Clinical Features And Risk Factors For Infection In Patients With Rheumatoid Arthritis

Background: To explore the infection characteristics of patients with rheumatoid arthritis(RA) and related risk factors for infection. Methods: A retrospective analysis of the clinical data of 648 hospitalized patients with RA, including related risk factors that may cause infection and infection sites, pathogens, and drug resistance. Chi-square test (cid:0) Mann-Whitney U test and binary Logistic-regression analysis were used to identify risk factors. Results: 648 patients with RA were 182 cases of infection, the infection rate 28.09%. Common infection were pneumonia(19.60%), urinary tract infection(5.25%), upper respiratory tract infection(5.09%). Gram-negative bacteria ranked rst in the pathogen composition (67.57%), the main pathogenic bacteria were Pseudomonas aeruginosa and Escherichia coli; Staphylococcus aureus was the main pathogenic bacteria among the Gram-positive bacteria . In addition, there were 7 strains of fungi, 3 strains each of Mycobacterium tuberculosis and herpes virus. The proportion of resistant strains was relatively high, and the gram-negative bacteria had a relatively high sensitivity to penicillins/cephalosporins+β-lactamase inhibitors, aminoglycosides, and carbopenems. The risk scores included higher age (P=0.020), long disesses duration (P=0.004), smoking (P=0.016), hypoproteinemia (P=0.010), use of corticosteroids (P<0.01).Use of nonbiologic DMARDs was negatively with infection(P= 0.006). Conclusions: Our results indicate that the common infection sites in patients with RA are the respiratory and urinary tract. Gram-negative bacteria are common pathogens. RA patients with higher age, long diseases duration, smoking, hypoproteinemia, and long-term use of corticosteroids are prone to infection. Nonbiologic DMARDs is signicantly associated with a decreased risk for infection. The proportion of drug-resistant patients with RA co-infection is relatively high.


Background
Rheumatoid arthritis(RA) is a chronic systemic autoimmune disease characterized by erosive and symmetrical polyarthritis that may lead to irreversible joint damage with disability and deformity .Patients with RA have increased susceptibility for infction,infection rate are reported to be almost twice those of the general population [1]. Numerous studies have reported endogenous and exogenous risk factors for infection in RA patients,attributed to three major factors:RA itself as a chronic disorder with immunological dysfuctions,organ involvement of RA and other comorbidities,as well as the use of potent immunomodulatory medication [2].This article retrospectively analyzed the clinical characteristics of infection in patients with RA in the past two years, aims to improve the understanding of RA complicated by infection, and reducec and prevent the occurrence of the infections.

Patients Selection
From April 2017 to April 2019, inpatients with RA in the General Hospital of Northern Theater Command and the Fourth A liated Hospital of China Medical University (Patients with severe cerebrovascular diseases, malignant tumors, and individual clinical data missing severely were not included in the study). Patients ful lled the 2010 American College of Rheumatology /European League Against Rheumatism criteria for RA [3]. The diagnosis of patients with RA coinfection had clear pathogenic biological laboratory or imaging evidence, typical clinical manifestations. Some patients with infections that could be diagnosed by clinical manifestations, such as typical upper respiratory tract infections and patients with skin shingles diagnosed by a dermatologist, had not undergone relevant imaging or laboratory examinations. The patients with RA co-infection collected in this study included community acquired infections and nosocomial infections [4].

Statistical Analysis
Descriptive statistics were presented as mean±SD or number (%) where appropriate.Non-normally distributed data were analyzed using nonparametric tests(Mann-Whitney U test). Chi-square test to test the association of categorical variables. Risk factors for infections were analyzed by multivariate analysis with binary logistic regression model. Continuous variables were transformed into categorical variables with a predetermined thresheold. The p values less than 0.05 were considered signi cant. Statistical analysis was performed using SPSS software version 23 .

Infection Rate of the RA Patients
A total of 648 patients with RA were 182 cases of infection, the infection rate 28.09%.Among them, 99 cases of 517 RA patients in the Department of Rheumatology and Immunology were infected, and the infection rate was 19.15%.The incidence of infection in the whole hospital was higher than that of the Department of Rheumatology and Immunology. 21 cases were infected at 2 sites at the same time, 2 cases were infected at 3 sites. Community-acquired infections were 175 cases, 7 cases of hospital-acquired infections.

