Nucleosides, Nucleotides and Nucleic Acids, 33:174180, 2014

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ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2013.853786

EFFICACY AND SAFETY OF A URATE LOWERING REGIMEN

IN PRIMARY GOUT

1
1 Nicolas
M. Gonzalez

Rebeca Bailen,
Senac,1 Monica
M. Lopez,
1
1
1
M. Luisa Llena, Marta Migoya, M. Teresa Rodrguez, Eugenio de Miguel,2
Rosa J. Torres,3 and Juan G. Puig1
1
Division of Internal Medicine, Metabolic-Vascular Unit, La Paz University Hospital,
Madrid, Spain
2
Division of Rheumatology and 3Biochemistry, La Paz University Hospital, Madrid, Spain

Background and Objectives. Pharmacologic urate lowering therapy (ULT), at full maintenance
doses, has been associated with acute gout arthritis (in up to 80% of patients). The American
College of Rheumatology has recently advocated gradually titrating the maintenance dose upward
to chosen serum urate target. Few studies have examined the efficacy and safety of a ULT in primary
gout. Patients and Methods. The ULT regimen examined included allopurinol (50 mg/day, with
increases of 50 mg/month up to 300 mg/day) and colchicine, as prophylaxis to prevent acute gouty
attacks. The efficacy and safety of this regimen was examined in 42 patients in whom allopurinol
was withheld for 3 months and restarted after this assessment and followed up for 12 months. The
efficacy and safety of the ULT regimen was related to the serum urate decrease and to the incidence
of acute gout flares, respectively. Results. Fifty-nine patients (mean age 59 years, 56 men) with
primary gout received the gradually titrated ULT regimen. Baseline serum urate was (mean SD)
8.4 0.8 mg/dL. At 3, 6, 9, and 12 months serum urate fell by a mean of 1.8, 2.5, 2.7, and
2.5 mg/dL, respectively (p < 0.001). A serum urate level <6.0 mg/dL was achieved by 38/59
(64%) patients. During the 12 months following the start of the ULT we documented 10 acute
arthritis episodes (17% of patients). Conclusions. A gradually titrated hypouricemic regimen for
6 months in patients with primary gout appears to be effective and safe.
Keywords

Gout; hyperuricemia; allopurinol

Received 30 August 2013; accepted 6 October 2013.

We thank the physicians who participated in the Grupo MAPA-Madrid for referring their patients to
the Metabolic Unit. We are indebted to Carolina Velasco Garca, the research manager of the Metabolic
Vascular Unit, and its nursing staff (Ines Narillos and Arantxa Sanchez) for their excellent patient care
and follow-up. We thank Almudena Ligos Daz for her assistance in preparing the manuscript.
Disclosure statement: All authors declare that they have no potential conflicts of interest.
Address correspondence to Juan Garca Puig, MD, PhD, Servicio de Medicina Interna, Unidad

Metabolico-Vascular,
Edificio de Consultas Externas, Planta SEMISOTANO,
Hospital Universitario La
Paz, Paseo de la Castellana 261, 28046 Madrid, Spain. E-mail: juangarciapuig@gmail.com

174

Efficacy and Safety of a Urate Lowering Regimen in Primary Gout

175

INTRODUCTION
Urate lowering therapy (ULT) is the cornerstone of gout treatment.[13]
At standard therapeutic doses the xanthine oxidase inhibitors allopurinol
or febuxostat commonly cause acute gout flares. During the first year of
ULT acute gout flares have been reported in up to 80% of gout patients.[46]
Titration of ULT is not common clinical practice. However, the American
College of Rheumatology Association has recently advocated to gradually
titrating the ULT maintenance dose upward to chosen serum urate target.[710] We do not know the optimal titrated hypouricemic regimen to
achieve the desired serum urate level without relevant side effects. We herein
report the efficacy and safety of a ULT regimen used at La Paz University
Hospital.

