PHWR Public Health Weekly Report

Although the number of patients affected by each specific rare disease is low, there are approximately 7,000 types of rare diseases, and approximately 250 rare diseases are newly identified every year. These numbers are expected to continue rising. However, information regarding rare diseases is generally lacking, with little known about most of them. Public health research and support are inadequate owing to the lack of shared information about the population with rare diseases [1]. In response to this situation, the government has established and announced the “Comprehensive Plan for Rare Disease Management” under the Rare Disease Management Act to reduce the personal and social burdens caused by rare diseases and improve the health and welfare of affected individuals. Moreover, the designation of new rare diseases has been expanded each year, starting with the announcement of the designation of rare diseases under national management in September 2018.

In December 2020, the Korea Disease Control and Prevention Agency (KDCA) published the “2019 Statistical Yearbook of People with Rare Diseases” (2019 Statistical Yearbook), which contains the first official data on the incidence of rare diseases in the Republic of Korea. The 2019 Statistical Yearbook listed the number of cases recorded in 2019 for rare diseases designated in 2018. From 2020 onward, the data sources and lists were expanded to include statistics on the number of cases recorded in 2020 for rare diseases designated and announced in 2019, as well as on the number of deaths and medical care use among people with rare diseases in 2019 [2].

However, as the data were collected from each data source at different times, information on the year of incidence, death, and medical care use for people with rare diseases varied, which limited the utilization of the data. To improve this situation and facilitate the use of the statistical yearbooks, the base year has been set to 2020 since 2021. Moreover, the publication schedule has been adjusted to include statistics on incidence, death, and utilization of medical care within the same year.

In this report, we have introduced the statistical data collection system for the “2020 Statistical Yearbook of People with Rare Diseases (2)” (2020 Statistical Yearbook (2)). We have also presented the main results of the 2020 Statistical Yearbook (2).

1. Statistical Data Collection

Data were collected from five affiliated organizations (National Health Insurance Service, Korea Social Security Information Service, Ministry of the Interior and Security, Statistics Korea, and Health Insurance Review and Assessment Service). The collected data were classified into three detailed statistical groups (incidence, death, and medical care use statistics). The collection system for each data source is shown in Figure 1.

Figure 1. Rare disease registration statistics data collection system

The data collected from the National Health Insurance Service and the Korea Social Security Information Service comprise the applications for special registration of rare diseases, which are submitted by people with rare diseases. Medical institutions submit or enter these data through systems related to the National Health Insurance Service or cities, counties, or districts (Korea Social Security Information Service). The KDCA collects the special registration data of rare diseases, sent online to the National Health Insurance Service and the Korea Social Security Information Service, and registers these patients in their internal integrated information management system for rare diseases.

The addresses of the patients with rare diseases were checked using data from the Ministry of the Interior and Security resident registration database. If the resident registration addresses were not confirmed, the addresses provided in the application form for special registration were used. The death data of registered patients with rare diseases were extracted from the statistical data on the cause of death of patients with rare diseases, provided on the Microdata Integrated Service (MDIS) website of Statistics Korea. In addition, data on medical care use for the first three months after patients with rare diseases were registered were obtained online from the Health Insurance Review and Assessment Service.

2. Data Analysis and Subjects of Analysis

From the collected patient data, the start date of the application for special registration was set as the base date of the incidence date. Newly registered patients whose start date of application fell between January 1 and December 31, 2020, were counted among the incidence cases. Data were analyzed for the items presented in Table 1. For the analysis, 1,014 rare diseases designated for national management under the Rare Disease Management Act (announced on October 16, 2019, corrected on December 10, 2019) were used.

