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.
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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