PHWR Public Health Weekly Report

Rare diseases represent a major challenge to public health, creating structural constraints pertaining to national policy development and resource allocation owing to the large number of distinct conditions, each affecting a very small patient population [1]. Although definitions of rare diseases vary by country, most are based on prevalence or a patient count that falls below a specified threshold [2]. In the Republic of Korea (ROK), the Rare Disease Management Act defines a rare disease as a condition affecting 20,000 or fewer individuals, or whose prevalence is difficult to determine owing to diagnostic challenges. The Korea Disease Control and Prevention Agency (KDCA) is responsible for designating and officially listing these conditions under the authority of the Ministry of Health and Welfare [3]. Estimates of the number of rare diseases worldwide vary because of differing definitional criteria and national demographic data. However, recent studies suggest the number ranges from 5,000 to over 10,000, depending on the classification criteria and scope [4]. In ROK, approximately 1,000 conditions are officially designated as rare diseases [3,5,6].

Rare diseases are often characterized by a significant genetic component, frequent association with disability or reduced life expectancy, and substantial healthcare costs. These characteristics exacerbate the socioeconomic burden on patients and their families [7], underscoring the need for a national periodic monitoring system and evidence-based strategies as core priorities in rare disease policy [8]. However, a persistent lack of reliable epidemiological data, coupled with insufficient diagnostic criteria and treatment guidelines, has led to substantial practical limitations in clinical diagnosis, patient support, and policy development [9]. In response, ROK launched its national Rare Disease Statistics Project in 2019, publishing the first government-approved “Annual Report on Rare Disease Patients in Korea” in December 2020. With four consecutive annual reports published until 2022, a system for the sustained production of rare disease statistics has now been established. This report is currently the only official, nationally produced statistical source on rare diseases in ROK, providing foundational data for healthcare policy, disease surveillance, and academic and institutional research. The accumulation of annual data on metrics, such as incidence, mortality, and healthcare utilization, provides a robust empirical basis for precision policy-making and resource allocation for the future.

The 2022 annual report featured an improved indicator, which included new mortality statistics stratified by sex, standardized 10-year age intervals across all items, and healthcare utilization data categorized by healthcare coverage type (National Health Insurance [NHI] or Medical Aid) [10]. Furthermore, the elimination of “Unknown” categories for disease classification codes and age groups in the 2022 reports signifies improved data quality and a more sophisticated analytical framework. This study, therefore, provides the latest epidemiological information on patients with rare diseases in ROK by comprehensively analyzing the 2022 incidence statistics in comparison with data for the period 2019–2021, presenting characteristics by sex, age, and healthcare utilization. Based on these findings, we aimed to outline future directions for advancing the national rare disease statistics system and contribute to establishing a more precise evidence base for policy.

1. Study Design

This study is a retrospective, descriptive analysis based on raw data from the “2022 Annual Report on the Rare Disease Patients in Korea,” published by the KDCA. The objective of this study was to characterize the status of patients with rare diseases and to recommend improvements for the annual statistics report.

2. Study Population and Data Collection

The study population comprised patients newly registered in the special co-payment reduction program for rare diseases between January 1 and December 31, 2022. To account for potential registration delays, data registered until December 31, 2023, were included. Data were collected from the National Health Insurance Service (NHIS) for NHI subscribers and from the Korea Social Security Information Service (SSIS) for Medical Aid beneficiaries. Disease classification was based on the official list of 1,123 designated conditions as of December 28, 2021. If an individual had multiple conditions across different categories (rare diseases, ultra-rare diseases, and other chromosomal abnormalities), each was counted as a separate incident case. For confirmed incident cases, data were linked from multiple sources: healthcare utilization data from the Health Insurance Review and Assessment Service (HIRA), mortality data from Statistics Korea, and residential address information from the Ministry of the Interior and Safety.

3. Analysis of Patient Status

First, 2022 incident cases were identified from the registration data for the special co-payment reduction program, collected from the NHIS and SSIS. This involved standardizing the data structures from each institution and realigning disease classification codes according to the KDCA’s official rare disease list. Second, a unique personal identifier was generated to confirm new case status by checking against records from 2019 to 2021 and to deduplicate records arising from changes in national resident registration numbers, names, or eligibility status. Finally, for the selected incident cases, residential information from the Ministry of the Interior and Safety was linked with 12-month healthcare utilization data from HIRA, starting from the program’s effective date. Mortality statistics were also compiled using data on deaths occurring within the 2022 calendar year, provided by Statistics Korea. This comprehensive process enabled the “2022 Annual Report on the Rare Disease Patients in Korea” to provide key statistics, including the number of incident cases per disease, same-year mortality, and 12-month healthcare utilization details.