Table 1 Collected and analyzed data for 2020 Annual Report on the Rare Disease Patients in Korea (2)

Category	Collected data (source)	Analyzed data
		Variables	Contents
Occurrence statistics	Information of differential co-payments (National Health Insurance Service, NHIS & Korea Social Security Information Service)	Patient’s sex	Male/female
		Patient’s age	Patient’s age when patient is diagnosed
		Korean Standard Classification of Diseases (KCD)	Classification of disease
		Serial number	Classification of disease
		Specific code	Classification of disease
		New- or re-registered for differential co-payments	New reigstered patient
		Registration date for differential co-payments	Registration date
	Information of resident registration placea) (Ministry of the Interior and Safety)	Patient’s address (city & province)	Patient’s postal code for the day when patient is diagnosed (city & province)
Death statisticsb)	Death information (Statistics Korea)	Name of disease	Name of disease in Korean listed from the announcement by the Ministry of Health and Welfare
		Patient’s age	Patient’s age when patient dies
		Patient’s address (city & province)	Patient’s postal code for the day when patient dies (city & province)
National Health Insurance Service benefit statisticsc)	Information of NHIS benefit (Health Insurance Review & Assessment Serivce, HIRA) and NHIS benefit cost by treatment category	Patient’s sex	Male/female
		KCD	Classification of disease
		Serial number	Classification of disease
		Number of claims	The number of completed claims rendered by providers
		Number of visits	The number of visits or the number of hospitalized days of the patient indicated in the claim statement
		Number of days paid	The number of total treatment days indicated in the claim statement which includes drug prescription days without medical treatment
National Health Insurance Service benefit statisticsc)	Information of NHIS benefit (Health Insurance Review & Assessment Serivce, HIRA) and NHIS benefit cost by treatment category	Medical expenses	The total cost rendered during the treatment and determined to be valid by the HIRA review process. The medical expenses is the sum of the insurance benefit and co-payment
		Insurance benefit	The amount of benefit paid by the insurer to the provider, out of the total medical fee determined by HIRA review
		Co-payment	The amount paid by the patient
		Treatement category	11 items from “consultation” to “radiology & radiotherapy” and “Others”d)
		Costs of NHIS benefits category	The total cost rendered during the treatment and determined to be valid by the HIRA review process. Sum of the medical expenses by insurance benefit and co-payment

^a)If resident registration place was not available or unclear, the postal code obtained from the information of differential co-payments was used. ^b)For the patients whose death was reported from January 1 to December 31 in 2020 after the registration during the same year, the number of those patients was produced. ^c)The statistics was produced from the information of National Health Insurance Service Benefit within three months after the registrations in 2020. ^d)11 items: consultation, admission, medication, injection, anesthesia, physiotherapy, psycho-therapy, treatment & surgery, examination, radiology & radiotherapy, others..

3. Tables Presenting the Statistical Results

The following tables presenting the statistical results have been included in the 2020 Statistical Yearbook (2), with approval from Statistics Korea.

• Number of incidences nationwide by sex and disease classification code (rare diseases excluding extremely rare and other chromosomal abnormalities), 2020.

• Number of incidences nationwide by sex and disease (extremely rare diseases), 2020.

• Number of incidences by sex and disease (other chromosomal abnormalities), 2020.

• Number of incidences nationwide by sex, age group, and disease classification code (diseases with more than 200 cases), 2020.

• Number of incidences by disease classification code and region (diseases with more than 200 cases), 2020.

• Number of deaths nationwide by age group and disease classification code, 2020.

• Number of deaths by disease classification code and region, 2020.

• Reimbursement status by sex and disease classification code (3 months after registration), 2020.

• Medical care expenses reimbursement by medical treatment history item and disease classification code (3 months after registration), 2020.

This report summarizes the tables presenting the statistical results in the 2020 Statistical Yearbook (2), and some of the contents have been reclassified and presented as images.

1. Incidence Statistics

In 2020, 694 new patients with one of the 1,014 designated rare diseases were registered, and these patients were considered incidence cases. Based on the classification of special cases for registration of rare diseases, which is provided in the Standards for Special Cases for Registration for Copay [Appendix 4], rare diseases were classified as “rare diseases (excluding extremely rare diseases and other chromosomal abnormalities),” “extremely rare diseases,” or “other chromosomal abnormalities.” The designated rare diseases have been compared by number of patients and disease category, as shown in Table 2.

