Journal of Community Medicine & Health Education
Open Access

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, chronic, multi system, and potentially fatal hematological disorder [1-3]. If left untreated, it is characterized by intravascular hemolysis, thrombotic events, smooth muscle dystonia, serious infections, and bone marrow failure [1-5]. Other symptoms include anemia, fatigue, chest pain, dyspnea, renal failure, and pulmonary hypertension [1-5]. Typically, PNH is diagnosed between the ages of 30 and 40, although some cases do occur in childhood [6, 7]. Globally, the prevalence of PNH ranges from 10–38 per million people [8-10]. The above mentioned symptoms affect patients’ Quality of Life (QoL). In untreated patients, thrombotic events, hemolysis, renal impairment, and PNH-cytopenia are known to increase the risk of mortality [5, 11].

Complement 5 inhibitors (C5i), the standard of care for PNH, target the C5 complement cascade to reduce intravascular hemolysis, prevent complications, increase life expectancy, and improve QoL [12-17]. However, survey-based studies have reported that despite C5i treatment, patients suffer from significant burden of illness, anemia- related symptoms, limitations in regular activities, impaired work productivity, and reduced QoL [18-21].

Additionally, an ethnographic study conducted in European patients with PNH receiving C5i treatment showed significant symptom burden and a greater breadth of experienced symptoms [22]. Japanese patients also reported low QoL, symptomatic effects on daily life and health resource requirements [3].

There is a limited understanding of day-to-day challenges and unmet needs of patients with PNH receiving C5i therapy due to lack of qualitative studies and evidence [3]. Ethnography is a qualitative research method used to gain a deep understanding of human behavior, by immersing oneself in participants' natural environments, conducting in-depth studies of their experiences, and uncovering otherwise hidden insights from their lives [23].

This is the first ethnographic study in Japanese patients with PNH (UMIN ID 000054172) that aims to understand what it means for patients to live well with PNH, to identify their challenges during C5i treatment, to determine their unmet needs, and to understand the dynamics between patients and their support networks or carers. The results aim to provide awareness of the patient perspective and obtain insights to optimize PNH treatment and patient care in Japan.

Ethical considerations

An independent ethics committee for research approved the study protocol (MINS-REC-230218). The study was conducted in compliance with Ethical Guidelines for Medical and Health Research Involving Human Subjects issued by the Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labor and Welfare and Ministry of Economy, Trade and Industry in Japan [24]. The study also followed the ethical principles of the Declaration of Helsinki [25]. Patients’ identities were protected through anonymity by assigning each patient with a unique identification number, a pseudonym and blurring their faces in the photographs. All elements of the research adhered to Japanese Privacy Policy and the European Union’s General Data Protection Regulation (GDPR) [26, 27]. Quotations from interviews in Japanese were translated into English by the interviewing researcher.

Sample size

For this qualitative study, a sample size of 6–8 patients with PNH and 3–5 professionals was considered sufficient for clinical immersion and to derive patterns from the obtained data.

Fieldwork preparation

Semi-structured, qualitative interviews were conducted face-to- face with Japanese PNH experts to understand the history and background of PNH before planning the study. The interviewed included: a disability expert, a chronic disease patient advocate, and a medical anthropologist with expertise in Japan. Field guide was prepared based on the insights obtained from the experts and included the following research themes: the disease journey, daily life, the ecology of supporting care around patients, and treatment experiences. The field guide comprised an interview guide, exercise instructions, and other essential fieldwork information (see supplementary file).

Researchers conducted the field work using the field guide and sharing real-time field notes to align and collaborate effectively. Interviews were recorded and photographs were taken with the participants’ consent.

Study population

Patients with PNH were recruited through patient organizations: The PNH Club [28] and Saisei Tsubasa no kai [29]. The study inclusion criteria were ≥ 18 years of age, a confirmed diagnosis of PNH, current treatment with a C5i (ravulizumab or eculizumab), and signed informed consent. Patients were excluded if they were enrolled in a clinical trial at the time of screening, had participated in another PNH ethnographic study within the past 3 months or were receiving a C3 inhibitor (C3i) treatment.