4. Data Analysis

Key analytical variables were established to analyze the status of patients with rare diseases, including disease classification, demographics, healthcare utilization, and mortality. Diseases were classified as rare, ultra-rare, or other chromosomal abnormalities. Demographics were analyzed by sex and age. A rare disease is a condition with a prevalence of ≤20,000 persons or with unknown prevalence owing to diagnostic difficulty. An ultra-rare disease is a diagnosable, independent condition with a prevalence of ≤200 persons in ROK or one that lacks a specific disease code. Other chromosomal abnormalities are novel aberrations (e.g., deletions and duplications) discovered through scientific advances that lack a specific disease name or code but are defined as disease entities [10]. Healthcare utilization was analyzed based on total medical costs during the 12 months following program registration, stratified by healthcare coverage type (NHI vs. Medical Aid). Mortality status included the number of death among the 2022 incident cases that occurred within the same calendar year. Descriptive statistics, including frequencies, proportions, and means, were used to analyze distributions by sex and age and to identify differences in healthcare utilization patterns. To contextualize the 2022 findings, a comparative analysis of annual trends for the same indicators from 2019 to 2021 was conducted.

1. Trends in Rare Disease Incidence

In 2022, a total of 54,952 new incident cases (27,357 and 27,595 male and female patients, respectively) were reported for 770 of the 1,123 officially designated rare diseases. While the number of designated rare diseases increased annually from 926 in 2019 to 1,123 in 2022, the number of new incident cases remained in the mid-50,000s: 55,549 in 2019, 52,310 in 2020, 55,874 in 2021, and 54,952 in 2022. Based on the total population as of July 1 of each year [11], the crude incidence rate per 100,000 population was 107.3 in 2019, 100.9 in 2020, 107.9 in 2021, and 106.3 in 2022. In terms of disease category, rare diseases accounted for 96.1% (52,790) of all incident cases in 2022, followed by ultra-rare diseases (3.8%; 2,074) and other chromosomal abnormalities (0.2%; 88). The number of deaths among incident cases within the same calendar year increased from 1,596 in 2019 to 1,902 in 2022 (Figure 1).

Figure 1. Trends in the number of rare disease cases and deaths (2019–2022)

2. Incidence of Rare Diseases by Sex and Age in 2022

1) Most frequent diseases and those with the highest proportions by sex

In 2022, the five diseases with the highest number of incident cases were idiopathic pulmonary fibrosis (n=4,819), irreversible dilated cardiomyopathy (n=3,039), systemic lupus erythematosus with organ or system involvement (n=2,825), Crohn’s disease of both the small and large intestines (n=2,392), and Moyamoya disease (n=2,261). Stratified by sex, the most frequent diseases in male individuals were idiopathic pulmonary fibrosis, irreversible dilated cardiomyopathy, Crohn’s disease of both the small and large intestines, Crohn’s disease of the small intestine, and nonobstructive hypertrophic cardiomyopathy. In female individuals, the most frequent diseases were systemic lupus erythematosus with organ or system involvement, Sicca syndrome (Sjögren), Moyamoya disease, idiopathic pulmonary fibrosis, and irreversible dilated cardiomyopathy (Figure 2).

Figure 2. Top 5 most frequently diagnosed rare diseases by sex

Among diseases with over 200 incident cases, those with the highest proportion of male patients, ranging from 71.0% to 78.7%, were severe hidradenitis suppurativa, idiopathic pulmonary fibrosis, Crohn’s disease of both the small and large intestines, Crohn’s disease of the small intestine, and Crohn’s disease of the large intestine. Those with the highest proportion of female patients, ranging from 83.5% to 92.1%, were Sjögren’s syndrome with myopathy, Sicca syndrome (Sjögren), systemic lupus erythematosus with organ or system involvement, progressive systemic sclerosis, and autoimmune hepatitis (Table 1).

