Sinus problems, whose symptoms are primarily associated with fatigue and increased pain 12, are comm

1
Sinus Disorders in Rheumatoid Arthritis
Prevalence and Treatment Effects
Kaleb Michaud and Fred Wolfe -- National Data
Bank for Rheumatic Diseases, Wichita, KS, USA
Introduction Sinus problems, whose symptoms are
primarily associated with fatigue and increased
pain (12), are common in the general population
and may be increased in persons with immune
disorders (34). In addition, clinical trials
suggest an increase in sinus symptoms in antiTNF
treated persons with RA (5).
In the current study we had several aims 1) to
determine that rate of sinus problems and whether
they occurred more frequently in persons with RA
2) to determine which clinical symptoms were
associated with sinus problems 3) to determine
if anti-TNF therapy or other DMARD therapy was
associated with sinus problems and 4) to
determine the incidence rate of hospitalization
for sinus disease in persons with RA.
Results There was no significant difference amo
ng RA, OA and fibromyalgia patients as to the
rate of sinus problems (Table 1). Following
adjustment for age and sex, rates were RA
(22.1, OA 24.8, fibromyalgia 22.0).
Differences between OA and RA were significant
(p0.02). Sinus problems were more common in yo
unger persons, and in women (Table 2). The
strongest correlates of sinus problems were
allergies (odds ratio (OR) 2.27 (95 C.I.
2.01-2.57)) and asthma (OR 1.64 (95 C.I.
1.43-1.89)). Sinus problems were also associated
with severity of RA, as measured by HAQ, pain and
fatigue. Among treatments, leflunomide (OR 0.83
(95 C.I. 0.71-0.99)) and sulfasalazine (OR
0.62 (0.47-0.82)) had a protective effect. Sinus
problem risk increased in those using etanercept
(OR 1.21 (95 C.I. 1.04-1.41)). To evaluate
treatment effect in a multivariable environment,
we regressed sinus problems on major treatment
variables (Table 3). The variables significant in
Table 2 remained significant except for
etanercept (p 0.066). We tested whether the
coefficients were different between etanercept
and infliximab. The results showed that the risk
of sinus problems was greater among those
receiving etanercept (OR 1.23 (95 C.I.
1.03-1.48)). We also studied the incidence and
prevalence of sinus surgery in the RA group. In
these analyses we made use of patients in the NDB
who did not complete the 2003 sinus survey. Of
13,682 RA patients seen from 1999 through 2003,
the prevalence of sinus surgery was 4.01 per
10,000 patients (95 C.I. 2.21 to 5.82) and the
incidence rate through 122,381 patient years of
exposure was 1.55 (95 C.I.0.93 to 2.42) per
10,000 years. When stratified by sex, the rates
were 2.66 (95 C.I. 1.07 to 5.48) for men and
1.25 (95 C.I. 0.65 to 2.18) for women per
10,000 patient-years of exposure.
Abstract PURPOSE Sinus problems are common in
the population. In rheumatoid arthritis
randomized clinical trials (RCT) the incidence of
sinus infection was increased among patients
receiving anti-TNF therapies compared with
persons not on such therapies. Patients with RA
might be at increased risk for sinus disorders
because of rheumatoid arthritis (RA) or because
of immuno-modulatory therapies. The purpose of
this study is to determine if rates of sinus
disease are increased in RA and whether RA
treatments alter the risk of sinus disease.
METHODS As part of a longitudinal study of
rheumatic disease outcomes, 7,243 patients with
RA, 1,667 with osteoarthritis (OA) and 447 with
fibromyalgia were evaluated in 2003 as to sinus
problems. We determined medical visits and
prescription medication use for sinus problems,
and defined an important sinus problem as one
that required a physician visit.
RESULTS The lifetime prevalence of sinus
disorders diagnosed by a physician was 42.9.
During the previous 6 months 22.4 of RA
patients, 24.0 of OA patients and 25.1 of
fibromyalgia patients visited a physician for a
sinus problem (p 0.181) and 22.3, 24.0 and
25.1 received a prescription medication for a
sinus problem (p 0.184). After adjustment for
age and sex, the rate of physician visits was
significantly lower for RA patients (22.1)
compared with OA patients (24.8), p 0.021. We
developed a predictive multivariable model for
sinus problem physician visits in RA patients
(Table 1). The strongest predictor of sinus
problems was a history of allergies and younger
age. Sinus problems were also more common in
whites and among those with an asthma history.
Etanercept (odds ratio 1.2 (95 C.I. 1.0 to 1.4)
increased the risk of sinus problems while
leflunomide (OR 0.8 (0.8 to 1.0)) and
sulfasalazine (OR 0.7 (0.5 to 0.9)) were
associated with reduced risk. Other
(non-significant) variables are omitted from
Table 1. In contradistinction to the modest
associations of treatment with outpatient medical
visits, a strong association was seen for
hospitalization for sinus disease with prior
(lagged) prednisone therapy (OR 10.7 (95 C.I.
3.1 to 36.4)) but not with lagged DMARD or
biologic therapy, after controlling for age, sex
and allergies. CONCLUSIONS Medical visits for
sinus problems are not increased in RA compared
to OA and fibromyalgia. Among RA patients
etanercept is a modest risk factor for sinus
problems, and sulfasalazine and leflunomide
appear to reduce the risk. Antecedent prednisone
substantially increases the risk of
hospitalization for sinus surgery. However, as
prednisone may have been used as a sinus
treatment, it is not possible to say if
prednisone is causally linked to sinus surgery.
Discussion (cont.) Upper respiratory and sinus
infections are more common in anti-TNF treated
patients than in control subjects in clinical
trials (5), with very slight increases in those
treated with adalimumab and for sinusitis in
those treated with infliximab (12 vs. 6) (5).
In clinical trials, upper respiratory infections
and sinusitis were the most frequently reported
infections in patients receiving etanercept or
placebo, and the rate of upper respiratory tract
infections was 17 in placebo group and 22 in
etanercept group. There were no increases in the
rates of serious infections (requiring
hospitalization) (19). However, the data of the
current study indicate that sinus problems are
not increased in persons with RA, and after
adjustment for age and sex are even slightly
reduced compared with OA, although the
difference, though statistically significant, is
small (24.8 vs. 22.1). We found that
sulfasalazine, although use by few patients
(5.8) has a protective effect on sinus problems,
OR 0.62 (95 C.I. 0.47-0.82). This reduction
might be related to its anti-bacterial effect
(2021). We also found that leflunomide had a
reduced association with sinus problems (OR 0.83
(95 C.I. 0.77-0.99). Persons receiving etane
rcept had an increased risk of sinus infections
in age and sex adjusted analyses of Table 2 (OR
1.21 (95 C.I. 1.04-1.41)). The effect was
decreased in multivariate analyses of Table 3 (OR
1.16 (95 C.I. 0.99-1.36). However, compared
with infliximab the increased risk remained OR
1.23 (95 C.I. 1.03-1.48). In summary, sinus
problems are not increased in RA compared with
patients with OA and fibromyalgia. Slight
protective effects on sinus problems are noted
with sulfasalazine and leflunomide, and a slight
increase in risk of sinus problems is noted with
etanercept.
Methods Patients in this study were participant
s in the National Data Bank for Rheumatic
Diseases (NDB) longitudinal study of RA outcomes.
Patients are recruited from the practices of
United States rheumatologists, and are followed
with semi-annual questionnaires (6-10).
This report concerns 9,357 rheumatoid disease pa
tients who completed a questionnaire in December
2003 that included questions related to sinus
problems. In this questionnaire we asked patients
if during the last 6 months they 1) had used
over-the-counter medications for a sinus
problems, 2) used medications for a sinus problem
prescribed by a physician and 3) if they had
visited a physician specifically because of a
sinus problem during this period. For the
purposes of this study we operationally defined a
sinus problem as being present if patients
specifically visited a physician because of the
sinus problem.