Table 2 Number of rare diseases and number of the new registered rare disease patients (2020) (Unit: case)

Category	Total	Rare diseasea) (excluding ultra-rare, other chromosomal abnormalities)	Ultra-rare diseaseb)	Other chromosomal abnormalitiesc)
Number of disease
No. of rare diseases officially announced	1,014	773	189	52
No. of rare diseases without new registered patients	320	212	51	17
No. of rare diseases with new registered patients	694	521	138	35
No. of rare diseases with more than 200 new registered patients	50	48	2	0
No. of rare diseases with not more than 200 new registered patients	644	473	136	35
Number of patients
Rare diseases with new registered patients
Total	52,310	50,455	1,767	88
Male	25,353	24,309	998	46
Female	26,957	26,146	769	42
Rare diseases with more than 200 new registered patients
Subtotal	40,149	39,430	719	0
Male	19,218	18,800	418	0
Female	20,815	20,630	301	0
Rare diseases with not more than 200 new registered patients
Subtotal	12,161	11,025	1,048	88
Male	6,135	5,509	580	46
Female	6,142	5,516	468	42

^a)Rare disease: disease that affects less than 20,000 people or disease by which the number of people affected is unknown because it is difficult to diagnose that disease. ^b)Ultra-rare disease: disease has a specific diagnostic criteria and it satisfies one of the followings; (i) its affected people is less than 200, or (ii) it does not have a specific Korean Standard Calssification of Diseases (KCD). ^c)Other chromosomal abnormalities: new chromosomal abnormalities (deletion, duplication, etc) which were detected by scientific and medical technology development meeting with the following criteria; (i) the abnormalities do not have a specific KCD, and (ii) it can be classified as a disease, not as a symptom..

In total, 52,310 rare disease cases were reported. Of them, 25,353 (48.5%) patients were male and 26,957 (51.5%) were female. More than 200 cases were reported each for 50 out of 694 diseases (7.2%), for a total of 40,149 cases, which accounted for 76.8% of the total rare disease cases.

In terms of the proportion of rare diseases according to the Korean standard disease and cause of death classification, the number of cases was highest for diseases affecting the musculoskeletal system and connective tissue (23.0%), followed by diseases of the nervous system (16.0%), diseases of the circulatory system (14.3%), conditions with congenital anomalies, deformities, and chromosomal abnormalities (12.9%), and diseases of the digestive system (12.0%) (Figure 2).

Figure 2. Proportion of the new registered rare disease patients by Korean Standard Classification of Diseases (KCD) in 2020
a)Rare diseases for which plural KCD can be given by the Statistics Korea. b)Rare diseases for which KCD is given by the symptom guidelines developed by the Statistics Korea. c)KCD is given by the morphology of neoplasms. d)KCD is given by the pathology confirmed. e)Rare diseases for which KCD cannot be given because a specific KCD was not entered.

The number of diseases with more than 200 cases, classified by age group and region, is shown in Figure 3. In terms of the number of cases by age group, the 60–64 age group had the highest number of cases (4,078, 10.2%), followed by the 55–59 age group (3,687, 9.2%) and the 65–69 age group (3,649, 9.1%) (Figure 3). In terms of region of residence, 51.8% of the cases resided in metropolitan areas, including Seoul, Incheon, and Gyeonggi-do (Figure 3).

Figure 3. Number of registered rare disease patients by age group and by province in 2020 (for rare diseases with more than 200registered patients)
(A) Number of registered rare disease patients by age group in 2020, (B) number of registered rare disease patients by province in 2020. a)Represented as ‘unknown’ if one of the following cases exists; (i) resident registration place was not available or (ii) information from the application for differential co-payments was unclear.

2. Statistics of Death and Medical Care Use

Death statistics were compiled for those who died during the same registration period (from January 1 to December 31, 2020). The disease presented in the death statistics table is not the cause of death but the disease registered as a rare disease. In other words, the death statistics show the number of patients diagnosed with the disease who died in the same year. Of the 52,310 rare disease cases in 2020, 1,662 died that year, and of them 1,219 (73.3%) were 65 years or older (Table 3).