Healthcare Professionals (HCPs): Doctors with expertise in PNH and a nurse were recruited to provide additional clinical perspective to the patient-derived data. Eligible HCPs signed an informed consent to participate in the study, were treating patients with PNH, and working at a medical institution where patients with PNH were treated.

Data collection

After written informed consent was obtained, researchers spent 1–2 days with each patient and their family and friends, participating in routine common activities such as sharing a meal together. Researchers typically met the patients at their homes and followed their everyday lives. As part of the immersion, the researchers attended one Tsubasa no kai patient event and organized one social gathering which included four individuals with PNH (2 participants from this study and 2 friends with PNH, from within their social circles). Semi-structured, researcher-led interviews were conducted with the patients with PNH. HCPs were interviewed in the hospitals and where the patients were treated. Additionally, questions were tailored to the interview situation/ context and patients being interviewed.

Data analysis

Data were collected from 10 June 2023 to 30 November 2023 and analysed using a multi-grounded theory approach [30-34]. As part of a bottom-up qualitative research design, the combined data were analysed using cross-case analysis, clustering exercises, and needs mapping. Cross-case analysis was used to detect larger patterns in the material and clustering exercise was used to record and analyze general themes and trends. Needs mapping was used to record unmet disease- related needs. After identifying key themes and unmet needs through these analyses, the main topics for the reported results were established.

Study population

Six patients (males=2, females=4) with PNH, all receiving ravulizumab, and aged from 29 to 62 years were included in the study (Table 1). Family and/or friends (n=13) of the patients were also interviewed. Two physicians with PNH expertise and one nurse were interviewed. Approximately 70 hours of data were captured.

Table 1: Patient characteristics.

Identification of key themes from patient and HCP insights

The key unmet needs identified include persistent post-treatment symptoms, current treatment satisfaction and perceived risks of future treatment, difficulties with information seeking, a double social burden of using shared social resources without contributing to society, and difficulties accessing support for life with PNH.

Disease journey: Interruptions in lives and plans

Although anemia was diagnosed in three out of six (50%) patients prior to their PNH diagnosis, the path to a PNH diagnosis was long and problematic for some patients. It was felt that inexperienced non-specialists contributed to delays in diagnosis of up to 2 years. Consequently, patients felt frustration and a sense that the medical system had failed them. The onset and diagnosis of PNH has interrupted the lives and plans of all six patients. After the onset of PNH, patients felt they had to give up their dreams, and subsequently build lives with a new direction. This commonly meant a change of ambitions or career e.g., a patient had to abandon the aspirations of starting up a family. Additionally, patients were worried of future complications, and had unanswered questions such as “will my PNH evolve into leukemia or myelodysplastic syndrome?”, “will my hemoglobin drop?”, “will I always be able to afford treatment?”, “who will take care of me?” However, it was observed across the sample that despite these sacrifices and uncertainty caused by PNH, patients were able to reflect with gratitude on the alternative opportunities they had had to embrace.

Persistent post-treatment symptoms

Despite the C5i treatment, PNH symptoms continued to affect patients’ daily lives reducing their QoL. While receiving treatment, most patients experienced fatigue (5/6, 83.3%). In addition to classic PNH symptoms, patients experienced expanded symptoms (brain fog, diarrhea, strained muscles, neck/back pain) which they struggled to identify as PNH symptoms (3/6, 50.0%) or periods of debilitating symptoms (2/6, 33.3%) (Figure 1). One patient had regular transfusions in addition to the C5i treatment.

Figure 1: Persistent and unresolved symptoms. Note: PNH: Paroxysmal Nocturnal Hemoglobinuria.

Debilitating periods of symptoms: Due to the debilitating symptoms despite treatment, patients rearranged their lives around PNH and made accommodations at work. The impacts of symptomatic flare ups include being reliant on care from other family members to care for themselves or dependent children, having concerns about missing work or relying on colleagues for support.

