Increased Risk of Human Leukocyte Antigen Related Autoimmune Diseases in Narcolepsy

Seung-Chul Hong, MD, PhD

In a new study published in Sleep Medicine, results demonstrated that narcolepsy is significantly associated with high risk of various autoimmune diseases related to human leukocyte antigen (HLA) genes. This study was the first attempt in using big data analytics to investigate comorbid autoimmune diseases in patients with narcolepsy and suggests that the pathophysiology of type 1 and type 2 narcolepsy and idiopathic hypersomnia may be similar.¹

The incidence rate of narcolepsy was 0.05% among 8710 patients (59.8% men and 40.2% women) identified with the condition. Results from a multivariate analysis revealed patients with narcolepsy were at a significantly high risk of comorbid ankylosing spondylitis (OR, 4.397; 95% CI, 4.008–4.824), rheumatoid arthritis (OR, 4.420; 95% CI, 4.028–4.849), Sjögren's syndrome (OR, 1.732, 95% CI, 1.479–2.208), vitiligo (OR, 1.556, 95% CI, 1.385–1.748), atopic dermatitis (OR, 1.379, 95% CI, 1.328–1.432) and Graves' disease (OR, 1.451, 95% CI, 1.366–1.541) compared with controls (n = 87,100).

Additionally in patients with narcolepsy, the comorbidity OR for Bechet's disease (OR, 0.178; 95% CI, 0.099–0.322), systemic lupus erythematosus (SLE; OR, 0.230, 95% CI, 0.127–0.415), Hashimoto's thyroiditis (OR, 0.670, 95% CI, 0.578–0.777), and type 1 diabetes (OR, 0.585, 95% CI, 0.509–0.672) was significantly lower than in controls.

Senior author Seung-Chul Hong, MD, PhD, professor and director of the sleep study center at St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea in South Korea, and colleagues wrote, “Our results show that narcolepsy is closely related to several systemic autoimmune diseases. Multivariable analysis with covariates of age, sex, and health insurance status was used to confirm the correlation. Among rheumatoid diseases, ankylosing spondylitis, rheumatic arthritis, and Sjögren’s syndrome showed a high predilection for narcolepsy.”¹

In this nationwide, population-based, retrospective study, patients with narcolepsy or idiopathic hypersomnia were recruited from the National Health Insurance (NHI) database between 2010 and 2019. Diagnoses were recorded using International Classification of Diseases (ICD-10), 10th revision, in the database. Patients with narcolepsy as well as age- and sex-matched controls without the condition were included using an optimal method of propensity scores. Patients who underwent appendectomy during the study collection period were also included. A logistic regression analysis was used to evaluate the association between narcolepsy and systemic autoimmune diseases.

Of the total number of patients with narcolepsy, 5916 were type 1 and 2794 were type 2; 2279 patients had idiopathic hypersomnia. For context, the incidence of narcolepsy was 0.017% in South Korea between 2010 and 2019. Additionally, the incidence rates for type 1 and 2 narcolepsy were 0.011% and 0.006%, respectively, while the incidence rate of idiopathic hypersomnia was 0.005%. In comparison with other countries, the U.S. national prevalence rate was 0.08% for narcolepsy, and 0.082% and 0.056% for Canada and Taiwan, respectively.²

Hong et al noted, “Our study results showed a significantly lower incidence rate for both types of narcolepsies when compared to other developed nations. There may be several factors contributing to such low rates: a significant diagnostic delay from the onset of the disease, a high level of internalized stigma, and a lack of awareness for seeking consultation for psychiatric/sleep-related concerns.”¹

Only insurance benefit information was included when medical use was required hence, a disadvantage of the Korean health insurance data, the study authors noted. Also, since mean sleep latency test (MSLT) is not covered by insurance in South Korea, narcolepsy was defined as visiting a clinician more than three times and receiving stimulants for the condition. In addition, data on the subtype of ICD-10 diagnosis was unavailable as it did not distinguish type 1 from type 2 narcolepsy. Another important note of limitations was that the control group was set to patients who performed appendectomy with appendicitis, which may have developed bias because of inflammation in the intestines.

“Conversely, while our study found a high rate of comorbidity between narcolepsy and ankylosing spondylitis and Sjögren's syndrome, CNS involvement is rare in these two diseases. From this information, we can deduce that the pattern of association between narcolepsy and systemic autoimmune diseases witnessed in our analysis may be attributed to pathophysiology other than the autoimmune disease manifestation in the CNS,” Hong et al wrote.¹

REFERENCES
1. Oh J, Cho E, Um YH, Oh SH, Hong SC. Narcolepsy is associated with an increased risk of HLA-related autoimmune diseases: Evidence from a nationwide healthcare system data in South Korea. Sleep Med. 2023;105:37-42. doi:10.1016/j.sleep.2023.03.006
2. Dodd CN, de Ridder M, Huang WT, et al. Incidence rates of narcolepsy diagnoses in Taiwan, Canada, and Europe: The use of statistical simulation to evaluate methods for the rapid assessment of potential safety issues on a population level in the SOMNIA study. PLoS One. 2018;13(10):e0204799. Published 2018 Oct 17. doi:10.1371/journal.pone.0204799