Table 3 Number of deaths and National Health Insurance Service benefit for the new registered patients (2020) (Unit: case, day, KRW 10,000)

Category	Total	Rare diseasea) (excluding ultra-rare, other chromosomal abnormalities)	Ultra-rare diseaseb)	Other chromosomal abnormalitiesc)
No. of new registered patients
Total	52,310d)	50,455	1,767	88
No. of deathse)
Total	1,662	1,643	18	1
<1 yr	44	43	0	1
1–14 yr	9	8	1	0
15–24 yr	10	10	0	0
25–44 yr	64	62	2	0
45–64 yr	316	311	5	0
≥65 yr	1,219	1,209	10	0
National Health Insurance Service benefitf)
No. of patients who received healthcare service	48,155	46,513	1,578	64
No. of claims per persong)	6	6	6	11
No. of visits per persong)	7	7	8	10
No. of days paid per persong)	58	59	39	21
Medical expenses per persong)	310	312	276	59
Insurance benefit per persong)	276	278	245	54
Co-payment per persong)	34	34	34	6
National Health Insurance Service benefit cost by treatment categoryf),h)
Total	15,699,851	15,162,936	533,078	3,836
Consultation	2,160,110	2,104,064	55,199	847
Admission	2,942,635	2,828,059	114,526	50
Medication	268,327	258,189	10,121	17
Injection	3,246,147	3,143,111	102,925	111
Anesthesia	61,315	59,027	2,288	-
Physiotherapy	401,256	372,444	26,637	2,175
Psycho-therapy	7,233	6,320	895	19
Treatment & surgery	1,421,231	1,374,114	47,108	9
Examination	2,827,490	2,716,890	110,052	549
Radiology & radiotherapy	371,216	361,982	9,193	41
Others	1,992,890	1,938,736	54,135

^a)Rare disease: disease that affects less than 20,000 people or disease by which the number of people affected is unknown because it is difficult to diagnose that disease. ^b)Ultra-rare disease: disease has a specific diagnostic criteria and it satisfies one of the followings; (i) its affected people is less than 200, or (ii) it does not have a specific Korean Standard Calssification of Diseases (KCD). ^c)Other chromosomal abnormalities: new chromosomal abnormalities (deletion, duplication, etc) which were detected by scientific and medical technology development meeting with the following criteria; (i) the abnormalities do not have a specific KCD, and (ii) it can be classified as a disease, not as a symptom. ^d)Although 52,069 patients had been previously reported as the new registered rare disease patients in 2020 (shown in ‘2020 Annual Report on the Rare Disease Patients in Korea’), total 52,310 patients were reported as the final new registered rare disease patients in 2020 (shown in ‘2020 Annual Report on the Rare Disease Patients in Korea (2)’) because of the following reason; the difference in the time for obtaining the information about the differential co-payments. ^e)For the patients whose death was reported from January 1 to December 31 in 2020 after the registration during the same year, the number of those patients was produced. ^f)The statistics was produced from the information of National Health Insurance Service benefit within three months after the registrations in 2020. ^g)Mean. ^h)–: not applicable..

Medical care use statistics were calculated using data on reimbursement for the three-month period after registration and medical treatment details of 11 items from January 1 to December 31, 2020. Among the 52,310 patients with rare diseases, 48,155 patients received at least one consultation in the three-month period following registration of the special case. Hence, they accounted for 92.0% of the total number of cases (Table 3). When the cases are divided by disease type, 92.2% of cases with rare diseases (excluding extremely rare and other chromosomal abnormalities), 89.3% cases with extremely rare diseases, and 72.7% cases with other chromosomal abnormalities received at least one consultation (Table 3).

Regarding the statistics on utilization of medical care, the average cost of medical treatment was 3.1 million won per person; of this amount, the patient’s out-of-pocket expenses were 340,000 won (Table 3). Among the 11 medical cost items, injection fees were the highest, at KRW 32.4 billion, followed by hospitalization fees, examination fees, consultation fees, and other expenses (Table 3).

