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- PATIENTS AND METHODS
Our results indicate that persons with RA are at twice the risk of developing an objectively confirmed infection compared with age- and sex-matched individuals in the same community who do not have RA. This excess risk is present to a varying degree for all infections examined and if infections requiring hospitalization and all documented infections are used as outcome measures. Furthermore, the magnitude of infection risk for patients with RA was greater after adjustment for potential confounders. The sites of infection that are associated with the highest rate ratios when any of these outcomes are used are the bone, joints, skin, and soft tissues.
Only 2 published controlled studies have examined the risk of infection in RA (17, 18). Neither of these studies, which were performed at the same center, showed a difference in infection rates between cases and controls. The first of these studies demonstrated an odds ratio of 0.83 (95% CI 0.57–1.2) for genitourinary infections and an odds ratio of 0.61 (95% CI 0.39–0.96) for bronchopulmonary infections, in patients with RA compared with control subjects with either osteoarthritis or soft tissue rheumatism (17). The second study examined 448 RA patients and 185 control subjects and showed that at least 1 infection occurred in 101 RA patients (23%) versus 50 controls (27%), and that the types of infection in the 2 groups were similar (18).
Major methodologic differences may explain the discrepancy between our results and those in these 2 previous studies. One methodologic difference is that the case subjects in the 2 earlier controlled studies were prevalent cases of RA, selected from a specialized treatment center. Such cases may not be representative of RA patients in the community, since patients whose disease is in remission or those who are seen only in a primary care setting will not be included. Furthermore, the use of prevalent cases of RA may lead to underrepresentation of the number of patients with fatal infections, who died early in their disease course. Our study avoids this possibility of incidence-prevalence bias by including all incident cases of RA in a geographically defined population. Also, the control subjects in the previous studies were selected from rheumatology outpatient clinics, which they attended for osteoarthritis or soft tissue rheumatism. These chronic illnesses may have rendered the controls more susceptible than healthy individuals to infections. In our study, matched controls were selected at random from the same general population as the cases.
Another methodologic difference is that the previous investigators used questionnaire and interview techniques to ascertain infection occurrence, and thus relied on the study subjects' recall. In our study, we reviewed each patient's complete medical history, including that from primary care. Therefore, we did not rely on symptom reporting by patients and controls, which is subject to the possibility of differential recall between groups. We were also able to obtain objective confirmatory evidence of infections by examining results of microbiologic cultures and radiographic imaging. Use of medical records also enabled us to obtain information about a broad range of infection sites, whereas the previous studies were limited to genitourinary, bronchopulmonary, skin, and “miscellaneous” infections.
Unlike the earlier controlled studies, ours had an extended length of followup after RA incidence. This prolonged followup, combined with our relatively large sample size, yielded a total of 7,729.7 person-years of followup in subjects with RA and 9,132.7 person-years in the non-RA subjects. The short followup period (1 year) in one of the previous studies (18) may not reflect the long-term risk of infection in patients with RA.
In addition to the 2 controlled studies discussed above, occurrence of infections in patients with RA has been described in reports of several case series (1, 3, 19–22). In 1 such report, based on a study of 195 consecutive RA patients seen in an outpatient clinic, the estimated rate of incidence of all infections was 17 new infections per 100 patient-years of followup (21). This is comparable with the rate of 19.64 infections per 100 patient-years that we demonstrated in the present study using the definition of objectively confirmed infections, which is closest to the definition used in that study.
In most case series reports in which infections in RA patients are described, the sites most frequently affected are the joints, respiratory tract, and skin (1, 19, 20). In a recent report documenting the incidence of infections requiring inpatient hospitalization in a series of RA patients, 32.3% of all such infections were pulmonary, 24.1% involved skin and wounds, and 17.8% involved bone and joints (22). These sites correspond to those with the highest rate ratios for patients with RA in our study. Our findings thus support earlier evidence that RA patients are more susceptible to infections of bone, joints, skin and soft tissues, and the respiratory tract.
All previous reports of infection occurrence in RA are based on studies of patients seen in hospitals, often secondary or tertiary referral centers. These studies do not provide a reliable estimate of the frequency of infections in patients with RA in the community. In the present study, we characterized the occurrence of infections in a population-based cohort of RA patients and obtained data on the frequency and sites of infections in these individuals. This should facilitate comparisons with rates of infection in RA patients who are receiving biologic and other recently introduced immunomodulatory therapies (9, 10).
There are a number of possible explanations for an increased risk of infection in patients with RA. Recent evidence suggests that RA patients have immunologic abnormalities involving the majority of circulating T cells, from an early stage in the disease course (23). Thus, the ability of the immune system to respond to novel antigenic stimuli may be compromised. Alternatively, therapy with corticosteroids and other immunosuppressive medications may also predispose RA patients to the development of sepsis (24, 25). Other factors that may influence infection risk in patients with RA are disease-related factors (immobility, joint surgery), extraarticular manifestations of RA (Felty's syndrome, rheumatoid lung disease), and comorbidities (diabetes mellitus). The relative contribution of each of these to infection risk has not been established.
One limitation of the present study is that only infections that came to medical attention could be included. For this reason, we did not include infections of the upper respiratory tract. Another limitation is that we did not record details of herpes zoster infections separately from other skin infections, so we are unable to compare rates with those in other studies that have shown high rates of this infection in patients with RA. RA patients might be more likely to seek medical care when they develop minor infections, which may lead to relative overreporting in cases. However, our findings of a higher magnitude of risk for development of infections with objective confirmation and for infections serious enough to require hospitalization in patients with RA are evidence against the existence of such a bias. Finally, because some racial and ethnic groups are underrepresented in Rochester, Minnesota, where the population in 1990 was 96% white according to US Census data, the results of our population-based study are generalizable only to the US white population.
In conclusion, we have shown that patients with RA have nearly twice the rate of infection compared with matched non-RA controls, and that this excess risk is present for objectively confirmed infections, infections requiring hospitalization, and all physician-diagnosed infections. The higher frequency of infection in RA cases compared with controls might be related to the disease itself, through either altered immunologic function or other factors such as decreased mobility and skin defects. These results underscore the need for additional research to discover the determinants of this increased infection risk in RA.