Arthritis & Rheumatism (Arthritis Care & Research)

Vol. 51, No. 3, June 15, 2004, pp 321325

DOI 10.1002/art.20405
2004, American College of Rheumatology
ORIGINAL ARTICLE

A Retrospective Study of the Relationship

Between Serum Urate Level and Recurrent
Attacks of Gouty Arthritis: Evidence for Reduction
of Recurrent Gouty Arthritis With
Antihyperuricemic Therapy
AKIRA SHOJI, HISASHI YAMANAKA, AND NAOYUKI KAMATANI

Objective. To evaluate the proposed relationship between persistent reduction of serum urate into the subsaturating
range and reduction in the frequency of acute gouty attacks.
Methods. We retrospectively examined data derived from 267 patients who had experienced at least 1 gouty attack before
their rst visit to our clinic. Serum urate concentration, history of recurrent gouty attacks, and information about
antihyperuricemic drug use were collected on each visit for up to 3 years from the rst visit of each patient. Data derived
from visits >1 year after study entry were subjected to statistical analysis.
Results. When adjusted for baseline serum urate level and the number of gouty attacks prior to study entry, reduction
of followup serum urate concentration and antihyperuricemic drug use were each signicantly associated with a reduced
risk of gouty attacks (odds ratio [OR] 0.42, 95% condence interval [95% CI] 0.31 0.57; OR 0.22, 95% CI 0.10 0.47,
respectively).
Conclusion. The data indicate that reduction of serum urate concentrations to 6 mg/dl or lower will eventually result in
a reduced frequency or prevention of future gouty attacks.

KEY WORDS: Gout; Serum urate; Antihyperuricemic drug.

INTRODUCTION
Acute gouty arthritis, the most common manifestation of
gout, is clearly associated with hyperuricemia (1), which is
best dened as extracellular uid urate supersaturation.
Hyperuricemia reects an enlarged body pool of uric acid
and increases the risk for precipitation of monosodium
urate crystals in joints, connective tissue, and parenchy-
mal organs, including the kidneys (2). Reduction of the
uric acid pool would thus appear most crucial in the
management of gout. For this reason, antihyperuricemic
drugs, such as allopurinol and uricosuric agents, have
been widely prescribed for patients with gout. These drugs
effectively reduce serum urate levels, and their use has
been shown to improve long-term prognosis in gout (3).
Although antihyperuricemic drugs are also widely re-
garded as useful in reducing the frequency of or preventing
acute gouty attacks, only a few reports have supported this
contention and even fewer have suggested a target serum
urate level for achieving this outcome (4,5). In this study,
we retrospectively analyzed the incidence of recurrent
gouty arthritis beginning 1 year after initial evaluation in
267 gout patients. The purpose of this study was to eval-
uate the proposed relationship between persistent reduc-
tion of serum urate into the subsaturating range and reduc-
tion in the frequency of acute gouty attacks.

Akira Shoji MSc, Hisashi Yamanaka, MD, Naoyuki Ka-

matani, MD: Tokyo Womens Medical University, Tokyo,
Japan.
Address correspondence to Hisashi Yamanaka, MD, In-
stitute of Rheumatology, Tokyo Womens Medical Univer-
sity, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054 Ja-
pan. E-mail: hisashi@pc4.so-net.ne.jp.
Submitted for publication May 1, 2003; accepted in re-
vised form August 8, 2003.
PATIENTS AND METHODS
Patients. We studied 267 patients with gout who rst
visited the Institute of Rheumatology, Tokyo Womens
Medical University for gout treatment between January 1,
1997 and June 30, 1998 and who attended the clinic for 1
year. By the time of the rst visit, all patients had experi-