Table 1 Rare diseases with a high sex-specific incidence rate in 2022 (≥200 cases)

Category	Total	Male	Female
Total number of newly diagnosed rare disease patients	42,429 (100.0)	21,201 (50.2)	21,048 (49.8)
Top rare diseases (≥200 cases) with higher incidence in males
Hidradenitis suppurativa, severe	230 (100.0)	181 (78.7)	49 (21.3)
Idiopathic pulmonary fibrosis	4,819 (100.0)	3,742 (77.7)	1,077 (22.3)
Crohn’s disease of both small and large intestine	2,392 (100.0)	1,797 (75.1)	595 (24.9)
Crohn’s disease of small intestine	1,149 (100.0)	859 (74.8)	290 (25.2)
Crohn’s disease of large intestine	677 (100.0)	481 (71.0)	196 (29.0)
Top rare diseases (≥200 cases) with higher incidence in females
Sjogren’s syndrome with myopathy	407 (100.0)	32 (7.9)	375 (92.1)
Sicca syndrome (Sjögren)	1,949 (100.0)	154 (7.9)	1,795 (92.1)
Systemic lupus erythematosus with organ or system involvement	2,825 (100.0)	352 (12.5)	2,473 (87.5)
Progressive systemic sclerosis	639 (100.0)	82 (12.8)	557 (87.2)
Autoimmune hepatitis	1,053 (100.0)	174 (16.5)	879 (83.5)

Values are presented as number (%)..

2) Most frequent diseases and those with the highest proportions by age

By age group, the most frequent diseases in individuals under 20 years of age were Crohn’s disease of both the small and large intestines, narcolepsy and cataplexy, juvenile rheumatoid arthritis, microtia, and neurofibromatosis (non-malignant) types 1 and 2. In the 20–59-year age group, the most frequent diseases were systemic lupus erythematosus with organ or system involvement, Crohn’s disease of both the small and large intestines, Moyamoya disease, irreversible dilated cardiomyopathy, and Sicca syndrome (Sjögren). In the ≥60-year age group, the most frequent diseases were idiopathic pulmonary fibrosis, irreversible dilated cardiomyopathy, polymyalgia rheumatica, nonobstructive hypertrophic cardiomyopathy, and Sicca syndrome (Sjögren) (Figure 3).

Figure 3. Top 5 most frequently diagnosed rare diseases by age group

Among diseases with over 200 incident cases, those with a high proportion of cases in the <20 years age group were juvenile rheumatoid arthritis, microtia, spina bifida unspecified, tetralogy of Fallot, and neurofibromatosis (non-malignant) types 1 and 2. The diseases with a high proportion in the 20–59-year age group were keratoconus, severe hidradenitis suppurativa, multiple sclerosis, Behçet’s disease, and Crohn’s disease of the small intestine. Furthermore, the diseases with a high proportion in the ≥60-year age group were progressive supranuclear ophthalmoplegia (Steele-Richardson-Olszewski), idiopathic pulmonary fibrosis, bullous pemphigoid, polymyalgia rheumatica, and microscopic polyangiitis (Table 2).

Table 2 Rare diseases with high age-specific incidence rate in 2022 (≥200 cases)

Category	Total	<20 yr	20–59 yr	≥60 yr
Total	42,249 (100.0)	3,485 (8.2)	19,726 (46.7)	19,038 (45.1)
Rare diseases with a high incidence proportion under age 20
Juvenile rheumatoid arthritis	250 (100.0)	219 (87.6)	24 (9.6)	7 (2.8)
Microtia	252 (100.0)	215 (85.3)	29 (11.5)	8 (3.2)
Spina bifida, unspecified	223 (100.0)	173 (77.6)	43 (19.3)	7 (3.1)
Tetralogy of Fallot	296 (100.0)	163 (55.1)	124 (41.9)	9 (3.0)
Neurofibromatosis (nonmalignant) type 1, type 2	377 (100.0)	199 (52.8)	157 (41.6)	21 (5.6)
Rare diseases with a high incidence proportion among individuals aged 20–59
Keratoconus	853 (100.0)	42 (4.9)	785 (92.0)	26 (3.0)
Hidradenitis suppurativa, severe	230 (100.0)	21 (9.1)	205 (89.1)	4 (1.7)
Multiple sclerosis	222 (100.0)	16 (7.2)	183 (82.4)	23 (10.4)
Behçet’s disease	892 (100.0)	26 (2.9)	673 (75.4)	193 (21.6)
Crohn’s disease of small intestine	1,149 (100.0)	158 (13.8)	851 (74.1)	140 (12.2)
Rare diseases with a high incidence proportion in individuals aged 60 and over
Progressive supranuclear ophthalmoplegia (Steele-Richardson-Olszewski)	314 (100.0)	-	13 (4.1)	301 (95.9)
Idiopathic pulmonary fibrosis	4,819 (100.0)	-	289 (6.0)	4,530 (94.0)
Bullous pemphigoid	648 (100.0)	-	54 (8.3)	594 (91.7)
Polymyalgia rheumatica	927 (100.0)	-	139 (15.0)	788 (85.0)
Microscopic polyarteritis	212 (100.0)	5 (2.4)	32 (15.1)	175 (82.5)

Values are presented as number (%)..

