 years vs. 6.91 years, p < 0.001). Alarmingly, patients with laryngeal or gastrointestinal involvement had more than 10 years of delay (12.75 and 13.17 years, respectively) [26]. Similarly in Hong Kong, prior to any medication available at the time of writing, a significant proportion of patients presented with laryngeal (41.4%) and gastrointestinal involvement (48.3%), with even higher rates in the proband (laryngeal: 73.3%, abdominal 60%) [28]. In comparison, the reported median diagnostic delay in high‐income countries have been reported to only 1.4 years in a large multi‐center European cohort [29], 7.8 years in Korea [30], 13.8 years in Japan [31]. Diagnostic delays are comparably prolonged in low and middle‐income countries, with cohorts reporting 13.7 years in Brazil [32], 4.9 years in North India [33] and 20.5 years in Romania [34]. Additionally, more than half of all HAE patients experienced more than 10 years of diagnostic delay in South Africa [35]. Improvement in disease awareness along with increased access to diagnostics and medications could perhaps explain the change in reported patient symptoms and improvement in the time to diagnosis. Further studies are needed to ascertain this.

2.1. Advancing Awareness in the GBA: Among Doctors

The recognition of gastrointestinal involvement has improved over the years, with numerous unique case reports emerging from literature detailing the experiences among Chinese HAE patients [36, 37, 38, 39]. Several initiatives emerging from centres in the GBA utilises multidisciplinary collaborations to address diagnostic inertia. For example, a group from Guangzhou led the first diagnostic HAE pathway for gastroenterologists, focusing on improving awareness of HAE among patients with recurrent, unexplained abdominal pain and advocating to check serum C4 as initial screening [40]. Likewise, simplified diagnostic and treatment pathways for emergency physicians have also been advocated for [41]. Hong Kong also identified an excessive amount of mislabelled drug allergies among AE patients, advocating to improve both drug allergy delabelling and HAE diagnosis during allergist consultations [42].

Mast‐cell mediated angioedema (being the most common type of angioedema) and HAE are frequently confused and misdiagnosed, often leading to prolonged diagnostic delays for many HAE patients who were previously misdiagnosed with recurrent urticaria. Furthermore, it has been shown that establishing regional guidelines was associated with improved access to treatments [9]. Therefore, the Hong Kong‐Macau Severe Hives and Angioedema Referral Pathway (SHARP) was established [7]. This collaborative initiative between the Hong Kong Institute of Allergy and the Macau Society of Dermatology, operating across two Special Administrative Regions of China, aims to promote awareness and foster a multidisciplinary exchange of expertise in urticaria/angioedema. SHARP provides a referral pathway for frontline physicians dealing with patients with recurrent urticaria (defined as hives, angioedema or both). Being the first recommendations to incorporate both urticaria and HAE in the diagnostic approach and referral pathway, SHARP highlights important distinctions between urticaria and HAE in diagnosis and indications for referral, specifically designed to accommodate for the region's expertise and accessibility to HAE care. These recommendations distinctly contrast with international WAO/EAACI guidelines, especially in approach to diagnosis, family screening and explicit recommendations against the use of non‐HAE‐specific medications [2, 7]. Following such initiatives, the GBA recently reported the successful diagnosis of multiple new HAE families initiated through Chinese paediatric probands in Shenzhen [43]. The first HAE family in Macau was also diagnosed following the publication of SHARP.

Advancing post‐graduate education and specialisation is also a key component in improving disease awareness and management of HAE. Up until 2017, local allergy and immunology subspecialist training was only available under the Hong Kong College of Paediatricians. Recognising this gap in adults, the Hong Kong College of Physicians (HKCP) established its first training programme in immunology and allergy. In 2019, the first locally accredited adult allergy and immunology specialist received conferment under the HKCP. Queen Mary Hospital (QMH) has since been the sole accredited training centre in Hong Kong. To date, the allergist to adult population ratio is approximately 1 to 1 million in Hong Kong [44]. All HAE patients are referred to QMH. In the Mainland, there are approximately 300 allergists/immunologists, giving an approximate ratio of 1 in 4.5 million. Additionally, these specialists mainly concentrate in large cities such as Beijing, Guangzhou and Wuhan [45]. Unfortunately, there is no formal accreditation or training programme for immunology and allergy and many HAE patients may see other related specialties, such as dermatologist, respirologists, otolaryngologist and gastroenterologists. China and the GBA should leverage Hong Kong's robust post‐graduate specialty programme to expand both undergraduate and postgraduate allergy/immunology education through affiliated hospitals, such as the University of Hong Kong‐Shenzhen (HKU‐SZH) hospital.

