Journal of Rheumatology Research (ISSN:2641-6999)
Research Article
Impact of Premorbid Infection on Disease Activity of Rheumatoid Arthritis
Ruijun Zhang, Jing Li, Ru Li, Jiali Chen, Xiaomei Chen, Xue Li, Chun Li, Yuan Jia, Yunshan Zhou, Limin Ren, Lijun Wu, Jing He* and Zhanguo Li*
Corresponding Author: Jing He & Zhanguo Li, Department of Rheumatology and Immunology, Peking University People’s Hospital, 11 Xizhimen St. Beijing 100044, China
Received: December 31, 2018; Revised: July 15, 2019; Accepted: February 04, 2019
Citation: Zhang R, Li J, Chen J, Chen X, Li X, et al. (2019) Impact of Premorbid Infection on Disease Activity of Rheumatoid Arthritis. J Rheumatol Res, 1(2): 33-38.
Copyrights: ©2019 Zhang R, Li J, Chen J, Chen X, Li X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Objective: Infections have been implicated in rheumatoid arthritis (RA) development. However, the impact of premorbid infection on initiation and perpetuation of RA has not been well elucidated. Thus, we sought to conduct a large scale on-site survey to study whether premorbid infection may trigger RA and influence status of the disease.

Methods: Premorbid infectious events were collected in cohort of 902 RA patients from December 2015 to June 2016. Type of infections prior to RA onset and its possible effects on disease status were analyzed.

Results: Three hundred and thirty-four out of 902 patients (37.03%) experienced infections within one month preceding RA onset. The most frequent infections were respiratory (16.08%), intestinal (11.09%) and urinary tract (9.87%) infection, respectively. The infection was associated with increased disease activity. High disease activity risk was increased in patients who pre-exposure to urinary infection (Odds ratio (OR)=3.813, 95% confidence interval (95% CI)=1.717-12.418) and upper respiratory infection (OR=2.475, 95% CI=0.971-6.312).

Conclusion: Pre-exposure infections are associated with development of RA. Severe disease status of RA and persistent of active disease status are related to preceding infections.

 

Keywords: Premorbid infection, Rheumatoid arthritis, Disease activity

INTRODUCTION

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint destruction and auto-antibodies production [1]. Many studies have demonstrated that infectious agents may contribute to the initiation or perpetuation of RA through a variety of mechanisms. Infection can cause a local inflammatory response. The innate immune system could also be affected by infections agents and then cause RA onset, for instance, pathogen-associated molecular pattern receptors; especially the Toll-like receptors (TLRs) could release inflammatory mediators rapidly after recognizing some preserved structures in bacteria and other infectious agents [2].

Although a definite causative link between a specific infectious agent and the disease has not been established, several arguments support such a possibility. First, in the absence of a certain pathogen, the spectrum of microorganisms involved in triggering RA may include poly-microbial communities or the cumulative effect of bacterial or virus factors [3]. Secondly, infections didn’t lead to RA in all cases, but initiate it in a certain subset of patients who was born with a genetic susceptibility [4-7]. Thirdly, some arthritis occurred based on pre-exposure to microorganism. Several animal models of arthritis are dependent on TLR2, TLR3, TLR4 or TLR9, for instance, rodents injected with streptococcal cell walls (TLR2 ligand) develop severe polyarticular arthritis and TLR4 ligand also play a role in passive K/BxN arthritis [8]. Many studies have shown that components derived from infectious agents can cause autoimmune reaction by molecular mimicry and other mechanisms. Epstein-Barr virus (EBV) is a polyclonal B lymphocyte activator which can increase the production of RF [4]. Oral pathogens may trigger the production of disease-specific  autoantibodies  and  arthritis  in  susceptible individuals. It has been shown recently that RA is associated with exposure to some microorganism such as Aggregatibacter actinomycetemcomitans (Aa) [1].

 In this study, we sought to conduct a large-scale survey to explore potential infectious agents which might initiate RA and the clinical consequence of this disease [9].

METHODS

Patients

Survey results were collected from 902 RA patients admitted to the Department of Rheumatology and Immunology, People’s Hospital, Peking University, between December 2015 and June 2016. All the studied patients fulfilled the American College of Rheumatology/European League against Rheumatism Classification criteria for RA in 2010 [10] and written informed consent was obtained.

The clinical data were recorded including tender and swollen 28-joint counts, general health on visual analog scales, erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28) and the infections one month before the onset of RA. Only premorbid infections which were diagnosed by physicians were carefully recorded in this study.

The questionnaire also included age, sex, disease duration, age at symptom, smoking status and treatments (one DMARD, more than one DMARDs, DMARDs plus low-dose glucocorticoid and bDMARDs).

STATISTICAL ANALYSIS

Analysis of covariance and multivariate logistic regression analysis were applied to compare the disease activity in patients with or without prior infections. T test was used to analyze the Gaussian distribution data. ANOVA was used to analyze the non-normal distribution data. The categorical variables were compared with chi-squared test. Multinomial logistic analysis was used to find risk factor which perhaps affected the current disease activity in RA patients. Data was expressed as mean ± standard deviation for continuous variables. The SPSS statistical package, version 23.0 was used for all statistical analyze and p value less than 0.05 were considered statistically significant.

RESULTS

Prevalence of infections in RA

Within one month prior to RA onset, 37.03% (334/902) patients experienced infections and the most frequent sites were respiratory (16.08%), intestinal (11.09%) and urinary (9.87%), respectively (Table 1).