Assessing, understanding, and addressing symptoms: Some patients had trouble in assessing, understanding, and differentiating symptoms from other causes to PNH symptoms. To better understand their symptoms, patients developed routines such as assessing whether their hemoglobin level was low by how out of breath they felt and how strained their leg muscles felt on a daily walk; checking their color of urine every morning; recording weight, blood pressure, and body temperature every day to assess changes. Some patients found ways to manage their symptoms and worked around them because they did not believe the symptoms to be severe enough or were related to PNH to be discussed with the HCPs. Many symptoms therefore remained unaddressed. One of the HCPs believed that the patients’ tendency to delay discussing/addressing symptoms was a characteristic of Japanese patients.

Current treatment satisfaction and perceived risks of future treatment

Current treatment experience: Despite persistent symptoms, patients, and HCPs expressed satisfaction with the current C5i treatment, considering that it offers solutions to many of the challenges of living with PNH. With the current C5i treatment regimen, patients (4/6, 66.7%) felt a level of comfort with the 8-weekly routine of receiving treatment at the hospital and with an opportunity for regular check-ups with the doctor (Figure 2).

Figure 2: A typical treatment day of a patient.

The majority of patients (5/6, 83.3%) also liked the freedom of the 8-week cadence in the treatment regimen, of not thinking about their illness, and having stable hemoglobin levels of >10 g/dL. All patients felt effective symptom relief compared to the period when blood transfusion was the only treatment for PNH.

Patients expressed several challenges with the current treatment options and regimens (Figure 3). They reported experiencing side effects following treatment infusion, including brain fog, debilitating headache, drowsiness and fatigue. As reported earlier, although this affected the patients’ QoL, they did not discuss these symptoms with their HCPs. They felt that doctors were more concerned with the treatment than the patient’s QoL.

Figure 3: Challenges with current treatment options and regimens.

HCPs were satisfied with the control and relief of symptoms. But contrary to patients’ experience, HCPs felt satisfied with the improved QoL offered by current treatment. HCPs felt that patients with PNH were now living normal lives. The disability expert believed that patients with PNH feel fortunate, the treatment allows them to live without worry in contrast to the time when these drugs were not available.

Perceived risks of future treatment: The future treatments were perceived as posing unmitigated risks which outweighed the abovementioned challenges. Patients believed that regular interactions with the HCPs were important even with the new treatment options. One patient was concerned about the risks of infections when switching from terminal inhibitors to proximal inhibitors. Another patient anticipated that the new treatment would address fatigue while offering an administration route that wouldn’t strain their veins. While the administration method was not a particular concern, patients generally preferred treatments that are easy to integrate into daily routine and minimize disruptions.

Difficulties with information seeking

An important aspect for patients with PNH is being well-informed about all aspects of living with PNH. Patients identified that finding correct and sufficient information about PNH was a challenge; one patient was shocked to only find negative information about PNH and its outcome. Patients felt frustrated because of the limited amount of information available in Japanese, when they could find much more information in English. Also, the scientific information on PNH was inaccessible for patients who were unfamiliar with reading medical content.

Information from HCPs: Most patients (5/6; 83.3%) considered their specialists as a respected and trusted source of authority on PNH, although interactions with specialists were rare. Some patients would travel over 3 hours to receive specialist care, which they highly valued. A specialist also noted that some patients would fly to appointments for specialist consultations regarding PNH. Experts/specialists provided in-depth discussion of symptoms, support in navigating the healthcare system, support in balancing QoL with health outcomes, assessment of current treatment and up-to-date information about future options, recommendations for additional resources about PNH, and technical explanations of PNH. Local hematologists provide a routine check-up discussing blood work and any changes since the last treatment, but patients feel generally unsupported and that the hematologists lacked the knowledge and information to provide the care they seek. An additional source of complexity and stress for patients was being under primary doctor and specialist care, where conflicting information and advice were given.

Information from patient organizations: The patient organizations provided a source of knowledge, and a form of advocacy. Many patients depended on the Japanese patient group “PNH club” for information. Patients received summarized information in Japanese through newsletters or received further explanations from other members when the content was too technical. For patients, having accessible and adequate information gave them a sense of being prepared and having the capacity to cope with PNH. They believed that patients who felt well-informed by their doctors might not have considered it necessary to join a patient society. In addition to providing a setting to access information, patient societies helped overcome isolation felt because of PNH through the sense of community that they offered.