2.2. Advancing Awareness in the GBA: Among Patients

Innovative family screening strategies aim to increase awareness and diagnosis among families with known HAE. Even beyond China, although many guidelines suggest some form of family screening for HAE, recommendations vary and the practice is still not commonly adopted [2, 46, 47, 48, 49, 50, 51]. Hong Kong was the first to demonstrate that, through its Cascade Screening and Evaluation of Hereditary Angioedema (CaSE‐HAE) programme, cascade family screening—a method of systematically screening all potentially affected family members, even when certain at‐risk relatives are unavailable—is extremely effective in diagnosing new HAE patients [28]. With impressive family screening success rate of over 46%, patients diagnosed through the CaSE‐HAE programme reported significantly improved disease control, reduced anxiety, enhanced quality of life, and even experienced a reduction in annual HAE‐related costs. Most notably, following the implementation of the CaSE‐HAE programme, the estimated point prevalence of HAE in Hong Kong saw a significant increase from 1:640,000 to 1:166,000.

To further improve awareness and the timely management of HAE among patients, a team from Guangzhou developed a dedicated internet mobile platform for HAE patients [52]. This platform, featuring a ‘one‐click help’ function, provides a swift emergency response system for HAE patients experiencing acute attacks, demonstrating its invaluable utility, particularly for the relatively underserved patients in China.

Further studies are needed to address barriers in disease awareness on the individual, societal, economic and cultural level.

3. Access

3.1. Access to Diagnostic Facilities

Diagnosis of HAE‐C1INH requires measurement of C1INH level and function, which require accredited laboratories and specialised expertise [2]. C1INH function in particular requires careful sample handling and may be challenging to perform in rural areas. Given the rarity of the condition, it is not practical nor cost‐effective to be made available across the country's entirety. In Hong Kong for example, there is only one accredited laboratory in the public sector at QMH providing territory‐wide testing of C1INH and function [53]. Genetic testing including SERPING1 genotyping, nl‐C1INH‐HAE gene panel and in‐house next‐generation‐sequencing immune super panel is also available. All physicians who request for C1INH function or genetic testing will have direct communication with an immunologist to ensure correct indications are adhered to, and instructed on proper sample handling. Given the narrow time window for sample handling, widespread access to C1INH function, important in the diagnosis of HAE‐C1INH‐Type 2 can present considerable challenges. This may partially account for the disproportionate lack of reported HAE‐C1INH‐Type2 (< 2%) in Mainland China [54]. In Macau, there is a lack of accredited immunologists/allergists and no available C1INH level or function [7]. As mentioned, the SHARP pathway allows for cross‐regional referrals between Macau to Hong. In China, referral pathways to ‘HAE centers’ are not clearly established or transparent. In the GBA, lack of formal diagnostic facilities often result in heavily relying point‐of‐care tests, such as dried blood spots. Indeed, literature on the unmet needs of HAE in China is scarce, and further research is urgently needed to investigate diagnostic availability before optimal solutions can emerge.

3.2. Advancing Access to Diagnostics in the GBA

Whereas the utilisation of C4 as the sole screening method has been empirically shown to have very low diagnostic yield, a regional study led by Hong Kong demonstrated that centers with availability of C1INH testing have reported significantly younger age of HAE diagnosis [9, 28, 55]. Owing to the lack of tests availability in India, Hong Kong initiated an international, multiethnic study with collaborators from India to assess the diagnostic performance of a novel strategy to screen HAE‐C1INH‐Type2 [56]. Taking advantage of the paradoxical increase in C1INH level among HAE‐C1INH‐Type2 patients, this study demonstrated that by combining a low C4 level and a raised C1INH level, 100% positive and 83% negative predictive values were achieved, respectively, for the diagnosis of HAE‐C1INH‐Type2. This novel screening strategy using the combination of these two tests, aptly termed as the ‘poor man's C1INH function’, has now been adopted in the GBA, India, and other resource‐limited countries that lack ready access to C1INH function testing.