Patients in severe disease status showed high prevalence of premorbid infections

Four-hundred and ninety out of 902 RA patients with complete clinical data were analyzed in this study. These patients were divided into two groups based on DAS28 (DAS28<3.2 as group 1; DAS28 ≥ 3.2 as group 2). Compared with patients in group 2, patients in group 1 showed high prevalence of non-premorbid infection (χ2=18.193, P=0.000) (Table 2). Notably, patients with high disease activity suffered more pre-exposure of respiratory, intestinal and urinary infections (P=0.000, P=0.000, P=0.023; respectively) (Table 2). Clinical characteristics of RA patients were shown in Table 3. Higher ESR, CRP and HAQ score were observed in patients with higher DASD28 scores (Table 3).

Urinary and upper respiratory infection increased high disease activity risk of RA patients

In our study, patients showed higher DAS28 in urinary (P=0.000) and respiratory (P=0.001) infection groups (Table 4) before adjusting confounding factors such as the different therapies, age and smoking status which can affect disease activity.

One hundred and forty-five RA patients experienced respiratory tract infections one month prior to onset of the disease. Among these patients, 13.30% (120/902) patients showed upper respiratory tract infection while 2.77% (25/902) patients with lower respiratory tract infection. The number of tender and swollen joints (Figures 1A and 1B), HAQ scores (Figure 1D) and DAS 28 (Figure 1E) were higher in patients who had the respiratory tract infection compared with patients who had no infection before RA occurred. Furthermore, DAS28 was higher in respiratory infection group after adjusting for the age (P=0.002) and smoking (P=0.002) (Table 4). There were 89 patients with urinary infection who developed RA in one month before disease initiation. More deformed joints (Figure 1C) were found in patients who had premorbid urinary infection. The age at onset was younger in patients who had urinary infection (Figure 1F). DAS28 was still higher in urinary infection group after adjusting for the therapy type (P=0.000) and smoking (P=0.002) group (Table 4).

Intestinal infection occurred in 100 patients who developed RA. No difference was observed in these patients compared to patients with no infection (Figures 1A-1F). After adjusting age and smoking, DAS28 didn’t show significant difference between intestinal infection group and no infection group (Table 4).

The multinomial logistic regression was trained for predicting the disease activity with the factors which showed statistical significance in single-factor analysis (Supplementary Table). These model parameters were for the low, moderate and high levels of disease activity, measured relative to the remission level (reference outcome). High disease activity risk was increased in patients who had urinary infection (OR=3.813, 95% CI=1.717-12.418) (Figure 2) and upper respiratory infection (OR=2.475, 95% CI=0.971-6.312) (Figure 2). 

DISCUSSION

There is increasing awareness that mucosal surfaces, including the gut and lungs, are sites of disease initiation in RA [8]. Recent studies showed that infectious agents including virus and bacterial infection had been associated with several kinds of autoimmune disease [7,11-13]. For instance, upper respiratory tract and other infections are well-known risk factors for multiple sclerosis [14]. However, it was not clearly whether infectious agents play the causative role in the onset or outcome of autoimmune disease; this is mainly due to the lack of strictly perspective epidemiological study. And even in animal models, these relationships are complex and depend on the timing of exposure, antigen type and genetic background [15]. In our study, the age of disease onset was younger in patients who had urinary tract infection, which perhaps indicates that RA occurred earlier in patients with this pre-exposure infection and later in the other patients.

It has been certified that many virus can play a role in the production of auto-antibodies such as anti-cyclic citrullinated peptide [16]. Infections are known to cause or enhance autoimmunity through expansion of auto-reactive T-cell clones by molecular mimicry and enhanced antigen presentation [15]. The patients with infection events during the disease duration could have advanced RA status [17]. To our knowledge, there was no study to prove the relationship between the premorbid infection history and onset or outcomes of RA in large populations. Here, we made the first report that analyzed this relationship in RA patients from outpatient of department of rheumatology and immunology in People’s Hospital, Peking University.

There were many factors reflected the disease activity in RA, such as the number of tender or swollen joints, ESR, CRP and so on. Patients with respiratory tract infection had higher DAS28 and more swollen/tender joints. This probably because of respiratory tract infection was mainly caused by viruses. Acute viral infection in adult has long been suggested to induce transient autoimmune responses, including generation of autoantibody [7]. As reported in a recent study, Arleevskaya et al. [4] found that higher percentages of first-degree healthy relatives (HR) than health control (HC) had upper respiratory and urinary tract infections. During 10 year follow-up, 26 out of 251 (10.36%) HR subjects developed to RA, while no RA was found in HC group [4]. In our study, we found that 9.87% (89/902) patients had pre-exposure of urinary tract infection and 13.30% (120/902) patients with upper respiratory infection. Besides, the patients with urinary infection were more likely to stay in disease activity stage and have more deformity joints. Moreover, the patients with respiratory infection had higher disease activity compared with no infection patients.

In fact, it is impossible to make a causal link between a specific pathogen and the disease. Our study has several limitations. First, because the study was done in a retrospective manner, the patients who had no complete clinical data were excluded from this study. Second, the number of the studied patients was not large enough to see the statistical difference in clinical features and odds ratio in lower respiratory tract infection subgroup patients. It may be due to this study group with very few patients. Third, our studied patients may have selection bias because it was performed in a single university hospital. In order to determine the impact of premorbid infectious agents for RA outcome, the disease activity at RA onset and radiographic joint damage should be followed up in a larger prospective study.

ACKNOWLEDGEMENT

No.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

FUNDING

This work was supported by National Natural Science Foundation of China [NSFC 31530020 to Dr. Li, 31570880 and 81373117 to Dr. He.

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