3. Healthcare Utilization during the 12 Months Following Program Registration

Of the 2022 incident cases, 52,818 individuals received medical care within 12 months of registration in the program. The average total medical cost per person was 6.39 million KRW, comprising 5.72 million KRW in reimbursement costs and 0.66 million KRW in out-of-pocket payments. By disease category, the average total medical costs per person were 6.38 million KRW for rare diseases, 6.81 million KRW for ultra-rare diseases, and 2.48 million KRW for other chromosomal abnormalities. Analysis by healthcare coverage type showed that 93.7% (n=49,500) of individuals receiving care were NHI subscribers, while 6.3% (n=3,318) were Medical Aid beneficiaries. The average total medical cost per person was higher for Medical Aid beneficiaries (7.60 million KRW) than for NHI subscribers (6.31 million KRW). The per capita reimbursement costs were 5.60 million KRW for NHI subscribers and 7.44 million KRW for Medical Aid beneficiaries (Table 3).

Table 3 Medical service use during 12 month after rare disease registration in 2022

Category		Case	Average medical expense per patient
			Total	Benefit	Co-payment
Total	Total	52,818 (100.0)	6,387	5,719	665
	Health insurance	49,500 (93.7)	6,306	5,604	699
	Medical aid	3,318 (6.3)	7,598	7,439	157
Rare disease	Total	50,789 (100.0)	6,377	5,713	660
	Health insurance	47,541 (93.6)	6,294	5,596	695
	Medical aid	3,248 (6.4)	7,582	7,423	157
Ultra-rare disease	Total	1,955 (100.0)	6,811	6,018	793
	Health insurance	1,888 (96.6)	6,746	5,930	815
	Medical aid	67 (3.4)	8,661	8,500	161
Other chromosomal abnormalities	Total	74 (100.0)	2,482	2,240	242
	Health insurance	71 (95.9)	2,562	2,310	252
	Medical aid	3 (4.1)	581	581	-

Values are presented as number (%) or KRW 1,000..

This study analyzed the incidence of rare diseases in ROK in 2022, providing a comprehensive overview of demographic characteristics and healthcare utilization during the 12 months following registration in the special co-payment reduction program. The total number of new incident cases in 2022 was 54,952. While this represents a slight decrease from the previous year, the annual incidence has remained in the mid-50,000s since 2019. The crude incidence rate for all rare diseases in 2022 was 106.3 per 100,000 population, equivalent to 19.3% of the crude incidence rate for all cancers in ROK during the same year (550.2 per 100,000) [12]. Although direct cross-national comparisons are challenging, a study of European cancer registries from 1988 to 2002 estimated the annual incidence of all rare cancers to be approximately 108 per 100,000, accounting for 22% of all cancer diagnoses annually [13]. However, given that this figure is limited to cancers and that national definitions and statistical methodologies vary, international standardization and caution in interpretation are warranted. Furthermore, Annual Report on Rare Disease Patients in Korea includes non-nationals, necessitating the presentation of incidence data specific to the national population.

Incidence patterns of rare diseases varied significantly by sex and age. Female patients exhibited a higher incidence of autoimmune diseases; notably, there was a striking sex disparity in the case of Sicca syndrome (Sjögren) and systemic lupus erythematosus. This finding is consistent with previous research indicating that approximately 80% of patients with autoimmune diseases are female [14]. In contrast, the incidences of inflammatory bowel diseases and cardiomyopathies were relatively higher in male patients. Distinct patterns also emerged by age: congenital malformations and autoimmune disorders were predominant in individuals younger than 20 years, whereas pulmonary fibrosis and cardiac diseases were most common in those aged 60 years and over [15,16].

The management of rare diseases is inherently challenging owing to low public awareness, a lack of standardized diagnostic guidelines that leads to diagnostic delays, and limited access to treatments. Previous studies have shown that female and adolescent patients experience longer than average diagnostic journeys, a factor that can accelerate disease progression and worsen prognosis [17]. These differentiated incidence patterns underscore that sex and age are critical factors to be considered when developing strategies for early diagnosis and management. Targeted approaches are particularly needed for diseases that are frequent or disproportionately affect specific sex and age groups. However, a limitation of this study is its focus on incident cases, which do not reflect the overall prevalence in the population and may not fully represent the total disease burden. Therefore, developing complementary statistical indicators that include prevalence and life-course data is essential for more sophisticated disease surveillance and health policy design.

