ARTHRITIS & RHEUMATISM
Vol. 46, No. 9, September 2002, pp 2287–2293
© 2002, American College of Rheumatology
Frequency of Infection in Patients With
Rheumatoid Arthritis Compared With Controls
A Population-Based Study
Michele F. Doran, Cynthia S. Crowson, Gregory R. Pond, W. Michael O’Fallon,
and Sherine E. Gabriel
Objective. A high frequency of infections compli-
cating rheumatoid arthritis (RA) has been described in
reports of case series. This retrospective longitudinal
cohort study was undertaken to compare the frequency
of infections in a population-based incidence cohort of
RA patients with that in a group of individuals without
RA from the same population.
Methods. RA patients included all members of an
incidence cohort of Rochester, Minnesota residents ages
>18 years who were first diagnosed as having RA
between 1955 and 1994. One age- and sex-matched
subject without RA was selected for each patient with
RA. Study subjects were followed up by review of their
entire medical record until death, migration from the
area, or study end (January 1, 2000), and details of all
documented infections, along with information on po-
tential risk factors for infection, were recorded. Hazard
ratios for infections were estimated using stratified
Andersen-Gill proportional hazards models, with ad-
justment for potential confounders.
Results. The 609 RA patients and 609 non-RA
study subjects (mean age 58.0 years; 73.1% female) were
followed up for a mean of 12.7 years and 15.0 years,
respectively, reflecting higher mortality among the
group with RA. Hazards ratios for objectively confirmed
infections, infections requiring hospitalization, and any
documented infection in patients with RA were 1.70
(95% confidence interval [95% CI] 1.42–2.03), 1.83 (95%
CI 1.52–2.21), and 1.45 (95% CI 1.29–1.64), respectively,
after adjustment for age, sex, smoking status, leukope-
nia, corticosteroid use, and diabetes mellitus. Sites of
infection with the highest risk ratios were bone, joints,
skin, soft tissues, and the respiratory tract.
Conclusion. In this study, patients with RA were
at increased risk of developing infections compared with
non-RA subjects. This may be due to immunomodula-
tory effects of RA, or to agents with immunosuppressive
effects used in its treatment.
A high frequency of infections complicating rheu-
matoid arthritis (RA) has been reported during the last
40 years. In particular, high rates of septic arthritis and
pulmonary infections have been described (1,2). Reports
in the literature suggested, even in the pre-steroid era,
that patients with RA may have an increased suscepti-
bility to infection (3). In further support of the notion of
increased infection risk in patients with RA is the finding
that up to 40% of patients with septic arthritis have RA
(4). Patients with RA have increased mortality com-
pared with the general population, and at least part of
this excess mortality appears to be due to infectious
diseases, in particular, genitourinary and bronchopul-
monary infections (5–8). Recently, the question of
whether patients with RA are at increased risk of
developing infections compared with the general popu-
lation has gained interest in light of reports of serious
infections in patients receiving biologic therapies for the
disease (9,10). The objectives of the present study were
to characterize the occurrence of infections in members
of a population-based RA incidence cohort and to
Supported in part by a grant from the Immunex Corporation
and by grant AR-30582 from the NIH.
Michele F. Doran, MB, MRCPI (current address: Beaumont
Hospital, Dublin, Ireland), Cynthia S. Crowson, BS, Gregory R. Pond,
MSc, W. Michael O’Fallon, PhD, Sherine E. Gabriel, MD, MSc: Mayo
Clinic, Rochester, Minnesota.
Address correspondence and reprint requests to Sherine E.
Gabriel, MD, MSc, Department of Health Sciences Research, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905. E-mail:
Submitted for publication September 11, 2001; accepted in
revised form June 5, 2002.
determine whether these individuals are at increased
risk of developing infections compared with age- and
sex-matched subjects without RA from the same general
PATIENTS AND METHODS
Study population. We performed a retrospective lon-
gitudinal cohort study comparing infection rates in a group of
patients with RA with those in a group of individuals without
RA. The former group included the members of a population-
based RA inception cohort (11). These RA cases were identi-
fied using the data resources of the Rochester Epidemiology
Project, a diagnostic indexing and medical records linkage
system that exists at the Mayo Clinic and affords access to
medical records from all sources of care for community
residents. Population-based epidemiologic research in Roch-
ester, Minnesota is possible because of its relative geographic
isolation from other urban centers and the fact that nearly all
medical care is delivered to local residents by a small number
of providers. These providers include the Mayo Clinic, Olm-
sted Medical Group, and a few private practitioners. Each
provider uses a comprehensive medical record system whereby
all data collected on an individual are assembled in a single
record. Medical records are available for all residents dating
back to 1910. Medical diagnoses and other key information are
routinely abstracted in a summary record (“master sheet”) and
entered into computerized indices. The medical records link-
age system composed of these indices facilitates identification
of all cases of a given condition. Thus, this system ensures
virtually complete ascertainment of all clinically diagnosed
cases in a geographically defined community. The potential
utility of this data retrieval system for population-based studies
has been described in detail previously (12,13).
