This study determined the annual cumulative incidence of rare diseases in Korea using nationwide data obtained from the administrative register for the co-payment assistance policy for rare and incurable diseases in the Korean NHIS from 2011 to 2015. Our results showed that the number of rare diseases showing an increasing trend in average annual cumulative incidence was higher than the number of diseases showing a decreasing trend in average annual cumulative incidence (34 [8.19%] vs. 4 [0.96%]).
The rare disease with the highest average annual cumulative incidences and for which the increment trends per year were statistically significant was Parkinson’s disease. Parkinson’s disease was the most common rare disease (average annual cumulative incidence: 2066.43/10,000,000) and its annual cumulative incidence increased from 2011 to 2015 in our study. The annual cumulative incidence of Parkinson’s disease per 10,000,000 was 1884.36 in 2011, 1882.58 in 2012, 1945.05 in 2013, 2164.53 in 2014 and 2447.80 in 2015 (see Additional file 2). Parkinson’s disease is a representative age-related neurodegenerative disease . Several studies reported that older age was major risk factor for an increased risk of developing Parkinson’s disease . South Korea is undergoing unprecedented and rapid population aging and life expectancy at birth has increased steadily from 80.62 in 2011 to 82.06 in 2015 . Increased longevity might increase the incidence of Parkinson’s disease in South Korea. Considering the high burden and low quality of life observed with Parkinson’s disease, urgent attention should be directed towards developing national support systems to alleviate the burden on patients’ families [27, 28].
The number patients with sarcoidosis (D86, D86.0, D86.1, D86.2, D86.3, D86.8, D86.9) has also increased over the time. The annual cumulative incidence increased from 70.91 per 10,000,000 in 2011 to 101.86 per 10,000,000 in 2015 (see Additional file 2). Sarcoidosis is a multisystem disorder of which the aetiology is unknown. The case-control study of 706 newly diagnosed patients conducted by National Institutes of Health found positive associations between sarcoidosis and exposures including insecticides, agricultural employment and microbial bioaerosols . However, these exposures have decreased in Korea due to the shift of the economy from agriculture to the manufacturing and service sector. The increasing trend in the annual cumulative incidence of sarcoidosis might be explained by the increased detection rate of sarcoidosis due to the increased diagnostic techniques and frequent regular health check-ups [30,31,32]. The overall participation rate in primary health examinations, including the chest X-rays, has increased from 56% in 2006 to 72% in 2013 . The number of patients using computed tomography and magnetic resonance imaging, which are diagnostic tools for sarcoidosis, have also increased steadily from 4,118,434 and 631,305 in 2012 to 5,139,149 and 805,831 in 2015, respectively .
Upon comparison of the cumulative incidence of rare diseases in our study to the estimated incidence reported by the Orphanet , we observed a significant difference in the incidence of Moyamoya disease (I67.5; our result: 261.73/10,000,000 vs Orphanet: 3.5/10,000,000). A previous systematic review revealed that the incidence of definite Moyamoya disease in Asia (Japan, Hokkaido: 84 per 10,00,000; China: 41 per 10,00,000) was higher than in the USA (Iowa, 4 per 10,000,000) . Although Asian countries have a predilection for developing Moyamoya disease, the cumulative incidence of Moyamoya disease in South Korea was higher than in other Asian countries. This high incidence among South Koreans has also been supported by the findings from other studies which have used the medical claim data of NHIS (average annual cumulative incidence 2005–2013: 270/10,000,000) . The high incidence of Moyamoya disease in East Asia might be partly explained by genetic effects of developing the rare disease . A previous study showed a strong association between the p.R4810K mutation in RNF213 , which has a relatively high prevalence among East Asians and is a risk factor for the development of Moyamoya disease .
To the best of our knowledge, this is the first study to estimate the cumulative incidence of an entire spectrum of rare diseases in Korea by using data from a nationwide administrative database in the register of rare diseases. However, our results should be interpreted within the context of the study’s limitations. First, only patients with rare diseases who were supported by the government were included in our study. Considering the complexity of the diagnosis of rare diseases, there is a possibility that many patients with rare diseases did not receive a definite diagnosis by the physician, which is a prerequisite for national support for rare diseases. Furthermore, the method of grouping patients with rare diseases according to the ICD codes could overestimate the actual incidence of rare diseases when the specificity of the ICD coding was not validated . Therefore, our estimated annual cumulative incidence might not reflect the actual incidence of rare diseases. However, our results do supplement the disadvantages observed in other studies which have used the ICD codes in medical claim data leading to the ambiguity of the diagnosis of rare diseases. Our study included patients who met the diagnostic criteria on the basis of imaging studies, biochemistry, immunology, smear, culture test, histological examination and clinical diagnosis for benefiting from the national support. Second, our study could not include all rare diseases for which the prevalence was less than 20,000 patients in South Korea. Particularly, our result could not show the annual cumulative incidence of almost all cases of cancer because the medical expenses were covered by other co-payment assistance policies established by the NHIS. Third, owing to the available options for KCD codes on the application form of the register of the co-payment assistance policy for rare and incurable diseases, multiple diseases with similar characteristics were included under one KCD code. We could not separately analyse each rare disease included under one KCD code using these administrative data. Fourth, our study used the year of definite diagnosis by the physician in the application form as the year of disease occurrence. Because the definite diagnosis of a disease is usually confirmed after the disease progresses enough to affect the quality of life of patients , the year of disease onset in our study might not represent the actual incident date of the rare disease. Fifth, the total number of rare diseases increased abruptly from 2013 to 2014 after the Ministry of Health and Welfare of Korea adopted the agenda for expanding the health coverage for rare and incurable diseases. The number of patients enrolled in the register of the co-payment assistance policy was not constant and varied based on government policy, which might have therefore disrupted the calculation of the actual incidence of the rare diseases. For yearly comparisons of the incidence of each rare disease, the annual cumulative incidence of each rare disease is shown in Additional file 2. Sixth, no cases of 18 (4.34%) KCD code diseases (D56, D81, D82, D83, D84.0, E70, E73.0, E74.1, E74.9, E76, E76.8, E76.9, E77.1, E77.9, M30.2, M31.2, Q91, Q91.1) were reported during the study period. Given that the NHIS determined the target disease of the co-payment policy before 2011, it is possible that there were no cases of registrants with these KCD codes for 2011–2015. Seventh, in order to calculate the incidence of rare disease, the denominator should be limited to the “population at risk” for developing rare disease. However, we set the denominator as the number of residents with health insurance coverage in each year. Additional studies are needed to better understand the epidemiology of each rare disease by using administrative records of rare disease registries in Korea.