The same-year mortality rate among new incident cases of rare diseases showed a gradual increase. In 2022, the mortality rate was 3.5% (1,902 deaths among 54,952 incident cases), a 0.6 percentage-point increase from 2019. This trend may be attributable to a combination of factors, including a relative increase in the proportion of severe diseases, better identification of rare diseases owing to improved diagnostics, and cumulative disparities in healthcare access. An analysis of registry data from the Veneto region of Italy (2002–2019) reported a standardized mortality ratio of 1.93 for patients with rare diseases compared with the general population. Notably, severe conditions such as neurological disorders had a low 15-year survival rate of 18% [18]. This suggests that as registration and diagnostic systems advance, severe cases that previously went unidentified are being increasingly captured in statistics, potentially contributing to the observed increase in overall mortality. However, to determine the causes of this increase more accurately, multifaceted analyses using empirical data are required. The current annual report is limited in this regard, because it provides only the number of deaths and does not capture survival duration or cause of death. Therefore, the development of sophisticated, survival-based indicators and long-term follow-up is necessary.

The proportion of Medical Aid beneficiaries among incident rare disease cases (6.3%) was notably high, considering that this group constitutes only 3% of the total population and accounted for just 3.1% of all individuals receiving care in 2022 [19,20]. In 2022, the per capita total medical cost for incident cases was approximately 20% higher for Medical Aid beneficiaries than for NHI subscribers. The per capita reimbursement cost was 32.7% higher for Medical Aid beneficiaries (7.44 million KRW) than for NHI subscribers (5.60 million KRW). This figure is also 12.3% higher than the average per capita reimbursement cost of 6.63 million KRW for all Medical Aid beneficiaries in 2022 [20]. Medical Aid beneficiaries may have a higher incidence of rare diseases because of the greater overall health vulnerability associated with low income, poor living conditions, and a higher burden of comorbidities [21]. Alternatively, the lower out-of-pocket costs for Medical Aid beneficiaries may improve their access to high-cost diagnostic procedures for rare diseases, potentially leading to a higher rate of confirmed diagnoses being captured in the statistics for this group. Indeed, studies in the United States have reported that Medicaid beneficiaries tend to have higher diagnosis rates and greater post-diagnosis healthcare consumption for rare diseases compared to commercially insured populations [22]. These findings indicate the need for precise, differentiated policy interventions in the diagnosis, treatment, and coverage design for rare diseases that account for the structural health vulnerabilities and financial burdens of socioeconomically disadvantaged populations. While some Medical Aid beneficiaries may receive timely diagnoses, others may still face delays. Therefore, strategies must address gaps in the rare disease registration system and promote equitable access through tailored coverage expansions that consider income and regional disparities [23].

In conclusion, while the analysis of the 2022 data revealed continuous improvements in the clarity and sophistication of the Annual Report on Rare Disease Patients in Korea, it still lacked patient-centered indicators. The current report, based on processed administrative data from five institutions, is limited to patients registered in the special co-payment reduction program and does not capture unregistered individuals. Its aggregated nature also restricts detailed analyses of individual patient characteristics or the specifics of diagnosis and management. Specifically, incidence-focused, cross-sectional statistics are insufficient to fully capture the patient disease burden or long-term management needs. To effectively inform future prevention and management policies, rare disease statistics must evolve beyond calculating the overall scale to include the development of classifications and indicators based on disease characteristics. This requires moving beyond simple enumerations to create new, multidimensional indicators that incorporate disease-specific attributes and medical needs, including clinical course, severity, age at diagnosis, treatability, survival rate, functional impairment, and heritability. Therefore, future efforts should focus on generating more precise statistics grounded in the clinical characteristics of each disease. This necessitates the collection of patient-centered, dynamic data—such as data on diagnostic delay, treatment pathways, and survival rates—through the national rare disease registration project. Doing so will build a more robust scientific evidence base for effective policy-making and system design.

Ethics Statement: Not applicable.

Funding Source: This study was supported by the Korea Disease Control and Prevention Agency (no. 11-1790387- 001106-01).

Acknowledgments: None.

Conflict of Interest: The authors have no conflicts of interest to declare.

Author Contributions: Conceptualization: KAL. Data curation: ISP, KAL, KHC. Formal analysis: ISP, KAL. Funding acquisition: ISP. Investigation: ISP, KAL, THL. Methodology: ISP, KAL. Project administration: THL. Resources: JYK, JHS, KHC. Supervision: JYK, JHS. Visualization: KAL. Writing – original draft: KAL, ISP. Writing – review & editing: all authors.