To identify individuals with RA for this study, all
potential cases of RA were identified by searching the com-
puterized diagnostic index of the Rochester Epidemiology
Project for any diagnosis of arthritis (excluding degenerative
arthritis or osteoarthritis) made between January 1, 1955, and
December 31, 1994, among Rochester residents ?18 years of
age. The complete medical records were reviewed by a team
that included 3 trained nurse abstractors and 1 physician
(MFD), using a pretested data collection form. The diagnosis
was confirmed or rejected based on the American College of
Rheumatology (formerly, the American Rheumatism Associ-
ation) 1987 diagnostic criteria for RA (14).
To select non-RA study subjects, each case was indi-
vidually matched to 1 randomly selected Rochester resident
with no diagnosis of inflammatory arthritis, who was of the
same age (?3 years) and sex and had a similar length of
enrollment in the records linkage system. This ensured that the
non-RA subjects in the comparison group had a similar
duration of contact with the system prior to incidence date, and
were thus matched with the RA patients by calendar year.
Non-RA study subjects were assigned an index date corre-
sponding to the incidence date of their matched case.
All study subjects were followed up through their
entire (inpatient and outpatient) community medical record,
until death, migration from the county, or the date of study end
(January 1, 2000).
Data collection. Study personnel collected the data
according to a prespecified and pretested detailed protocol.
Three of the 4 abstractors were not aware of the study
hypotheses, the exception being the physician-abstractor
(MFD), who reviewed a small proportion of the records.
Reliability testing was carried out at the outset of the abstrac-
tion process and again at a point midway through the data
collection: a sample of medical records was reviewed by all
abstractors to ensure good interobserver and intraobserver
agreement. Regular meetings were held throughout the ab-
straction period to identify and correct problems in data
collection, interpretation of definitions, and application of
study criteria. Before commencing data analysis, we performed
an extensive series of checks for data consistency, proper
sequences of dates, and an evaluation of missing or incomplete
data. If necessary, medical records were reviewed again, and
questions were resolved by consensus of the investigative team.
Data on all episodes of infection requiring medical
care occurring after the incidence date (index date for subjects
without RA) were collected. Information on minor upper
respiratory tract infections was not collected. The primary
outcome measure was infections with objective confirmation,
defined as those with positive results of either microbiologic
cultures or radiologic imaging, or both. Secondary outcome
measures included infections that required hospitalization and
all physician-documented infections.
The operational definitions for each infection type
were as follows: bacteremia/septicemia, isolation of a patho-
genic microorganism from 1 or more blood cultures, with fever
(?38.0oC); septic arthritis, positive microbiologic culture from
joint aspirate fluid in the presence of suggestive clinical
features; urinary tract infection, including pyelonephritis and
urosepsis, isolation of ?100,000 colony-forming units/ml of
urine in the presence of suggestive clinical features; pneumo-
nia, presence of new infiltrates, consolidation, or effusion seen
by chest radiography and suggestive clinical features; osteomy-
elitis, clinical suspicion with confirmation by definite radiologic
findings or positive bone culture. Lower respiratory tract
infections, skin and soft tissue infections, and acute gastroen-
teritis could be included on the basis of a physician’s diagnosis
and relevant clinical findings alone, but microbiologic culture
results were recorded if available. Skin and soft tissue infec-
tions included cellulitis, abscesses, wound infections, herpes
zoster, and diabetic foot infections. Intra-abdominal infections
could be included on the basis of clinical findings alone, and
comprised acute cholecystitis, ascending cholangitis, suppura-
tive appendicitis, and peritonitis. The category “other infec-
tions” included episodes of otitis media and sinusitis that
required hospitalization, eye infections, male and female gen-
ital tract infections, culture-proven tuberculosis, and acute
For each episode of infection, we collected information
on accompanying fever, leukocytosis, and findings of relevant
investigations, including microbiologic cultures and radiologic
findings. We also recorded whether the infection required
hospitalization, and length of hospital stay. In the case of
urinary tract infections (other than those classified as
urosepsis/acute pyelonephritis), we recorded only the total
number of culture-positive infections. Patients who fulfilled
2288 DORAN ET AL
criteria for more than 1 infection simultaneously were classi-
fied in both categories, except in the case of septicemia, which
was classified in a single category referred to as septicemia with
a notation of the accompanying infectious condition (e.g.,
pneumonia with septicemia, urinary tract infection with septi-
Information on potential confounding factors for in-
fection (diabetes mellitus, leukopenia, neutropenia, smoking
status, alcoholism, chronic lung disease, and corticosteroid
use), along with dates of onset, was ascertained through
medical record review.