Other novel strategies include using dried blood spot (DBS) tests for genetic testing, especially in rural places without access to laboratories [57]. Additionally, DBS can be used to screen for C4, C1‐INH level and function, and can be utilised in different diagnostic strategies such as, enhancing the CaSE‐HAE programme by integrating DBS to support community‐based family screening initiatives [58]. Various barriers to screening can now undertake diagnostic testing with a simple finger prick, all in the convenience of their own homes, significantly boosting diagnostic yield (Figure 3). DBS tests also have a high potential for screening and diagnosing HAE given ease of sample handling, especially in areas where C1‐INH function is not available and its use in the GBA will be highly anticipated.

FIGURE 3.

Example of a HAE family demonstrating increased diagnostic yield after combining DBS to an outreach cascade family screening programme.

Guangdong has been actively involved in supporting innovative diagnostic strategies and promoting family screening throughout the province. Additionally, health authorities in Guangdong province have urged medical institutions to establish multidisciplinary teams to bolster local diagnostic capabilities, particularly in identifying challenging cases and screening family members. Such initiatives have offered screening (C4 and C1INH level) for patients with previously unexplained recurrent abdominal pain or laryngeal oedema. C1INH functional testing is reserved for patients with strong clinical suspicion but normal C1INH levels.

3.3. Access to HAE‐Specific Medications

Prior to the availability of icatibant and lanadelumab, patients were obliged to rely on second line treatments (mainly fresh frozen plasma for on‐demand treatment and attenuated androgens as prophylaxis widely accessible across China), which are associated with a myriad of side effects [59, 60, 61, 62, 63, 64]. The landscape of HAE management has drastically improved in the past 4–5 years in different regions of China.

In Hong Kong, under the Hospital Authority (the statuary body managing all public hospitals), Berinert and catibant have been approved under ‘Special Drugs’ as of 2023 and 2024 respectively, meaning these drugs may be provided at standard fees and charges in public hospitals for all Hong Kong citizens with HAE‐C1INH, regardless of symptoms, under specialists' authorization. Currently, patients are required to pay around 100HKD (13 USD) for specialist out‐patient consultation fee and an additional 15HKD, or 2USD, for 1 dose of Berinert or icatibant [65]. In Mainland China, both drugs are now included in the national medical insurance schemes. Reimbursement ratios differ across different cities and different employment statuses as illustrated in Table 1.

Regrettably and most notably, the unavailability of C1INH replacement therapies in Mainland China has resulted in a lack of HAE‐specific medications appropriate for pregnant or breastfeeding patients, as well as for short‐term prophylaxis (for instance, prior to invasive procedures). Moreover, patients may still face difficulties in affording these medications or finding them in their local hospitals. Many patients are therefore still obliged to rely on non‐HAE‐medications.

3.4. Advancing Access to HAE Medications in the GBA

The GBA has recently leveraged its unique advantages in medication registration to enhance access to HAE‐specific medications only available in Hong Kong and Macau. Specifically, C1INH replacement therapy is the only licensed medication for pregnant or breastfeeding patients and short‐term prophylaxis in Hong Kong and Macau. Soon, C1INH replacement therapy will be piloted and available at designated affiliated hospitals, such as the HKU‐SZH Hospital in the GBA. Rollout will be expedited through the GPMPA, instead of the NPMA, via the Work Plan initiative. To emphasise, concerted and transparent efforts, such as clear referral pathways and well publicised HAE centres, are essential for making already available medications more accessible to patients, and requires the collaborative efforts of physicians and patients.

4. Advocacy

Advocacy for HAE aims to intensify efforts to boost disease awareness for the public, healthcare professionals, and government bodies. Collaborating with patient support groups has proven to be an effective approach in advocacy efforts. It has been observed that countries with HAE patient support groups are more likely to successfully gain access to HAE‐specific medications, underlining the importance of these partnerships in advancing treatment access [9].