PATIENTS AND METHODS

Patients Enrollment
This study is part of a project to assess the prevalence of urinary uric acid
underexcretion or normoexcretion in primary gout.[11] After the assessment
of 24-hour urine uric acid excretion gout, patients were treated with a ULT
regimen. The efficacy and safety of this regimen was examined in patients
in whom allopurinol was withheld for 3 months to assess the condition of
normal or diminished urinary uric acid excretion. Patients with primary gout
were recruited from the outpatient clinic of the Metabolic-Vascular Unit, Division of Internal Medicine at La Paz University Hospital, Madrid. Primary
gout was diagnosed according to the American Rheumatic Association criteria.[12] Comorbidities were assessed following the definition proposed by the
European Society of Hypertension.[13] Only patients with two or more acute
arthritis episodes documented by a physician were selected for the study
(n = 127). The main exclusion criteria were secondary gout (i.e., psoriasis)
(n = 4), marked organ insufficiency that precluded participation on an ambulatory basis (n = 10), and unwillingness to participate (n = 9). A total of
104 patients were considered for this study. Seventy-six patients had been
treated with allopurinol and none with febuxostat. Thus, 28 patients were
nave gout patients. All studies were conducted according to local regulations and the Declaration of Helsinki and were approved by the Institutional
Research and Ethics Review Committees of La Paz University Hospital.
Urate Lowering Therapy
The ULT regimen used at La Paz University Hospital was empirically
established from the clinical experience gained over the last 25 years with
more than 300 patients with primary gout that came to our attention due

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R. Bailen et al.

to acute gout flares. The regimen consists on allopurinol (50 mg/day, with
increases of 50 mg each of 6 months up to 300 mg/day) and colchicine
prescribed as prophylaxis against acute arthritis[14] (0.5 mg/12-hour for
the first 6 months followed by 0.5 mg/day for the next 6 months). The
efficacy and safety of this ULT regimen was related to the serum urate
decrease at 3, 6, 9, and 12 months and to the incidence of acute gout
flares. The primary efficacy endpoint was reduction of serum urate levels to
<6.0 mg/dL at month 12. Every three months, each patient underwent a
physical examination, vital signs were recorded and serum urate and renal
function were assessed. Acute arthritis flares were purposely questioned (Did
you have any articular problem since last visit?) on each visit and registered by
a physician.
RESULTS
Patients Characteristics
Fifty nine patients (53 males, 95%) with primary gout were included in
the study. Ten patients did not receive ULT following the metabolic study
and 7 patients did not complete the 12-month follow up period, thus rendering 42 patients that completed the 52-week treatment period. The mean age
was 59.3 (range, 38 to 84 years). The most frequent comorbidities were arterial hypertension (48; 81%), hyperlipidaemia (34; 58%), obesity (25; 42%),
and type 2 diabetes mellitus (14; 24%). Twenty three (39%) patients showed
3 characteristics defining the metabolic syndrome.[15] Twenty-three (39%)
patients had not previously received allopurinol therapy. The mean age, sex
ratio, racial distribution, mean baseline serum urate concentration, and history or presence of tophi were similar in gout patients that had or had not received allopurinol (Table 1). The mean serum urate level was 8.4 mg/dL, and
6 (10%) subjects showed a baseline serum urate concentration 10 mg/dL.
Mean urinary uric acid excretion was 507 mg/day/1.73m. Fifty-three (90%)
patients were underexcretors of uric acid.
Efficacy and Safety of the ULT
At 3, 6, 9, and 12 months mean serum urate concentration diminished
1.8, 2.5, 2.7, and 2.5 mg/dL, respectively (p < 0.001). A serum urate level
<6.0 mg/dL (proposed by the American College of Rheumatology Medical
Association)[16] was achieved at 12 months in 38/59 (64%) of the patients.
During the first year of ULT, 10 patients (17%) presented acute gout flares
(Table 2). Each of the 10 patients reported one acute arthritis episode. Of
these, 7 patients had never been treated with allopurinol. Four acute gout
flares occurred within the first 3 months (one before the end of month 2),
two between months 3 and 6, and four within month 9. Acute gout flares were

