Respiratory Viral Infections and the Risk of Rheumatoid Arthritis

Young Bin Joo; Youn-Hee Lim; Ki-Jo Kim; Kyung-Su Park; Yune-Jung Park


Arthritis Res Ther. 2019;21(199) 

In This Article

Abstract and Introduction


Background: We aimed to investigate the effects of ambient respiratory viral infections in the general population on rheumatoid arthritis (RA) development.

Methods: Data of weekly incident RA (2012–2013) were obtained from the Korean National Health Insurance claims database, and those of weekly observations on eight respiratory viral infections were obtained from the Korea Centers for Disease Control and Prevention database. We estimated the percentage change in incident RA associated with ambient mean respiratory viral infections using a generalized linear model, after adjusting for time trend, air pollution, and meteorological data.

Results: A total of 24,117 cases of incident RA (mean age 54.7 years, 18,688 [77.5%] women) were analyzed. Ambient respiratory viral infections in the population were associated with a higher number of incident RA over time, and its effect peaked 6 or 7 weeks after exposure. Among the 8 viruses, parainfluenza virus (4.8% for 1% respiratory viral infection increase, 95% CI 1.6 to 8.1, P = .003), coronavirus (9.2%, 3.9 to 14.8, P < .001), and metapneumovirus (44%, 2.0 to 103.4, P = .038) were associated with increased number of incident RA. The impact of these respiratory viral infections remained significant in women (3.8%, 12.1%, and 67.4%, respectively, P < .05) and in older patients (10.7%, 14.6%, and 118.2%, respectively, P < .05).

Conclusions: Ambient respiratory viral infections in the population were associated with an increased number of incident RA, especially in women and older patients, suggesting that respiratory viral infections can be a novel environmental risk factor for the development of RA.


Rheumatoid arthritis (RA) is an immune-mediated disease involving interactions between genetic and environmental factors.[1,2] It has been considered that a pre-clinical RA phase comprising the generation of autoantibodies in genetically susceptible individuals lasts months to years then transitions to a clinical RA event by virtue of other driving factors.[2] These driving factors are currently poorly understood, but it is suspected that microvascular, neuroregulatory, microtrauma-related, or transient infection-dependent pathways are involved.[2,3]

We are interested in determining whether respiratory viral infections have the capacity to driving RA development, for several reasons. Smoking, periodontitis, and microbiomes—all prominent environmental risk factors for RA—interact with mucosal surfaces including the lungs, oral mucosa, and gastrointestinal tract.[4] It is thought that these local tissue stresses on the mucosa lead to post-translational modification of peptides involved in RA pathogenesis.[2,5,6] Initial respiratory virus infections usually involve both the oral mucosa and the lungs, and this may be relevant to the generation of immune responses potentially associated with RA development. Previous studies suggest that RA exhibits seasonal tendencies, whereby RA onset is more frequent in winter,[7] and relapses are more frequent in summer.[8] Thus, we hypothesized that respiratory viral infections that exhibit seasonality may be associated with RA development. This hypothesis is supported by studies investigating other autoimmune diseases.[9–17] Multiple sclerosis which exhibits seasonal tendencies has been associated with upper respiratory picornavirus, rhinovirus, and influenza infections.[9–15] Influenza virus infections triggered disease in a genetic model of experimental autoimmune encephalomyelitis.[16] Furthermore, the occurrence of pediatric Henoch-Schönlein purpura was highest in the spring and lowest in the summer, and it was associated with an outbreak of influenza.[17]

A few studies have investigated a potential link between respiratory viral infections and the development of RA.[18,19] In the population-based case-control study, previous respiratory tract infections including sinusitis and tonsillitis treated with antibiotics, and pneumonia showed no association with a risk of RA.[18] In this study, it is not certain whether respiratory infections were caused by viruses or bacteria, but rather bacterial respiratory infections seemed to be considered more. Another study, however, showed that viral infection symptoms confirmed by questionnaire were more frequent in patients with a new-onset RA in the previous year compared to healthy control, but this was a small-sized study using 59 RA patients and 69 controls.[19]

Reliable data reflecting respiratory viral epidemic burden in South Korea are available, because the Korea Centers for Disease Control and Prevention (KCDC) operates a well-established surveillance system for the detection of respiratory viruses via polymerase chain reaction (PCR) diagnosis in patients with respiratory symptoms.[20,21] In addition, population-based incident RA can be identified via claims data because the Korean National Health Insurance (KNHI) covers almost the entire South Korean population.

In the present study, the effects of ambient respiratory viral infections on the number of incident RA in South Korea were investigated using national public data. First, patterns of incident RA over time were investigated using claims data. A time-series analysis was then conducted to investigate associations between the detection rate of ambient respiratory viral infections and the number of incident RA.