High prevalence of rheumatoid arthritis and its risk factors among Tibetan highlanders living in Tsarang, Mustang district of Nepal
Authors: Arima Hiroaki , Koirala Sweta , Nema Kotaro , Nakano Masayuki , Ito Hiromu , Poudel Kapil Madi , Pandey Kishor , Pandey Basu Dev , Yamamoto Taro 
Published: April 2022

Abstract
Background
In Tsarang (at 3560 m), which is located in Mustang, 62.7% of the residents answered that they had a subjective medical history of arthritis, and 41.1% of the residents answered that their families had a subjective medical history of arthritis on a survey conducted in 2017. The expression of hypoxia-inducible factor (HIF) and its effects are deeply involved in hypoxic adaptation in Tibetan highlanders. At the same time, HIF is also related to the onset of rheumatoid arthritis. Therefore, the adaptive mechanism acquired by Tibetan highlanders may promote the development of rheumatoid arthritis. The prevalence of rheumatoid arthritis is estimated to be approximately 0.5–1.0% worldwide. The objective of this study was to estimate the prevalence of rheumatoid arthritis in Tsarang residents using existing diagnostic criteria and to explore its risk factors.

Methods
An epidemiological survey was conducted in Tsarang in 2019. Data obtained from anthropometry and questionnaires were statistically analyzed. Biochemical measurements using blood samples were also performed, and the results were used to assess arthritis status. Residents’ joint status was scored, and arthritis was assessed based on the clinical disease activity index and ACR/EULAR 2010 criteria.

Results
Twenty-seven males and 50 females participated in this survey. In Tsarang, ACR/EULAR 2010 classified 4.3% of males and 7.1% of females as having rheumatoid arthritis, indicating a very high estimated prevalence. We also performed a multivariate analysis to explore its risk factors, and two factors, older age (standardized parameter estimate = 4.84E−01, 95% CI = [9.19E−02, 8.76E−01], p = 0.0170) and a history of living in urban areas (standardized parameter estimate = − 5.49E−01, 95% CI = [− 9.21E−01, 1.77E−01], p = 0.0050), significantly contributed to the higher ACR/EULAR 2010 score in females. In addition, three factors, having no spouse (standardized parameter estimate = 3.17E−01, 95% CI = [5.74E−02, 5.77E−01], p = 0.0179), having a smoking habit (standardized parameter estimate = 2.88E−01, 95% CI = [1.71E−02, 5.59E−01], p = 0.0377), and a history of living in urban areas (standardized parameter estimate = − 3.69E−01, 95% CI = [− 6.83E−01, − 5.60E−02], p = 0.0219), resulted in significantly higher clinical disease activity index scores in females. Furthermore, smoking habits were found to significantly increase blood hyaluronic acid in both males (standardized parameter estimate = 6.03E−01, 95% CI = [3.06E−01, 9.01E−01], p = 0.0020) and females (standardized parameter estimate = 4.87E−01, 95% CI = [5.63E−02, 9.18E−01], p = 0.0291).

Conclusions
In this study, we evaluated the symptoms of arthritis and estimated the prevalence of rheumatoid arthritis using classification criteria for Tibetan highlanders who have adapted to the hypoxic environment and fostered their own culture. The high prevalence of rheumatoid arthritis among Tsarang residents suggests that the hypoxic adaptation mechanism involving HIF in Tibetan highlanders may promote the onset or exacerbation of rheumatoid arthritis. The high prevalence of rheumatoid arthritis among Tibetan highlanders may be related not only to the environmental factors analyzed in this study but also to hypoxic adaptation genes. Further investigation is needed to clarify the genetic factors involved.