Burden of illness in Japanese patients with paroxysmal nocturnal hemoglobinuria receiving C5 inhibitors

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening blood disorder, affecting 12–13 per million people in the United States (US) [1], with a median age at diagnosis of around 30–50 years globally [2]. PNH is characterized by anemia, thrombosis, fatigue, dyspnea, abdominal pain, smooth muscle dystonia, renal failure, arterial and pulmonary hypertension, and recurrent infection [3, 4]. In PNH, hemolysis, which is the complement-mediated destruction of red blood cells (RBC), is induced by somatic mutations in the PIGA gene. In general, untreated patients with PNH mainly suffer from intravascular hemolysis (IVH) [5].

In Japan, PNH is treated with terminal complement inhibitors, which target the C5 component of the complement cascade, suppressing IVH [6]. Both eculizumab and ravulizumab are terminal complement inhibitors that can improve renal function and lower the thrombotic risk and mortality rate in patients with PNH [3, 7]. However, these inhibitors lead to the accumulation of C3b on the cell membrane, resulting in manifestation of extravascular hemolysis (EVH) in the spleen and other reticuloendothelial systems [8].

The diagnostic criteria for PNH are similar in Japan [2], the US, and Europe. Although no differences have been identified in the gender ratio, ethnic distribution, or geographic trends among these countries [9], there are variations in symptoms and age at diagnosis. A previous study suggested that symptoms of hematopoietic failure are predominant in Asians, including Japanese, whereas more classic PNH symptoms are observed in Western cases [2]. The median age at PNH diagnosis (initial visit) is 45 years in Japan and this is significantly older than the US median of 30 years, according to the Study Group on Idiopathic Hematopoietic Disorders [10]. This may be due to that the diagnosis is more likely to be delayed in Asian cases, especially in Japanese cases, because of the less pronounced nature of PNH symptoms such as thrombosis [2]. Actually, one study demonstrated that Japanese patients are less likely to develop thrombosis (6.2 vs. 19.3%, p < 0.0001) and have a longer mean survival time (32.1 vs. 19.4 years) compared to Caucasian patients [10]. Despite the differences in PNH characteristics, treatment with eculizumab or ravulizumab is indicated in the treatment guidelines used by all of these countries [2].

A patient-reported outcome (PRO) study from the US showed that patients with PNH treated with C5 inhibitors experience substantial burden of illness, indicating a need for improved treatment [11]. In this study, 87.5% and 82.9%, respectively, of eculizumab- and ravulizumab-treated patients remained anemic and 52.2% and 22.6%, respectively, of the patients receiving eculizumab or ravulizumab for ≥ 12 months still required transfusions within the past year. It is also reported that 51/141 (36%) patients received at least one transfusion, with 23 (16%) requiring 3 or more transfusions, and that 30 (21%) patients were receiving a higher dose of eculizumab (1200 mg or more every 2 weeks) [12]. Moreover, the majority of the patients reported fatigue symptoms and the level of quality of life (QoL) of the patients was lower than that of the general population. A similar study was conducted in Europe, which reported that PNH symptoms persist despite C5 inhibitor therapy (eculizumab or ravulizumab) and patients with PNH experience greater fatigue and poorer health-related QoL compared to the European general population references [13]. However, few studies have examined PROs and the disease burden on patients with PNH treated with eculizumab or ravulizumab in Japan. In this study, we aimed to quantify the disease burden on patients with PNH currently receiving eculizumab or ravulizumab treatment in Japan and to understand the unmet needs of these patients.

This study investigated the burden of illness in patients with PNH treated with C5 inhibitors in Japan. The participants were diagnosed with PNH for an average of 16.8 years before the study, and > 80% had been on anti-C5 therapy for > 1 year (Table 1). However, despite treatment, the mean Hb level of the cohort was 10.2 g/dL, and 33 participants (58.9%) reported Hb levels < 10.5 g/dL (Fig. 2a). The results indicated that a substantial disease burden remains in patients with PNH receiving anti-C5 treatment, not only in patients with Hb levels below 10.5 g/dL but also in patients with Hb levels ≥ 10.5 g/dL, which resulted in low QoL and a great symptomatic impact on daily life.

A US study on all-cause healthcare resource utilization found an average of one ER visit and one hospitalization related to PNH in the last 12 months [11]. However, the majority of the participants in our study had not utilized health resources for their PNH in the last 12 months, including ER visits and hospitalizations.

The mean QoL of our patients with PNH in Japan, as measured with the EQ-5D-5L and EORTC, was lower than that of the general population. A previous study reported that EQ-5D-5L scores of Japanese population aged 50–59 years were 0.936 for men and 0.928 for women [26]. This was a comparable age group as the mean age of the participants in our study was 56.7 years. The mean EQ-5D-5L score of our cohort was 0.86, which was lower than that of the general population. The mean score on the global health status scale of the EORTC QLQ-C30 in this study was 66.5, which was similar to the scores of patients with PNH reported in previous studies in Europe (66.9) and the US (62.4 in the eculizumab group and 67.2 in the ravulizumab group) [11, 13]. Although there are some differences in clinical characteristics between Japanese and Caucasian patients, such as thrombosis and mean survival time, it is reported that interpretation of EORTC QLQ-C30 is not affected by Asian ethnicity [27]. Our results showed that Japanese patients with PNH had a similar level of QoL compared to that of PNH-patients in Europe or the US and that irrespective of the severity of the anemia PNH-patients treated with C5 inhibitors had reduced QoL compared with the general population.