Double social burden of PNH and difficulties navigating support for life with PNH

Double social burden of PNH: In addition to the burden of PNH, patients felt an additional social burden of not being able to contribute to society and of using valuable shared social resources. Patients felt the emotional burden of using blood when they needed blood transfusion anytime during their PNH treatment (3/6, 50.0%), receiving expensive treatment (6/6, 100.0%), and hearing comments from pharmacists and HCPs about the high costs of treatment (3/6, 50.0%).

Patients expressed concerns about securing employment; often feeling rejected due to the perception that they may be a burden or strain on insurance resources. While working they were concerned about their PNH-related burden to co-workers due to time off for necessary infusions, treatment, or increased susceptibility to illness. Work was negatively affected in all patients; transition to part-time work (2/6, 33.3%), forcing a career change (3/6, 50.0%), or giving up work completely (1/6, 16.7%). Some patients did not register with the patient organization as they did not want a record of their attendance, they feared that someone might inform their workplace, and also limit their professional possibilities.

Patients found ways to pay forward their gratitude by getting actively involved in patient organization to support other patients with PNH during and after diagnosis, and volunteering for clinical trials.

Navigating support for life with PNH: Navigating support for a life with PNH added to the emotional toll of living with PNH. Patients received support from family, HCPs, friends, and co-workers. They felt most comfortable receiving support from family and this support was integral for their life with PNH. Patients feel emotionally burdened by the need for care during their symptom flare ups and also worry about sustainability of care for future flare-ups. Patients’ spouses were at the center of their support systems.

Patients did not always share their diagnosis with friends fearing it might be dismissed, leading to being treated differently or labelled as a sick person. Consequently, the size of social circles shrank after diagnosis, leaving patients feeling that PNH can be an isolating disease. Many patients found it most challenging to navigate support in a professional setting. They felt discouraged from working or selected jobs which they could work at with PNH.

Ethnographic study methods of immersion and interactions allow the researchers to observe the patients closely in their natural environment. This is the first ethnographic study to explore and understand the challenges in patients’ living with PNH in Japan and receiving C5i treatment. The unmet needs identified provide calls to action to the society and medical community caring for patients with PNH (Figure 4).

Figure 4: Unmet needs of patients with PNH. Note: HCP: Healthcare Professional; PNH: Paroxysmal Nocturnal Hemoglobinuria

We observed that all patients’ lives were interrupted because of PNH. Similar observations of interruptions to lives, a breadth of persistent post-treatment symptoms, burden of treatment, and need for support have been reported in another ethnographic study in European patients with PNH receiving C5i treatment [22].

Our study patients continued to experience persistent symptoms despite the C5i treatment. Similar to our observations, despite the C5i treatment, persistent symptoms such as fatigue, and, shortness of breath have been reported by patients from Japan, the USA and Europe [3,18,20,22]. Additionally, patients from Europe and Japan also reported psychological symptoms such as depression, anxiety, irritability [3,22].

Before complement inhibitors became available treatment options for PNH were limited with thrombotic complications leading to death in nearly half of the patients, and a median life-expectancy of 22 years post-diagnosis [35,36]. Patients appreciated improved life expectancy due to the availability of C5i treatment. Despite the persistent symptoms affecting their daily life and QoL, patients may still have expressed treatment satisfaction. Some patients struggled to distinguish the "non-classic" symptoms from comorbid conditions, such as ageing or menopause, and as a result, did not report these symptoms to their HCP, leaving them unaddressed. In Japan, doctor-patient communication often includes long pauses, reflecting information processing but limiting discussion [37]. Encouraging patients to discuss symptoms with their HCPs and raising awareness of the full spectrum of PNH symptoms and treatment options are essential to improve symptom management and QoL.