Effective advocacy requires a thorough understanding of the disease's impact and the burden it imposes on local patients. It has been reported that Chinese HAE patients experience significantly lower health‐related quality‐of‐life than the general population, particularly among those with history of laryngeal edema and unsatisfactory disease control [66]. Leveraging this information and collaborating with patient support groups, several public awareness campaigns involving media and patient interviews have succeeded in boosting disease awareness and advocating for life‐saving HAE medications now registered in China. For example, prior to the subsidisation of icatibant and Berinert in Hong Kong, haehk (the local patient support group) and doctors utilised news outlets with titles that emphasised the expensive costs of these life‐saving drugs and directed the articles to the attention of the government [67, 68, 69, 70]. In addition, Rare Disease Hong Kong, a charitable institution recognised by the government has provided timely strategic advice in advocacy efforts and liaison with the government. Other platforms utilising audiovisual materials have also raised the voices of rare diseases and HAE, promoting disease education and awareness among the public [71].

4.1. Advancing Advocacy in the GBA: Generating Patient Data to Reflect Real‐World Need

Measurement of disease control, incorporating the combined physical, mental, and psychosocial burden, should be reflected through validated patient reported outcome measures (PROMs) with several regional and international guidelines advocating its use [2, 7]. Angioedema‐specific PROMs, including the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE‐QoL) questionnaire, and Angioedema Control Test (AECT), have all been translated into Chinese and validated in collaboration with ACARE [72]. These PROMs have been incorporated in ‘HAE Passports’, a patient diary developed by the patient support group in Hong Kong (‘hae hk’). These passports empower patients to consistently record disease activity, control, and medication use. Patients carry these HAE passports to all their immunologist visits, aiding consultations and eases the voluntary contribution of their clinical data to both local and international registries [73]. The data collected has led to publications and further advocacy efforts [22, 28, 72].

A previous study highlights the global disparities in the participation of non‐Western countries and non‐White races in HAE trials [74]. The report advocates for equal access to treatment, including clinical trial opportunities. Therefore, advocacy efforts in the GBA not only improve access to registered medications but also to opportunities in clinical trials. Hong Kong has proactively seized opportunities to participate in global clinical trials, leading to the successful inclusion of the first Chinese patients and Chinese centre in several new HAE‐specific medication trials, as well as aiding future drug registrations into China [22, 75].

5. Alliances: Clinical Research and International Collaborations

In addition to enhancing HAE management within China, fostering collaborative research is essential for enhancing outcomes for the global HAE community and closing the disparity gap. There has been significant progress in international collaboration, as demonstrated by the increase in HAE‐related publications (indexed in MEDLINE) co‐authored between China and other countries from 2018 to 2024 compared to 2011–2017, but there is still considerable scope for improvement (Figure 4). For example, the discovery of novel and distinct SERPING1 variants has also significantly contributed to the HAE literature and enhanced our understanding of the disease pathogenesis [76, 77, 78, 79, 80, 81, 82, 83]. Between 1979 and 2024, more than 100 publications related to HAE have been published, containing valuable insights, encompassing unique diagnostic approaches (e.g., diagnostic pathways for emergency and gastroenterology departments) and treatment methods (e.g., utilisation and response to traditional Chinese medicines) [40, 41, 84]. Regrettably, most have been limited to Chinese sources and not accessible through widely recognised international databases like MEDLINE and limiting its international visibility and impact (Appendix S1). It is crucial to enhance the visibility of Chinese HAE publications on international platforms and foster international collaborations that connect China with the global community.

FIGURE 4.

International collaborations of HAE research with China between the periods (A) 2011–2017 and (B) 2018–2024. Countries in darker shades of colour represent higher number of HAE‐related publications. Lines indicate ≥ 5 HAE‐related publications published together between China and those countries within time‐period.

5.1. Advancing Alliances in the GBA: Piloting From the GBA to Global Stage

Serving as an effective bridge between China and the rest of the world, the GBA has placed a high priority on fostering knowledge exchange between both the Chinese and international HAE communities. This effort has perhaps been best exemplified by the successes achieved by the collaborative projects with international HAE networks (e.g., ACARE) and patient support groups.