321
322
enced at least 1 attack of gouty arthritis and none were
then receiving antihyperuricemic medications. The diag-
nosis of gout was based on the 1977 criteria proposed by
the American College of Rheumatology (formerly Ameri-
can Rheumatism Association) (6). Where possible, diagno-
sis was denitively conrmed by joint or tophus aspiration
and demonstration of monosodium urate crystals by po-
larized light microscopy. The number of patients with
gouty tophi was quite few, as is typical in Japan. Among
the 267 patients, 35 patients did not receive antihyperuri-
cemic medication for at least 1 year after the rst clinic
visit. These patients comprised a no-medication group.
The remaining 232 patients received antihyperuricemic
medication and comprised a medication group. Decisions
regarding treatment with antihyperuricemic medications
were made on an individual basis by the physicians re-
sponsible for each patient.
The choice of antihyperuricemic medication prescribed
for an individual patient was based primarily on daily
urinary uric acid excretion, status of renal function, and
the presence or absence of urolithiasis, following recom-
mendations previously described (7). Allopurinol (95 pa-
tients), benzbromarone (136 patients) (8), or both (1 pa-
tient) were prescribed for patients in the medication
group. After initiation of treatment, benzbromarone was
replaced by allopurinol in 10 patients, probenecid in 2
patients, and sulnpyrazone in 1 patient and allopurinol
was replaced by benzbromarone in 2 patients because of
adverse reactions. Drug therapy was started at minimal
dosages (allopurinol 100 mg/day; benzbromarone 25 mg/
day) in an effort to minimize precipitation of acute gouty
arthritis, an adverse effect of antihyperuricemic treatment
that is especially common early in treatment if serum urate
levels are reduced rapidly (7). Dosing of antihyperurice-
mic drugs was titrated with serum urate levels and creat-
inine clearances. Therapeutic target urate levels were not
explicitly settled because of the retrospective design of
this study. Our consensus of the target levels, however,
was 6 mg/dl or below. Ninety-eight percent of patients
were prescribed up to 300 mg/day of allopurinol or up to
50 mg/day of benzbromarone. Colchicine or nonsteroidal
antiinammatory agents were prescribed for the purpose
of treatment but not of prophylaxis of acute gouty attacks,
as is historically typical in Japan. Patients were requested
to visit our clinic monthly, at which time the attending
physician measured serum urate concentration and re-
corded the occurrence of gouty attacks in the preceding
month.
Study measurements. The characteristics of the pa-
tients in each group, including sex, age, interval from the
rst gouty attack, number of gouty attacks before the rst
visit, serum urate level, frequency of recurrent gouty at-
tacks, and drugs prescribed and taken, were collected at
the rst and each subsequent visit. Data were collected for
up to 3 years after the rst visit, except in 12 patients in the
no-medication group who were subsequently treated and
whose data collected after initiation of antihyperuricemic
medication were excluded from analysis.
Shoji et al
Statistical analyses. The primary variable studied was
the incidence of acute gouty arthritis 1 year after each
patients rst visit. As mentioned in greater detail in the
Discussion section, attacks during the rst year were not
included in this assessment.
We evaluated the relationship between average serum
urate concentration during the whole investigation period
and recurrence of gouty attacks by a logistic regression
model. The investigation period of was at least 1 year and
up to 3 years. Average serum urate concentration was
calculated by the trapezoid method considering the serum
urate concentration at each visit and the intervals between
consecutive visits. The formula for the calculation was
i
(SUi1 SUi) (dayi1 dayi)/2
average SU
observation period (days)
where SU is the serum urate concentration; dayi is the
number of days since the rst visit of the i-th visit; obser-
vation period is the whole investigation period in days.
Baseline serum urate level was calculated using the same
formula above, in this case dening the observation period
as beginning with the rst visit and ending, as appropriate,
with initiation of antihyperuricemic medication.
Patients in the medication and no-medication groups
were further subdivided into attack and no-attack groups
on the basis of the occurrence or nonoccurrence of gouty
attacks 1 year after the rst visit. The relationship be-
tween antihyperuricemic medication and the recurrence
of gouty attacks was analyzed using a logistic regression
model. The mean average serum urate in each subgroup
was also analyzed.
All data were analyzed using SAS 8.02 (SAS Institute,
Cary, NC).
RESULTS
Relationship between average serum urate levels and
recurrence of gouty attacks. Of the 267 patients analyzed
in this study, 91 experienced at least 1 recurrence of
acute gouty arthritis a year or more after the initial visit
(attack subgroup); the remaining 176 patients had no re-
currences a year or more after the initial visit (no-attack
subgroup; Table 1). As discussed in greater detail below,
antihyperuricemic drug-treated patients in the no-attack
subgroup had a lower mean average serum urate concen-
tration during the whole investigation period than that of
treated patients in the attack subgroup (Table 1). There
was no association between recurrence of gouty attacks
and the type of antihyperuricemic drugs used (P 0.549,
Fishers exact test). Twenty-ve of 93 patients taking allo-
purinol (26.9%) and 38 of 123 patients taking benzbrom-
arone (30.9%) had recurrent gouty attacks.
Analysis of patient characteristics. The number of
gouty attacks prior to the observation period in the attack
subgroup was signicantly higher than that in the no-
attack subgroup (P 0.044, Fishers exact test). The initial
serum urate concentration in the attack subgroup was
Serum Urate and Recurrent Attacks of Gout 323

18.9 (0.368.3)

7.17 (0.49)

7.76 (0.23)
No attack

47.2 (3469)
13 (37.1)
13/0

11/2
No medication group

41.5 (0.7295.0)

7.76 (0.22)