Table 3. Multivariable analyses of association of
RA treatment variables with visits to a physician
for sinus problem in the last 6 months.

Table 1. Prevalence of Sinus problems in RA, OA
and fibromyalgia patients.
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Table 2. Means and univariate associations of RA
variables with visits to a physician for a sinus
problem in the last 6 months (N7,243)
Discussion Data from the third National Health
and Nutrition Examination Survey, 1988-1994
(NHANES) indicated that 25 of the adult
population reported having sinusitis or sinus
problems at least once during the previous 12
months (15), an estimate that is consistent with
the 6 months prevalence of sinus problems in the
current study (22.8). Chronic sinusitis is less
common, with annual estimates of 14.1 from
NHANES (16) and between 5.7 in women and 3.4
in men in Canada (17). Recently, using rigorous
methodology, researchers from the Mayo Clinic
group reported the annual age and sex adjusted
rate of chronic sinusitis to be 1.96. There is
some evidence that sinusitis is increased in
immuno-compromised patients (4) and in
inflammatory bowel disease (3). However, there
are no reports of studies of sinusitis in RA or
OA. A single report links chronic unexplained
fatigue to sinus symptoms (18), a finding with
similarities to the association of sinus problems
and fatigue noted in the current study.
Except for age and sex, variables are adjusted
for age and sex. PSupported by Grants from Bristol-Meyers-Squibb,
Centocor and Aventis