Infection Site of the RA Patients
The pneumonia was the most frequent infection ( = 127, 19.60%) followed by the urinary tract ( = 34, 5.25%),upper respiratory tract ( = 33, 5.09%).3 cases each of herpes virus and tuberculosis, 2 cases of skin and soft tissue infection, 1 case each of oral fungus, knee joint, and muscle infection.

Infection Pathogens of the RA Patients
A total of 74 strain pathogens were isolated and cultured from 182 infected patients. Bacteria was the most common pathogen, with 50 strains in total, among which 40 were gram-negative bacteria. Escherichia coli and Pseudomonas aeruginosa were the most common and caused urinary tract and respiratory tract infections respectively. There were 10 strains of Gram-positive bacteria, 9 of which were Staphylococcus aureus, which mainly cause respiratory tract infections, and 1 strain was Enterococcus hirae, which caused urinary tract infections. There were 11 strains of Mycoplasma and Chlamydia, two of which were Ureaplasma Urealyticum caused urinary tract infections, and the rest caused respiratory infections. There were 7 strains of fungi, 5 strains of Candida albicans caused respiratory and oral infections, and 2 strains of yeast-like fungi caused urinary tract infections. Three strains of Mycobacterium tuberculosis and herpes virus respectively caused tuberculosis and skin herpes ( Table 1). Table 1 The composition of pathogens in RA with infection

Antimicrobial Susceptibility Results
In this study, 27 strains of gram-negative bacteria were isolated for drug susceptibility testing (the specimens were all kept before anti-infection treatment). The results showed that the gram-negative bacteria were more sensitive to piperacillin of broad-spectrum penicillins, and generally resistant to ampicillin. For cephalosporins, except for the fourth-generation cefepime and the third-generation ceftazidime, gram-negative bacteria were generally resistant to the rst, second, and third-generation cephalosporins, with an average resistance rate of 47%. The resistance rate of sulfonamides was close to 70%. It was generally sensitive to penicillin/cephalosporin + β-lactamase inhibitors, aminoglycosides, and carbopenems. Relatively sensitive to quinolones( Table 2).