In addition to the persistent symptoms, patients felt frustrated with the logistics and inflexibility of the current C5i treatment, duration of administration, side effects of the treatment, deterioration of veins over time, and fluctuating symptoms over the 8-weeks period. C5i-treated patients from Europe reported challenges such as travel restrictions, difficult full-time work, and a change in routine [22]. With C5i treatment, residual intravascular hemolysis and extravascular hemolysis continue to occur and may lead to continuous low-grade hemolysis or transient breakthrough hemolysis episodes [38,39]. Although there is a need for better treatment for PNH [18], patients were worried about new treatments due to a lack of information. These worries included a potential increase in infection risk, storage requirements, risk of reduced interactions with the HCPs, and potential treatment adherence.

Pegcetacoplan, a C3i has shown improved efficacy in patients who had anemia despite being treated with C5i eculizumab [40]. Pegcetacoplan has shown superior efficacy to eculizumab and is approved in the U.S.A., Europe and Japan to treat PNH [41-43]. Additionally, it has demonstrated long-term efficacy, safety, improvement in QoL, and ability to address the unmet needs associated with extravascular and residual intravascular hemolysis [44]. Other new treatments such as a factor D inhibitor (danicopan) as an add-on to C5i, a factor B inhibitor (iptacopan), and another C5i (crovalimab) have been recently approved in Japan [45,46].

Patients need to be better educated and assured about new treatments. Recommendations from other people with PNH and awareness about time saving potential, medical necessity, and more effective symptom relief could encourage patients to switch to new treatments. Additionally, patients who have high symptom load, who are working, and have hobbies/activities requiring frequent travel might be interested in switching treatments.

A lack of accurate, sufficient, and accessible information on PNH in Japanese has been a major obstacle for patients in managing the disease and living fully. Molster, et al., reported that patients with rare diseases felt more satisfied receiving information from specialists rather than general practitioners [47]. They also found information more understandable when provided through multiple sources such as verbal explanations, printed materials or web resources [47]. Information plays a key role in daily living and improving QoL in patients with rare diseases. A lack of it can lead to feelings of resignation and fear in patients and their family [48-52]. To enhance QoL and alleviate fear, increasing the accessibility and dissemination of PNH information in Japan is essential.

In patients with PNH, clinical, humanistic, and economic burden associated with C5i treatment in addition to burden of illness has been reported in multiple studies [3,18-20,22]. In Japan, rare disease treatment is covered under universal health coverage system [53]. Japanese people including those having experience with rare disease have shown low acceptance of this financial support because of inadequate understanding of the disease epidemiology [53]. Our patients also experienced a double social burden of using society’s without contributing to society.

Dissemination of adequate information and a reduction in treatment cost may lead to acceptance of the support and a reduction in patients’ emotional burden. A reduction in costs with C3i than C5i treatment has been reported [54,55]. The C3i treatment and availability of biosimilars under development may aid in reducing the cost of treatment reducing the patients’ burden [38,54,55]. Additionally, it is necessary to provide opportunities to patients with PNH to give back to society which would help in alleviating their emotional burden.

Navigating support to live with PNH was challenging to the patients and added to the emotional burden of PNH. They mostly sought support from their spouses followed by HCPs, friends, and co-workers. In European patients, family and friends were primary support sources, and patient organizations were essential parts of the support system [22]. This is also highlighted in a systematic review, by von der Lippe, et al. that found patients with rare disorders relied on family, patient organizations, and others with the same conditions for support [48].

It is necessary to enable patients to navigate support with reduced emotional toll and more security, so that they can live better with PNH. HCPs can guide patients towards non-medical resources considering patient values and circumstances [56]. Resources such as Japan intractable diseases information center, patient associations, medical subsidy system can be leveraged based on patients’ needs of psychological and social support or improving their QoL [56].

This study was limited by its small sample size, all patients receiving ravulizumab, and all except one patient were enrolled through a patient organization. These limitations could have introduced volunteer bias potentially limiting the generalizability of the results. However, PNH is a rare disease and the patients’ age, and gender distribution was largely similar to other studies in patients with PNH treated with C5i [3]. The results of our study offer insights on the daily life challenges experienced by patients with PNH in Japan. These findings may raise awareness among patients and HCPs alike and inspire action to mitigate the challenges.