As an ACARE centre, the University of Hong Kong has been instrumental in not only providing diagnostic services for local patients but also offering complimentary diagnostic testing for surrounding countries in the Asia Pacific region [38, 56]. In collaboration with the international patient support group (HAE International) and ACARE, the centre has played a pivotal role in global physician education. This has been achieved through various educational activities, such as hosting regional preceptorship courses, regional patient meetings, webinars, and HAE masterclasses [85]. In the field of translational medicine, the University of Hong Kong has formed partnerships with international collaborators from Cambridge University. Together, they have established patient‐derived expanded potential stem cells to investigate the potential of curative gene editing in HAE and other immunological disorders [86]. The centre has also worked with industry to partake in and recruit Chinese patients into several multi‐centre and multi‐national clinical trials, thereby facilitating the early application for registration of new drugs (Table 3) [22, 75]. Hong Kong has also helped to establish an Asia‐focused collaboration (HAE‐ASIA [Angioedema Screening In Asia]) under the ACARE network [87]. HAE‐ASIA aims to improve access to diagnosis and treatment in its member countries, empower other countries to implement effective cascade family screening programmes based on the experience of CaSE‐HAE.

TABLE 3.

Available on‐demand and prophylactic HAE‐specific medications in Mainland China and the GBA (reported as of September 2024).

HAE‐specific medications		Mainland China (outside GBA)	Hong Kong SAR	Greater Bay Area
On‐demand#	C1INH (Human)	Not available	Registered	In progress
	C1INH (Recombinant)	Not available	Not available	Not available
	Deucrictibant	Not available	Clinical Trial	Not available
	Ecallantide	Not available	Not available	Not available
	Icatibant	Registered	Registered	Registered
Prophylaxis*	Berotralstat	Not available	Clinical Trial	Not available
	C1INH (Human)	Not available	Registered	In progress
	Deucrictibant	Not available	Clinical Trial	Not available
	Lanadelumab	Registered	Registered	Registered
	Garadacimab	Not available	Clinical Trial	Not available

Note: Non‐HAE‐specific medications for (#) on‐demand treatments, such as fresh frozen plasma and (*) prophylaxis, such as attenuated androgen and tranexamic acid are available and used off‐label in some areas of Mainland China and GBA.

Recently, the GBA has also established a new GBA HAE Alliance to promote multidisciplinary efforts in managing HAE (involving allergists, dermatologists, emergency care physicians, gastroenterologists, immunologists, otolaryngologists, paediatricians). It aimed to consolidate expertise, streamline diagnosis, and expand access to HAE treatments across the entire region. A ‘Hub‐and‐Spoke’ strategy will be piloted to extend the unique expertise and resources from specified ‘Hubs’ (centres with more HAE‐specific facilities and experience) to support all patients and providers in ‘Spoke’ centres. For instance, providers in Spoke centres will receive education, training, and support from Hub centres to enhance their diagnostic and treatment capabilities. Meanwhile, cases requiring more specialised testing (e.g., cases with suspected HAE with normal C1 inhibitor or acquired angioedema) or treatments (e.g., C1INH replacement for pregnant or breastfeeding patients, or for short‐term prophylaxis, only available in certain centres in GBA) can be referred to Hub centres. If this ‘Hub‐and‐Spoke’ pilot proves successful in the GBA, as it has for other allergy and immunology initiatives in Hong Kong and Macau, this model could potentially be expanded to benefit the entire country and the Asia Pacific region [7, 88, 89, 90, 91, 92, 93, 94].

6. Conclusions

With the recent advances in HAE management, China stands on a new frontier. Through the ‘4As’: Awareness, Access, Advocacy, and Alliance, the GBA will continue to leverage its unique advantages to confront ongoing challenges such as diagnostic delays and lack of access to diagnosis and HAE‐specific medications. Moving forward, it will be essential to persist in nurturing national and international collaborations, within China and beyond, encouraging the exchange of knowledge, research and best practices. By uniting as a worldwide community, we can advance efforts to improve the quality of life for those affected by HAE globally.

Author Contributions

P.H.L., G.H.L. and K.G. conceived the idea and led the write‐up. P.H.L., J.‐X.H., C.‐T.W. and J.C.Y.W. wrote the initial draft. All authors contributed to obtaining data. All authors revised and approved the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Appendix S1.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.