Discussion
In this retrospective study, we showed the infection rate of RA patients, common infection sites and strains, and antimicrobial susceptibility results.In addition,we illustrated several factor that increase the risk of development of infection in RA patients.
In this study,the incidence of infection in the whole hospital(28.09%) was higher than that of the Department of Rheumatology and Immunology(19.15%),the reason was that some patients did not go to the Department of Rheumatology and Immunology because of severe infection symptoms but went to the corresponding department for anti-infection treatment.Our results suggested that the most frequent infection site in RA patients was the respiratory tract,accounting for more than half of all infections,Pseudomonas aeruginosa and Staphylococcus aureus were the main pathogens.The next most frequent infection site was the urinary tract, Escherichia coli was the main pathogen.The rates of infections and common infection sites in our study were similar to some studies [5][6][7].In addition, several patients developed herpes, tuberculosis, and fungal infections. And the results of drug sensitivity showed that the proportion of resistant strains was relatively high. Therefore, in the process of diagnosis and treatment, we must be alert to the infection of the special pathogenic Mycobacterium tuberculosis. For patients with RA co-infection, antibiotics should be used rationally to avoid secondary fungal infections during anti-infection treatment.
We identi ed several factors that increased the risk of development of infection in RA patients. Increasing age as an important risk factor for infections. Aging generally induces age-related immune dysfunction, leading to the increased incidence and severity of infections [15,14].
A considerable exogenous risk factor for the development of infection was smoking.It was linked to the pathogenesis of RA and at the same time was a risk factor for infectious diseases [16,17].The signi cantly elevated serum levels of WBC and CRP were the detection indicators for whether the patient had infection.
A study showed that the DAS28 was slightly but signi cantly correlated with serum levels of IgA ,IgG,IgM but not RF or anti-CCP[18].In addition, one study had shown that each 0.6 unit increase in DAS28 score corresponded to a 4% increased rate of outpatient infections and a 25% increased rate of infections requiring hospitalization [19]. One other study found no association between disease activity (DAS28) and infection rate [13]. In our study, statistically signi cant difference in IgA,IgG,IgM between the infected group and the non-infected group was not observed. Whether IgA, IgG, IgM are related to infection in patients with RA still needs further research.
Corticosteroids are potent immune suppressive drugs that are widely used in rheumtological care. In our study,patients who had been treated with low-dose corticosteroids for long term in this study were susceptible to infection. Previous studies revealed no increase in infection risk of RA with corticosteroids at a low dosage [20][21][22]. Considering the timedependent and dose-dependent of the side effects of corticosteroids, corticosteroids should be actively and rationally used to control the condition when necessary.
Our Use of nonbiologic DMARDs was associated with a small decrease in mild infection risk and not associated with increased serious infection risk [9]. The reason for the ndings was not known but may relate to a bene cial effect of controlling RA in ammation, counterbalancing the potential immunosuppressive effects of nonbiologic DMARDs and resulting in a net neutral effect on infections [9].Patients taking nonbiologic DMARDs are likely to have been taking those drugs for a period of time, and the patients who continued to receive therapy during this study period may have had a lower risk for adverse events such as infections related to those medications[6].
MTX is an immunosuppressive non-biologic DMARD, which is used as a rst-line drug for the treatment of RA [23,24].
Some studies had also shown that long-term use of MTX did not appear to be a risk factor for infections in RA patients [8,9,25,26] Whether MTX contributes to increased susceptibility to infection is still controversial. An increased risk with methotrexate compared with other DMARDs was found in some studies [27,28,7,6,29].
Biologics play an important role in the treatment of RA and provide substantial bene t to many RA patients in controlling disease symptoms and progression,especially in patents whose disease is not responding to treatment with conventional DMARDs.However,biologic agents,due to their immunologic properties, are assumed to be contributing to the increased susceptibility to infection in RA.Previous studies had reported that biologic agents increased the risk of infection in RA patients [30][31][32]. There was con icting information regarding the increased risk for infection with biological.We found no evidence of an increased risk of infections associated with biologics ,which was consistent with the ndings of some others[26, 12,13]. A recent research of infection risk performed using the German biologics register RABBIT may help to explain these con icting reports [33]. An increased risk of infection during the rst year of treatment with biologics was found, with a subsequent decline in infection risk due to improvement in disease activity, reduction in concomitant corticosteroid use and discontinuation of biologics among patients with high risk of infections.In addition,previous studies had shown that biologics increased the incidence of opportunistic infections such as tuberculosis in RA patients [34,35].However, we had not found any patients with tuberculosis infection caused by the use of biological agents. In our study,biologics were assessed and appeared to confer no increased risk of infections,but these associations did not reach statistical signi cance due to low prevalence of use of these medications.
Pulmonary interstitial disease is one of the most common comorbidities in patients with RA. In this study, after excluded infected patients with non-pulmonary infections, the chi-square test showed no statistical signi cance(P=0.226). The results were inconsistent with some studies[8, 10,11], which may be related to the degree of pulmonary interstitial lesions.
This study was retrospective analysis and had several limitations. The overall number of cases was low, the strains in the drug susceptibility test of patients with RA co-infection were too low. Another limitation was that we were not able to quantify the dose of the therapeutic drugs. Information about comorbidities such as diabetes mellitus and cardiac disorders, and other chronic diseases were not available.

Conclusions
In conclusion, the common infection sites in patients with RA are the respiratory tract and urinary tract..Gram-negative bacteria are common pathogens. Patients with higher age, long disesses duration, hypoproteinemia, long-term smoking and corticosteroid therapy are more susceptible to infection. These results advance our understanding of the relationship between infections and RA, and may help to prospectively identify high-risk patients,For patients with RA co-infection, antibacterial drugs should be carefully selected based on the results of drug sensitivity.