7.75 (0.18)
47.0 (3069)
Attack

22 (62.9)
21/1

18/4

Figure 1. Relationship between average serum urate concentra-

tion and the incidence of acute gouty arthritis more than 1 year
after each patients rst visit. The symbols represent observed
Table 1. Characteristics of the patients in medication and no medication groups

53.6 (0.2299.9)

data and the line is the regression curve of a logistic analysis. The
7.47 (0.13)

6.36 (0.06)

logistic model used in this analysis is logit(P) a0 a1X a2Y

No attack

50.2 (1692)
163 (70.3)

124/39

a3Z. In this model, P is the proportion of patients with recurrent

160/3

gouty attacks more than 1 year after their rst visit, and explana-
tory variables are average serum urate during the whole investi-
Medication group

gation period (X), baseline serum urate (Y), and history of attacks
(Z). The odds ratio for the average serum urate concentration is
0.42 (95% condence interval 0.31 0.57). *Whole investigation
period was 3 years except for the no-medication group, for which
data after initiation of antihyperuricemic medication, where ap-
64.5 (0.1274.6)

propriate, were excluded from analysis.

7.80 (0.18)

7.01 (0.10)
45.0 (2480)
Attack

69 (29.7)

41/28

higher than that in no-attack subgroup, although it showed

69/0

only a trend toward signicance (P 0.068, 2-sample

Wilcoxons test; Table 1). These 2 parameters appeared to
inuence the likelihood of recurrence of acute gouty at-
tacks 1 year or more after the initial visit. We therefore
included both parameters as covariates in the subsequent
logistic regression model.
51.0 (0.2299.9)

7.45 (0.13)

6.46 (0.07)
No attack

50.0 (1692)
176 (65.9)

135/41
173/3

Logistic regression analysis. Recurrence of acute gouty

attacks was associated with average serum urate concen-
tration during the whole investigation period with an odds
All patients

ratio (OR) of 0.42 (P 0.001, 95% condence interval

[95% CI] 0.31 0.57) when average serum urate concentra-
tion was adjusted for the 2 covariates, baseline serum
urate, and the number of gouty attacks prior to the obser-
58.9 (0.1295.0)

7.79 (0.14)

7.20 (0.09)

vation period. Figure 1 shows the clear relationship dis-

45.5 (2480)
Attack

91 (34.1)

59/32

played between average serum urate concentration and the

90/1

percentage of patients who experienced at least 1 recurrent

gouty attack during the observation period.
Overall, average serum urate concentration in the attack
subgroup was 7.20 mg/dl (SE 0.09 mg/dl) and that in the
no-attack subgroup was 6.46 mg/dl (SE 0.07 mg/dl; Table
1).
Interval from rst attack, mean

Serum urate during the whole

investigation period, mean
No. with attacks before rst

Baseline serum urate, mean

Serum urate levels and the incidence of recurrent gouty

Age, mean (range) years
Characteristics

attacks in the medication and no-medication groups. Six-

ty-nine of the 232 patients (29.7%) in the medication
No. of patients (%)
Sex, male/female