177

Efficacy and Safety of a Urate Lowering Regimen in Primary Gout

TABLE 1 Baseline characteristics of gout patients

Age (years)
Men (%)
Body mass index (Kg/m2)
Associated conditions(a)
Smokers (%)
Alcohol abuse (%)
Clinical atherosclerosis
Stroke (%)
Coronary arterial disease (%)
Peripheral arterial disease (%)
Renal insufficiency (%)
Arterial hipertension (%)
Left ventricular hypertrophy (%)
Type 2 diabetes mellitus (%)
Hyperlipidemia (%)
Obesity (%)
Metabolic syndrome (%)
Gout characteristics
Estimated age at onset (years)
Estimated duration (years)
Estimated number of acute gout flares (per year)
Renal lithiasis (%)
Tophi (%)
Upper limb involvement (%)
Lower limb involvement (%)
First MTP joint involvement (%)
Poliarticular involvement (%)
Baseline serum urate (purine free diet, mg/dL)
(a)
(b)

Gout
patients
(n = 59)

With previous
ULT
(n = 36)

No previous
ULT
(n = 23)

59.3 8.0
55 (95%)
29.5 3.1

59.1 9.6
33 (92%)
29.2 3.9

59.6 11.3
22 (96%)
29.8 4.3

8 (14%)
18 (30%)

2 (6%)
9 (25%)

6 (26%)
9 (39%)

2 (3%)
1 (2%)
0 (0%)
3 (5%)
48 (81%)
14 (24%)
14 (24%)
34 (58%)
25 (42%)
23 (40%)

1 (3%)
1 (3%)
0 (0%)
3 (8%)
29 (81%)
10 (28%)
12 (33%)(b)
25 (69%)(b)
18 (50%)
16 (44%)

1 (4%)
0 (0%)
0 (0%)
0 (0%)
19 (83%)
4 (17%)
2 (9%)(b)
9 (39%)(b)
7 (30%)
7 (30%)

46.4 11.0
13.2 9.0
1.1 1.2
6 (8%)
3 (5%)
14 (24%)
56 (95%)
35 (60%)
9 (15%)
8.4 1.1

46.2 11.5
13.1 9.4
1.0 2.6
4 (11%)
3 (8%)
7 (19%)
34 (94%)
19 (53%)
7 (19%)
8.7 1.4(b)

46.5 15.9
12.2 2.5
1.1 2.1
2 (9%)
0 (0%)
7 (0%)
22 (96%)
16 (70%)
2 (9%)
7.9 0.65(b)

= Commorbidities were assessed by the European Society of Hypertension criteria.[13]

= p < 0.05

TABLE 2 Efficacy and safety of a urate lowering therapy regimen in primary gout patients
Efficacy
Serum urate <6.0 mg/dL at month 3 (%)
Serum urate <6.0 mg/dL at month 12 (%)
Percent change in serum urate concentration from baseline to
month 12 (mean % SD)
Safety
Incidence of gout flares (number of patients)
Day 1 to month 2 (%)
Month 3 (%)
Month 4 to month 6 (%)
Month 7 to month 9(%)
Month 10 to month 12 (%)
Articular pain (%)
Diarrhea (%)

13(22%)
38(68%)
43.5 1.8

10(17%)
1(2%)
3(5%)
2(3%)
4(7%)
0(0%)
7(12%)
1(2%)