The responses of our cohort on the EORTC QLQ-C30 subscales indicated that the levels of fatigue, dyspnea, and insomnia are particularly high in patients with PNH and likely contribute to their reduced QoL. Fatigue and shortness of breath were the most frequently occurring symptoms, which were reported at the time of diagnosis. These remained the most common symptoms at the time of the survey. Fatigue at the time of the survey was reported by 53.8% and 35.0% of the patients in the lower and higher Hb subgroups, while shortness of breath was reported by 50.0% and 20.0% in the two subgroups, respectively. All of the patients in our sample were receiving C5 inhibitor therapy, but the treatment did not sufficiently improve these symptoms and QoL.

More than half of the patients with low Hb levels at the time of the study, experienced fatigue. While the fatigue levels, as measured on the FACIT-Fatigue scale score, of the higher Hb subgroup were comparable (43.0) with those of the general population (43.6) [16]; the lower Hb group scored an average of 7.1 points less (36.5, lower scores indicate worse fatigue) than the general population, a difference greater than the clinically meaningful difference in a patient with PNH (a ≥ 5 points change in score is considered clinically meaningful) [28].

Previous studies have shown correlations between QoL and depression scores. For example, a study in Japan found that depression, measured using the Hospital Anxiety and Depression Scale, was significantly correlated with QoL, measured by EORTC QLQ-C30 functioning and global scores, in cancer patients [29]. In our study, the mean PHQ-8 score of patients with PNH was 4.0, and scores of 0–4 represent no significant depressive symptoms [17, 18]. However, the mean score of the lower Hb level subgroup was 5.0, and scores of 5–9 on this measure denote mild depressive symptoms. Within the lower Hb group, 15 patients (45.5%) had scores indicative of mild to moderately severe depressive symptoms.

As measured by the WPAI tool, the effect of PNH on work productivity was an absenteeism rate of 0.6% and a presenteeism rate of 24.6%. Compared with the rates reported in other countries, the absenteeism in this study was minimal. From our result, absenteeism due to PNH would appear to occur relatively rare in Japan. Our presenteeism rate was higher than that found in a European study (18.7%) [13] but lower than the rate in the US (31.5%) [11]. This result should be interpreted with caution as only 56.1% of those less than 65 years old in our cohort were in paid employment. This was 54.5% in the lower Hb subgroup and 58.8% in the higher Hb subgroup. Those patients most severely affected by PNH symptoms may not be in employment so the rates of presenteeism and absenteeism could lead to an underestimation of the impact of PNH on work productivity.

Activity impairment in the study participants, as measured by WPAI, was 26.6%, on average. This was lower than the rates reported in both Europe (39.7%) and the US (39.3%) [11, 13]. The level of impairment in performance of daily activities among patients with PNH, including those not in employment, was interpreted as low in Japan. However, the mean age ± SD of the participants in this study was approximately 10 years older than for participants in the European and US research (56.7 ± 14.3 years in this study; 43.0 ± 13.1 years in Europe; and 46.8 ± 15.7 years in the US) [11, 13]. Furthermore, the most frequently observed symptoms in the present study were fatigue and shortness of breath. Taken together, this could mean that the participants had misattributed PNH symptoms as age-related, which could have caused them to underestimate the degree of impairment due to PNH. Future studies with larger sample sizes are required, with subgroup comparisons between different age groups.

This study had some limitations. First, due to the cross-sectional design, we cannot ascribe cause-and-effect relationships, just associations, between variables. Second, because the participants of this study were recruited via a patient advocacy group rather than by random selection, volunteer bias may have occurred, potentially limiting the generalizability of the results. In particular, this may mean that the percentage of employed patients with PNH in our cohort does not reflect the percentage of working patients with PNH in Japan. However, demographics such as age and sex in our study population did not differ largely from the distributions in PNH-patients treated with anti-C5 in other research [30]. In addition, patients who belong to patient advocacy groups may be more likely to recognize the symptoms of PNH, and thus the results of this study may be biased toward such patients. Third, all study data were obtained from self-administered questionnaires, so the medical information could not be confirmed by clinicians. Therefore, the survey responses could be subject to recall bias and misclassification and the results regarding medical information such as Hb levels and history of RBC transfusions should be interpreted with caution. Also, special attention should be paid to the interpretation of history of RBC transfusion in past years because it includes the data for blood transfusion prior to receiving C5 inhibitor treatment. Moreover, clinical information other than a diagnosis of ongoing anemia, Hb level, history of RBC transfusions, history of thrombotic events, and history of renal function impairment could not be collected and evaluated. Fourth, the clinically significant cut-off of Hb levels among PNH-patients who have a suboptimal response to C5 inhibition is controversial. Some of the clinical trials with PNH-patients have used < 10 g/dL or ≤ 9.5 g/dL as the inclusion criteria [31, 32]. The 10.5 g/dL threshold used in our study has been discussed as a clinically validated cut-off by the National Institute for Health and Care Excellence in the United Kingdom [33]. However, its clinical significance remains unclear. Finally, due to the limited sample size in this study, our subgroup analyses, other than those for Hb levels, comprised groups too small for the results to be sufficiently valid and reliable. Therefore, the comparisons of other subgroups were not included in the results section.

This study has shown that many patients with PNH in Japan treated with eculizumab or ravulizumab still suffer a significant disease burden in terms of symptoms, QoL, work productivity, and health resource utilization. It is hoped that this research highlights the need of novel more effective therapeutics for the treatment of PNH.