In conclusion, the results from this first ethnographic study of patients with PNH in Japan suggest that despite treatment, the daily lives of patients with PNH were disrupted. Patients suffered from persistent PNH symptoms which affected their QoL. They experienced a double social burden of PNH, struggled to obtain adequate and correct information about PNH, were not well informed about new PNH treatments, and found it difficult to navigate support for a life with PNH. Further steps are needed to raise awareness of persistent PNH symptoms for communication with HCPs, to help empower patients with PNH and alleviate the burden, to increase access to information on PNH, and to enhance support around new treatments.

Funding

The study was carried out by ReD Associates with funding and input from Sobi. Sobi and ReD Associates reviewed and provided feedback on the manuscript. The authors had full editorial control of the manuscript.

Acknowledgements

The authors thank all the patients, family and friends, and the healthcare professionals for participating and sharing their experiences. We also thank the patient organizations for their support. Medical writing and editorial support were provided by Veena Ekbote of MIMS Co., Ltd., sponsored by Sobi Japan in compliance with Good Publication Practice ethical guidelines (updated on 30 August, 2022; https://www.ismpp.org/gpp-2022).

Authors' contributions

John Stevens was the project lead and was involved in the designing and validating of the study. John Stevens was also involved in the review and editing of the manuscript. Anne Mette Worsøe Lottrup, Mads Holme, Katherine Kamel, Natasha Jessen-Petersen were involved in the project design, implementation, data collection, formal methodology and data analysis, and were involved in the review and editing. Takayuki Ikezoe, Sayoko Murakami, Jun ichi Nishimura, and Akihiko Gotoh contributed to writing-reviewing, and editing. Takeshi Hayashi was involved in the project implementation and contributed to writing-first drafting, writing-reviewing, and editing. Masato Fujii contributed to writing-first drafting, writing-reviewing, and editing. All authors were involved in data interpretation, reviewed the manuscript, and approved the final version.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available upon reasonable requests, from the corresponding author or by sending a data sharing request form (available on www.sobi.com) to medical.info@sobi.com. All requests are evaluated by a cross-functional panel of experts within Sobi, and a decision on sharing will be based on the scientific merit and feasibility of the research proposal, maintenance of personal integrity, and commitment to publication of the results. Further information on Sobi’s data sharing policy and process for requesting access can be found at https://www.sobi.com/en/policies.

Ethics approval and consent to participate

The study protocol was approved by an independent research ethical committee (MINS-REC-230218). The study was conducted in compliance with Ethical Guidelines for Medical and Health Research Involving Human Subjects issued by the Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labor and Welfare and Ministry of Economy, Trade and Industry in Japan [24]. The study also followed the ethical principles of the declaration of Helsinki [25]. Signed informed consents were obtained from the participants before the commencement of the study.

Conflicts of interests

Takayuki Ikezoe has received research grants from AbbVie, Alexion, Asahi Kasei Pharma, Sumitomo Pharma, GlaxoSmithKline, Incyte Bioscience, Janssen, Nippon Shinyaku, Novartis, Otsuka and honoraria/lecture fees from Alexion, Asahi Kasei Pharma, Nippon Shinyaku, Sanofi, and Chugai unrelated to this study. Sayoko Murakami is a representative of PNH Club. Jun ichi Nishimura has received honoraria/ lecture fees from Alexion Pharma and Asahi Kasei Pharma. Anne Mette Worsøe Lottrup, Mads Holme, Katherine Kamel, and Natasha Jessen-Petersen are employees of ReD Associates. John Stevens and Takeshi Hayashi were an employees of Sobi Japan during the writing of this manuscript. Masato Fujii is an employee of Sobi Japan. Akihiko Gotoh has received research grants from Chugai, Asahi Kasei Pharma, Ono, Taiho, and Otsuka, and honoraria/lecture fees from AbbVie, Alexion, Chugai, Asahi Kasei Pharma, Ono, Taiho, Otsuka, Takeda, Kyowa Kirin, Daiichi Sankyo, Sanofi, Pfizer, Sumitomo Pharma, GlaxoSmithKline, Incyte Bioscience, Janssen, Nippon Shinyaku, Novartis, and PharmaEssentia unrelated to this study.

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