Data analysis. Baseline characteristics of the study
population were summarized using descriptive statistics. The
significance of the difference in mortality rates between pa-
tients and non-RA study subjects was tested using the log rank
test. Incidence rates for infections were calculated by dividing
the total number of events by the number of person-years of
followup. Rate ratios were obtained by dividing infection
incidence rates in RA patients by those in subjects without RA,
and 95% confidence intervals (95% CIs) for these rate ratios
were calculated as described by Cox (15).
The risks of infections between individuals with and
those without RA were compared using stratified Andersen-
Gill proportional hazards models (16). With these models, we
were able to examine all episodes of infection occurring in each
study subject. Included in these analyses were all types of
infection with the exception of minor urinary tract infections,
which were excluded because the dates of each of these
infections in each patient were not available. A forward
stepwise selection process (2-sided, ? ? 0.05) was used to
create an optimal multivariate model of potential confounding
variables. For each outcome, the hazard ratio comparing RA
patients with non-RA study subjects and the 95% CI was then
estimated, with adjustment for potential confounders. These
potentially confounding variables were included as time-
varying covariates in the analyses, with the one exception of
smoking status, which was recorded at baseline only.
The RA incidence cohort comprised 609 individ-
uals, each of whom was matched to 1 (non-RA) study
subject. The mean age at incidence was 58.0 years for
RA patients and 58.2 years for non-RA subjects. The
majority of subjects in each group were female (73.1%).
The mean followup time in the non-RA comparison
group (15.0 years) was longer than that in the RA group
(12.7 years); this was due to the significantly higher
mortality rate among RA patients (P ? 0.001). Total
followup in cases and controls was 7,729.7 and 9,132.7
person-years, respectively. RA patients and unaffected
subjects were similar at baseline in terms of age, sex, and
variables that might increase infection susceptibility,
including diabetes mellitus, chronic lung disease, alco-
holism, and leukopenia (Table 1), but subjects with RA
were more likely to be cigarette smokers and to have had
Infections with objective confirmation. For infec-
tions with objective confirmation (i.e., positive culture or
imaging result), the overall rate of infection per 100
person-years was higher in RA patients (19.64) than in
non-RA subjects (12.87). The rate ratio for developing
infections in patients with RA was 1.53 (95% CI 1.41–
1.65), indicating a significantly elevated risk of ?50% in
these subjects compared with those without RA. In fact,
the rate of infection in RA patients was higher than that
in the non-RA group in each of the 11 infection catego-
ries examined (Table 2). The difference in all but 2 of
these rate ratios (urosepsis/pyelonephritis and gastroen-
teritis) reached statistical significance. Infection sites
that were associated with the highest rate ratios were the
joints (rate ratio for septic arthritis 14.89 [95% CI
6.12–73.71]), bone (rate ratio for osteomyelitis 10.63
[95% CI 3.39–126.81]), and skin and soft tissues (rate
ratio 3.28 [95% CI 2.67–4.07]). We also calculated the
relative risks for infections overall after excluding all
episodes of septic arthritis and osteomyelitis, and found
Comparison of the frequency of potential confounding variables among rheumatoid arthritis (RA) and non-RA subjects
RA patients at
(n ? 609)
Non-RA subjects at
(n ? 609)
RA patients after
incidence date, no.
after incidence date,
Chronic lung disease
* Includes only individuals who did not have the condition prior to incidence date. NA ? not applicable.
† Smoking status was unknown in 35 cases and 21 controls.
‡ Defined as a total white blood cell count of ?3.5 ? 109. Leukopenia was never tested in 3 cases and 14 controls (assumed normal).
INFECTION FREQUENCY IN RA2289
that the risk was marginally lower, with incidence in
cases being 19.05/100 person-years and that in controls
being 12.84/100 person-years. The resulting rate ratio
was 1.48 (95% CI 1.37–1.60). Of the 31 cases of septic
arthritis in RA patients, 11 (35%) occurred in prosthetic
joints. There was 1 case of tuberculosis in the RA group
and 2 cases in the non-RA group.
Infections requiring hospitalization. Infections
requiring hospitalization were also significantly more
frequent in RA patients (9.57/100 person-years) than in
non-RA study subjects (5.09/100 person-years), with a
rate ratio of 1.88 (95% CI 1.71–2.07). When infections
were classified by site, RA patients again had a signifi-
cantly higher risk of developing infections, in all but 3
sites (Table 3). The risk pattern was similar to that seen
with objectively confirmed infections, with septic arthri-
tis, osteomyelitis, and skin and soft tissue infections
being associated with the highest rate ratios (21.66 [95%
CI 7.37–257.61], 10.63 [95% CI 3.39–126.81], and 2.76
[95% CI 2.22–3.47], respectively).