Among the rare diseases, the highest number of deaths was recorded for “idiopathic pulmonary fibrosis” (n=369, 22.2%), and the number of deaths under the top three diseases accounted for 43.2% (718 people) of the total number of deaths (Table 4). The disease for which the highest number of patients received treatment was “systemic lupus erythematosus with organ or system involvement” (Table 4). With respect to rare diseases with high cost in major treatment categories such as injection fees, hospitalization fees, and examination fees, the highest cost in injection fees was observed for “hereditary factor VIII deficiency” (12.9% of the total injection fees), and the highest cost in hospitalization and examination fees was observed for “status epilepticus, unspecified” (15.3% and 12.9% of the total hospitalization and examination fees, respectively) (Table 4).

Table 4 Top-ranked rare diseases in the number of deaths and National Health Insurance Service benefits (2020) (Unit: case, %, KRW 10,000)

Category	Ranked 1st	Ranked 2nd	Ranked 3rd
Ranked rare diseases in the number of deaths	Idiopathic pulmonary fibrosis	Status epilepticus, unspecified	Irreversible dilated cardiomyopathy
No. of deaths (%a))	369 (22.2)	212 (12.8)	137 (8.2)
Ranked rare disease in the number of patients who received healthcare service	Systemic lupus erythematosus with organ or system involvement	Idiopathic pulmonary fibrosis	Irreversible dilated cardiomyopathy
No. of patients who received healthcare service (%b))	4,287 (8.9)	3,501 (7.3)	3,133 (6.5)
Ranked rare disease in the admission cost	Status epilepticus, unspecified	Guillain-Barrésyndrome	Irreversible dilated cardiomyopathy
Admission cost (%c))	450,622 (15.3)	271,311 (9.2)	208,684 (7.1)
Ranked rare disease in the injection cost	Hereditary factor VIII deficiency	Crohn’s disease of both small and large intestine	Idiopathic aplastic anaemia
Injection cost (%d))	417,510 (12.9)	264,820 (8.2)	173,571 (5.3)
Ranked rare disease in the test cost	Status epilepticus, unspecified	Systemic lupus erythematosus with organ or system involvement	Irreversible dilated cardiomyopathy
Test cost (%e))	365,866 (12.9)	213,383 (7.5)	197,115 (7.0)

^a)Percentage of number of deaths with the ranked rare disease in total deaths (1,662 cases). ^b)Percentage of number of the ranked rare disease patients who received healthcare service in total number of the patients who received healthcare service (48,155 cases). ^c)Percentage of the admission cost for the ranked rare disease in total admission cost (29,426 million won). ^d)Percentage of the injection cost for the ranked rare disease in total injection (32,461 million won). ^e)Percentage of the examination cost for the ranked rare disease in total examination cost (28,274 million won)..

The KDCA has been promoting the National Statistics Project for Rare Diseases to identify the status of patients with rare diseases designated for national management under the Rare Disease Management Act. The Statistical Yearbook of People with Rare Diseases, which contains national statistics on the status of rare disease patients in the Republic of Korea, has been published every year since its announcement in December 2020.

The Statistical Yearbook of People with Rare Diseases contains statistics processed by compiling administrative data from related organizations. The data collection timing differed by data source, which led to differences in the publication timing for statistics on incidence, death, and medical care use within the yearbook of the same year (incidence statistics were published at the end of December of the following year, and death and medical care use statistics were published at the end of December after two years). This caused confusion among users, and limitations in the use of the statistics. To ensure that the statistical results table from a certain year would be included in the yearbook of the same year, the preparation and publication time of all detailed statistics was changed to October of the following year. Therefore, the “2021 Statistical Yearbook of People with Rare Diseases” will be published in October 2023. In the future, the KDCA will continue to improve its statistics to increase their demand and utilization by statistical users and will strive to develop and publish a new statistical result table that can show the status of rare diseases in the Republic of Korea from various perspectives. The Statistical Yearbook of People with Rare Diseases can be downloaded from the Rare Disease Helpline of the KDCA (https://helpline.kdca.go.kr/cdchelp/).

Ethics Statement: Not applicable.

Funding Source: None.

Acknowledgments: None.

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

Author Contributions: Conceptualization: KHC, WMC, JHS. Data curation: KHC, WMC, JHS. Formal analysis: KHC, WMC, JHS. Methodology: KHC, WMC, JHS. Supervision: JWL. Writing – original draft: KHC, WMC, JHS. Writing – review & editing: JWL.