178

R. Bailen et al.

treated with NSAID and the colchicine dose was increased to 0.5 mg/12-hour
for 1 month. Seven patients reported articular pain, with no inflammation
signs; pain resolved in a few days without medication.
DISCUSSION
The ULT empirically used at La Paz University Hospital showed to be effective and safe. Concerning efficacy, 38/59 (64%) of the patients achieved a
serum urate level below 6 mg/dL at 12 months. This figure is notably higher
than that reported by Becker et al. (36% at month 12),[6] Schumacher et al.
(39% at month 6)[6] and Becker et al. (42% at month 6).[5] One possible
explanation to account for this difference is that being the administered
allopurinol dose identical (300 mg/day), their gouty patients had a body
mass index about 3 kg/m2 higher than that of our gout subjects and, thus,
the allopurinol dose per kg prescribed was higher in our study. It has been
supposed that acute gout flares following ULT are due to urate crystal mobilization. A rapid lowering of serum urate concentration would increase the
removal of urate crystals. In contrast, it is conceivable that a slower rate of
serum urate reduction would diminish the removal of these deposits and
thus cause less acute gout flares.
The most relevant finding of this study is that only 10/59 (17%) of the
patients had acute gout flares following the first year of ULT. Several studies
have reported acute gout flares in up to 80% of the patients for the first year
when ULT is started.[4] However, the reported studies differ from ours not
only in gout patients characteristics but also on the ULT regimens employed
and on the prophylaxis used. Becker et al.[4] and Schumacher et al.[6] communicated an incidence of acute gout flares (8 weeks from the start of ULT)
with allopurinol of 21% and 23%, respectively, despite colchicine prophylaxis. The corresponding figure in our study is 1/10 (10%). One explanation
to account for this difference is the start dose of ULT, being 50 mg/day versus
300 mg/day.[4,6] These studies reported to withheld gout flares prophylaxis
after month 2 of ULT initiation. We have treated many many (this is not a
mistake, but to emphasize the high amount of gout attacks that we have treated) acute
arthritis episodes for the last 25 years and we have observed many acute gout
flares with full allopurinol doses. Thus, we decided to prescribe colchicine
prophylaxis for the first 12 months after the start of ULT. In fact, during
the period from 2 to 12 months, we documented 9 acute gout flares among
59 patients (15%). This figure contrast to an incidence of 64% reported
without gout prophylaxis in previous studies.[4,6] In addition to colchicine
prophylaxis, another issue that may have contributed to this difference (15%
versus 64%) is that 61% of our patients had received allopurinol therapy before ULT was started. This contrast to the figure of 44% and 29% reported
in previous studies.[4,6] In this sense, it is remarkable that the CONFIRMS
trial[5] reported an incidence of acute gout flares of about 15% following

Efficacy and Safety of a Urate Lowering Regimen in Primary Gout

179

ULT with allopurinol 300 mg/day and colchicine (0.6 mg/day) or naproxen
prophylaxis. An additional difference is that only 5% of our gout population
had tophi. This contrast with the higher prevalence of 25%[4] and 28%[6] in
other studies with increased incidence of acute gout flares following ULT.
It is widely known that tophaceous gout is much more prone to suffer gout
attacks as compared to nontophaceous gout.
One limitation of this observational study is that the number of patients included was about a third of the patients studied by Becker[4] and
Schumacher[6] and all were Caucasic. Another limitation is that ULT was
empirically established. In addition, we had not evaluated the impact of this
ULT regimen on tophi reduction, since only 3 patients had mild tophaceous gout,[10] and on the comorbidities associated to primary gout[17] and
secondary gout.[18] Obviously, a more valid comparison would have been in
the context of a randomized clinical trial with different titration regimens
and/or acute flare prophylaxis.
In summary, a gradually titrated hypouricemic regimen for 6 months in
patients with primary gout appears to be effective and safe, with a marked
reduction in the incidence of acute gout arthritis episodes as compared with
ULT starting at full maintenance doses with limited prophylaxis.[49] Further
studies are needed to asses whether a more intensive ULT to achieve the
serum urate target in a reduced period may be cost-effective with minimum
side effects.
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