(range) months

group and 22 of the 35 patients (62.9%) in the no-medica-

visit 4 / 4

tion group experienced at least 1 recurrent gouty attack

(SE) mg/dl

(SE) mg/dl

during the observation period (Table 1). Adjusted for the 2

covariates, baseline serum urate and the number of gouty
attacks prior to the observation period, antihyperuricemic
medication decreased the risk of recurrent attacks with an
OR of 0.22 (P 0.001, 95% CI 0.10 0.47).
324
Figure 2. Plot of the percentage of patients with gouty attacks in
the medication and the no-medication groups at 3-month inter-
vals from the rst visit.
Among patients in the medication group, the adjusted
means of the average serum urate values in attack and
no-attack subgroups were 7.01 mg/dl (SE 0.10 mg/dl) and
6.36 mg/dl (SE 0.06 mg/dl), respectively (Table 1).
Temporal patterns of gouty recurrence in medication
and no-medication groups. Figure 2 shows the incidence
of recurrent gouty attacks from the initial visit through the
observation period in the medication and no-medication
groups. Although the incidence of acute gouty arthritis
was greater during the rst year in the medication than in
the no-medication group, the percentage of patients with
gouty attacks gradually decreased in the medication group
to a level exceeded by that in the no-medication group. An
underestimation in later incidence rates among members
of the no-medication group seems likely due to the small
number of subjects followed, in part because 12 members
of this group were withdrawn to recieve treatment of re-
current gouty attacks.
DISCUSSION
This study demonstrated that the lower the serum urate
levels, the less the likelihood of recurrent acute gouty
attacks. Recurrence of acute gouty attacks was signicantly
associated with average serum urate concentration during
the whole investigation period. We used the recurrence of
acute gouty arthritis during an observation period begin-
ning 1 year after the rst visit as our primary measure of
the clinical efcacy of antihyperuricemic medication be-
cause use of these agents is frequently associated with
gouty attacks in the early weeks and months of treatment
(7,9), particularly if prophylactic colchicine or nonsteroi-
dal antiinammatory drugs are not prescribed (10). We
conrmed this phenomenon in our study (Figure 2).
Because the primary aim of treating gout patients with
antihyperuricemic drugs is to maintain subsaturating lev-
els for a period sufcient to normalize body uric acid
pools, we chose the average serum urate concentration
during a lengthy investigation period as an explanatory
variable. During long-term administration of these agents,
patient compliance with drug administration is often an
issue in an asymptomatic individual, and, as with others
Shoji et al
before us (11), we assumed that poorer compliance was
associated with higher serum urate concentrations in this
study. We therefore considered average serum urate con-
centration to be an appropriate explanatory variable in
evaluating the relationship of antihyperuricemic treatment
and reduction in the recurrence of gouty attacks, regard-
less of patient compliance with drug. Our results showed
that 25% of patients returned to our clinic on a monthly
basis and 50% of patients came to our clinic at least once
every-other month, on the average. As we assumed, the
longer average visit interval trended toward the higher
average serum urate level.
In this study, antihyperuricemic drugs effectively re-
duced the risk of recurrent gouty attacks during the obser-
vation period by signicantly reducing the average serum
urate concentration, with a signicant OR of 0.22. The
patients in the medication group had experienced more
gouty attacks before starting medication and had longer
duration of gouty arthritis than patients in the no-medica-
tion group. Although these differences were not statisti-
cally signicant, we believe the group assignments
reected the standard therapeutic strategy of antihyper-
uricemic medication in gout patients who have experi-
enced frequent versus infrequent gouty attacks. That is,
patients who have experienced fewer attacks are less likely
to be treated with antihyperuricemic medication. Al-
though the patients in the no-medication group were con-
sidered to be at lower risk at the beginning of the investi-
gation period, they nevertheless experienced a higher
incidence of recurrent gouty attacks than patients in the
medication group. This result demonstrated that maintain-
ing serum urate at subsaturating levels was effective in
gout patients and that antihyperuricemic drugs were
clearly useful for this purpose.
A target serum urate level to be achieved with antihy-
peruricemic drug therapy has been controversial (5,10,11).
In theory, urate levels below 7 mg/dl may be considered
appropriate because at the sodium concentrations prevail-
ing in extracellular uids, serum at 37C is supersaturated
for monosodium urate at concentrations 6.8 mg/dl (12).
As shown in Table 1, however, the mean average serum
urate concentration in the patients in the medication
group who experienced recurrent gouty attacks was only
7.01 mg/dl, whereas those in the no-attack subgroup aver-
aged 6.36 mg/dl. This result suggests that 7 mg/dl is not a
suitable target level. The logistic analysis shown in Figure
1 demonstrated that the lower the serum urate level, the
lower the incidence of recurrent gouty attacks. On the
other hand, larger doses of antihyperuricemic drugs are
generally required to achieve lower serum urate levels but
may increase the risk of adverse events. Excessive doses of
allopurinol in patients with renal insufciency clearly in-
crease the risk of adverse reactions (13). Also, excessive
hypouricemia caused by inappropriate usage of uricosuric
drugs, such as benzbromarone, may provoke hyperuricos-
uria, which may, in turn, increase the risk of urinary stone
formation in the rst 4 8 weeks after the initiation of
therapy (14).
Among 81 patients in this study whose average serum
urate concentrations were 6.0 mg/dl, all in the medica-
tion group, 71 patients (86%) had no recurrent gouty at-
Serum Urate and Recurrent Attacks of Gout
tacks during the observation period. Also, Li-Yu et al (15)
recently reported that maintaining serum urate levels 6
mg/dl for several years effectively reduced urate crystal
stores in the knee joint synovial uid (15). In view of these
results, we recommend a target serum urate level 6.0
mg/dl as an aim of antihyperuricemic therapy for purposes
of reducing the incidence of acute arthritic attacks in pa-
tients with gout. Our results also suggest that higher serum
urate levels may be the risk of the incidence of recurrent
gouty attack. Patients who have had high serum urate
levels for long duration and have more gouty attack history
could be regarded as high-risk patients and should be
treated with antihyperuricemic drug.
This recommendation should be further evaluated in
prospective clinical studies.
ACKNOWLEDGMENTS
We wish to thank Professor Michael A. Becker (University
of Chicago, Chicago, IL) and Dr. Nancy Joseph-Ridge (Lake
Forest, IL) for their thoughtful review of the manuscript
and valuable suggestions.
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