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Embargoed for Release at 6:15 pm
ET , Sunday Oct. 17, 2004
Arthritis News
GENETIC PROFILES MAY PLAY ROLE IN DETERMINING
RISKS OF COMMON INFECTIONS FOR RHEUMATOID ARTHRITIS PATIENTS
SAN ANTONIO, TEXAS - Identifiable genetic factors may pre-dispose
rheumatoid arthritis patients to common infections, according
to research presented this week at the American College of Rheumatology
Annual Scientific Meeting in San Antonio, Texas.
In the largest reported analysis of associations between genetic
variations and risks of common infection, researchers studied
data on 632 patients with early rheumatoid arthritis who were
taking part in a clinical trial of methotrexate versus the TNF
inhibitor etanercept. Serious infections were found to be rare,
but 62 percent of patients reported at least one common infection
during the year-long study. Analysis of the 457 patients who
consented to genotyping revealed that upper respiratory infections
and urinary tract infections occurred more often in those patients
with particular variants in genes known to be important for immune
function.
Rheumatoid arthritis, which causes inflammation in joints and
other organs of the body, is an autoimmune disease that leaves
patients more prone to common infections than the general population.
This study demonstrates that genetics may play an important role
in defining this susceptibility to common infections in patients
with early rheumatoid arthritis. While researchers did not compare
the frequency of infections in subjects taking disease modifying
anti-rheumatic drugs (DMARDs) to participants not on DMARD therapy,
upper respiratory infections were found to be more common in
those being treated with methotrexate than in those treated with
etanercept.
"This study is the first to use data on a large number of patients
with early rheumatoid arthritis and demonstrates that a combination
of genotypes predispose those patients to common infections such
as upper respiratory and urinary tract infections," said S. Louis
Bridges, Jr., MD, PhD, University of Alabama at Birmingham, Division
of Clinical Immunology and Rheumatology, Birmingham,
Alabama, and an investigator in the study. "These findings are
preliminary and need to be corroborated in additional studies
to assess the clinical utility of this genetic information in
rheumatoid arthritis and other inflammatory diseases."
The American College of Rheumatology is the professional organization
for rheumatologists and health professionals who share a dedication
to healing, preventing disability and curing arthritis and related
rheumatic and musculoskeletal diseases. For more information
on the ACR's annual meeting, see www.rheumatology.org/annual .
###
Editor's Notes: Dr. Bridges will present this research during
a scientific session at the ACR Annual Scientific Meeting from
2:30 - 2:45 pm CT (3:30 - 3:45 pm ET) on Monday, October
18, in Ballroom B of the Henry B. Gonzalez Convention
Center. He will be available for media questions during a briefing
at 8:30 am CT (9:30am ET) on Tuesday, October 19, in the on-site
Press Conference Room, Room 218.
Presentation Number: 532
Genetic Risk Factors for Infection in Patients with
Early Rheumatoid Arthritis taking Etanercept or Methotrexate
Laura B. Hughes 1 , Lindsey A. Criswell 2 , T. Mark Beasley
1 , Jeffrey C. Edberg 1 , Robert P. Kimberly 1 , Larry W. Moreland
1 , Michael F. Seldin 3 , S. Louis Bridges, Jr. 1 . 1 University
of Alabama at Birmingham, Birmingham, AL; 2 University of California,
San Francisco, CA; 3 University of California, Davis, CA
PURPOSE: Patients with rheumatoid arthritis
(RA) have increased susceptibility to infections compared to
the general population and are frequently treated with immunosuppressive
drugs. We analyzed the impact of single nucleotide polymorphisms
(SNPs) in genes encoding tumor necrosis factor-α ( TNF ),
lymphotoxin-α ( LTA ), and Fc gamma receptors
on susceptibility to infection in subjects with early RA treated
with methotrexate or etanercept.
METHODS: We utilized detailed clinical data
and genomic DNA from subjects enrolled in a prospective, one
year clinical trial comparing the efficacy and safety of methotrexate
(MTX) and the TNF inhibitor etanercept. Of the 632 subjects in
the trial, 457 consented to genetic studies and were genotyped
at the following polymorphisms: TNF -308, -238, and
+488; LTA +249, +365, and +720; FCGR2A 131
H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2. Over
the 1 year study period 62% of the subjects reported at least
one infection. We examined the association between SNP alleles
and haplotypes and infections using multivariate logistic regression
and an ANOVA model, adjusting for prednisone dose.
RESULTS: The neutrophil-specific FCGR3B NA2
allele was associated with an increased risk of upper respiratory
infections (URI). At least one URI was noted in 52% of subjects
(99/191) with the FCGR3B NA2/NA2 genotype compared
to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59)
of those with the NA1/NA1 genotype (P=0.037; Table 1). Urinary
tract infections (UTI) were significantly associated with the TNF -238
A (P=0.038), LTA +365 C (P=0.024), and FCGR3A F
(P=0.052) alleles. The likelihood of having a UTI during the
study period increased according to the number of risk alleles
defined by these three SNPs (P=0.001; Figure 1).
CONCLUSIONS: This is the largest reported
analysis of the impact of genetic polymorphisms and risk for
prospectively identified common infections. We have identified
several polymorphisms in genes with important roles in inflammation
and host defense that are associated with susceptibility to URI
and UTI in RA patients receiving MTX or etanercept. These findings
have important implications for the role of genetics in susceptibility
to infection.
Table 1. Association between
URI and FCGR3B genotype. |
|
NA1/NA1 |
NA1/NA2 |
NA2/NA2 |
Total |
No URI |
61% (36/59) |
58% (104/181) |
48% (92/191) |
232 |
1 URI |
20% (12/59) |
24% (44/181) |
23% (44/191) |
100 |
≥2 URIs |
19% (11/59) |
18% (33/181) |
29% (55/191) |
99 |
Total |
59 |
181 |
191 |
431 |
Disclosure: L.B. Hughes , None; L.A.
Criswell , None; T.M. Beasley ,
None; J.C. Edberg , None; R.P.
Kimberly , None; L.W. Moreland ,
None; M.F. Seldin , None; S.L.
Bridges , None.