All physician-documented infections. The inci-
dence rate for all physician-documented infections in
patients with RA was 32.05/100 patient-years, compared
with 24.04/100 patient-years in the non-RA subjects
Objectively confirmed infections in 609 rheumatoid arthritis (RA) and 609 non-RA subjects*
Patients, no. Infections, no.
interval‡ RA Non-RARA Non-RARA Non-RA
Lower respiratory tract
Urinary tract infections
* Defined as infections with either a positive microbiologic culture or relevant radiologic finding.
† Obtained by dividing infection incidence rates in RA patients by those in non-RA subjects.
‡ Calculated by the method of Cox (15).
Infections requiring hospitalization in 609 rheumatoid arthritis (RA) and 609 non-RA subjects*
Patients, no. Infections, no.
Lower respiratory tract
Urinary tract infections‡
* Obtained by dividing infection incidence rates in RA patients by those in non-RA subjects.
† Calculated by the method of Cox (15).
‡ Any urinary tract infection that required hospitalization was classified as urosepsis/pyelonephritis. NA ? not applicable.
2290DORAN ET AL
(rate ratio 1.33 [95% CI 1.26–1.41]) (Table 4). For
physician-documented infections, the infection sites that
were associated with the highest rate ratios in patients
with RA were the same as those for infections with
objective confirmation and those requiring hospitaliza-
Multivariate analyses. The hazard ratio for the
development of objectively confirmed infections in RA
patients compared with non-RA subjects, after adjust-
ment for confounding variables, was 1.70 (95% CI
1.42–2.03). These confounding variables were leukope-
nia, diabetes mellitus, and chronic lung disease, each of
which was a statistically significant predictor of infection
occurrence (P ? 0.001 for each). There were no signif-
icant interactions between these variables. In multivari-
ate analyses of the secondary outcome measures, infec-
tion that required hospitalization and any physician-
documented infection, the hazard ratios for RA patients
developing an infection during followup were 1.83 (95%
CI 1.52–2.21) and 1.45 (95% CI 1.29–1.64), respectively.
To investigate whether the relative risk for infec-
tion has changed in more recent years, we calculated the
relative risks among patients with incident RA in each of
the 4 decades. The risk for infections in all 4 decades was
significantly higher in RA patients compared with
non-RA subjects. The confidence intervals for all of
these relative risks overlapped, indicating that the excess
risks were not significantly different according to de-
cade. We also examined the infection rate per 100
person-years over time, and found that infection rates
rose similarly in cases and controls. This overall increase
likely reflects improvements over time in the ability to
Our results indicate that persons with RA are at
twice the risk of developing an objectively confirmed
infection compared with age- and sex-matched individ-
uals in the same community who do not have RA. This
excess risk is present to a varying degree for all infec-
tions examined and if infections requiring hospitaliza-
tion 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
Only 2 published controlled studies have exam-
ined 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 infec-
tions and an odds ratio of 0.61 (95% CI 0.39–0.96) for
bronchopulmonary infections, in patients with RA com-
pared 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
All physician-documented infections in 609 rheumatoid arthritis (RA) and 609 non-RA subjects
Patients, no. Infections, no.
interval† RANon-RA RANon-RARA Non-RA
Lower respiratory tract
Urinary tract infections
* Obtained by dividing infection incidence rates in RA patients by those in non-RA subjects.
† Calculated by the method of Cox (15).
INFECTION FREQUENCY IN RA2291
(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 underrep-
resentation of the number of patients with fatal infec-
tions, 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 out-
patient 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 popu-
lation as the cases.
Another methodologic difference is that the pre-
vious 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, in-
cluding 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, broncho-
pulmonary, 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 compara-
ble 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
All previous reports of infection occurrence in
RA are based on studies of patients seen in hospitals,
often secondary or tertiary referral centers. These stud-
ies 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 infec-
tions 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 immunomodula-
tory 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 immu-
nologic abnormalities involving the majority of circulat-
ing 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. Alterna-
tively, therapy with corticosteroids and other immuno-
suppressive medications may also predispose RA pa-
tients 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), ex-
traarticular 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
2292 DORAN ET AL
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 underrepre-
sented 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 func-
tion 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.
The authors thank Denise Herman, RN, Deanne
Stiebner, RN, and Patricia Hartkopf, RN, for their assistance
with data collection, and Deborah Fogarty for assistance in
preparation of the manuscript.
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