Nucleosides, Nucleotides and Nucleic Acids, 33:174–180, 2014Copyright C© Taylor and Francis Group, LLCISSN: 1525-7770 print / 1532-2335 onlineDOI: 10.1080/15257770.2013.853786

EFFICACY AND SAFETY OF A URATE LOWERING REGIMEN

IN PRIMARY GOUT

Rebeca Bailen,1 Nicolas M. Gonzalez Senac,1 Monica M. Lopez,1

M. Luisa Llena,1 Marta Migoya,1 M. Teresa Rodrıguez,1 Eugenio de Miguel,2

Rosa J. Torres,3 and Juan G. Puig1

1Division of Internal Medicine, Metabolic-Vascular Unit, La Paz University Hospital,Madrid, Spain2Division of Rheumatology and 3Biochemistry, La Paz University Hospital, Madrid, Spain

� Background and Objectives. Pharmacologic urate lowering therapy (ULT), at full maintenancedoses, has been associated with acute gout arthritis (in up to 80% of patients). The AmericanCollege of Rheumatology has recently advocated gradually titrating the maintenance dose upwardto chosen serum urate target. Few studies have examined the efficacy and safety of a ULT in primarygout. Patients and Methods. The ULT regimen examined included allopurinol (50 mg/day, withincreases of 50 mg/month up to 300 mg/day) and colchicine, as prophylaxis to prevent acute goutyattacks. The efficacy and safety of this regimen was examined in 42 patients in whom allopurinolwas withheld for ≥3 months and restarted after this assessment and followed up for 12 months. Theefficacy and safety of the ULT regimen was related to the serum urate decrease and to the incidenceof acute gout flares, respectively. Results. Fifty-nine patients (mean age 59 years, 56 men) withprimary 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, and2.5 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 acutearthritis episodes (17% of patients). Conclusions. A gradually titrated hypouricemic regimen for6 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 Garcıa, the research manager of the MetabolicVascular Unit, and its nursing staff (Ines Narillos and Arantxa Sanchez) for their excellent patient careand follow-up. We thank Almudena Ligos Dıaz for her assistance in preparing the manuscript.

Disclosure statement: All authors declare that they have no potential conflicts of interest.Address correspondence to Juan Garcıa Puig, MD, PhD, Servicio de Medicina Interna, Unidad

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

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Efficacy and Safety of a Urate Lowering Regimen in Primary Gout 175

INTRODUCTION

Urate lowering therapy (ULT) is the cornerstone of gout treatment.[1–3]

At standard therapeutic doses the xanthine oxidase inhibitors allopurinolor febuxostat commonly cause acute gout flares. During the first year ofULT acute gout flares have been reported in up to 80% of gout patients.[4–6]

Titration of ULT is not common clinical practice. However, the AmericanCollege of Rheumatology Association has recently advocated to graduallytitrating the ULT maintenance dose upward to chosen serum urate tar-get.[7–10] We do not know the optimal titrated hypouricemic regimen toachieve the desired serum urate level without relevant side effects. We hereinreport the efficacy and safety of a ULT regimen used at La Paz UniversityHospital.

PATIENTS AND METHODS

Patient’s Enrollment

This study is part of a project to assess the prevalence of urinary uric acidunderexcretion or normoexcretion in primary gout.[11] After the assessmentof 24-hour urine uric acid excretion gout, patients were treated with a ULTregimen. The efficacy and safety of this regimen was examined in patientsin whom allopurinol was withheld for ≥3 months to assess the condition ofnormal or diminished urinary uric acid excretion. Patients with primary goutwere recruited from the outpatient clinic of the Metabolic-Vascular Unit, Di-vision of Internal Medicine at La Paz University Hospital, Madrid. Primarygout was diagnosed according to the American Rheumatic Association crite-ria.[12] Comorbidities were assessed following the definition proposed by theEuropean Society of Hypertension.[13] Only patients with two or more acutearthritis 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 am-bulatory basis (n = 10), and unwillingness to participate (n = 9). A total of104 patients were considered for this study. Seventy-six patients had beentreated with allopurinol and none with febuxostat. Thus, 28 patients werenaıve gout patients. All studies were conducted according to local regula-tions and the Declaration of Helsinki and were approved by the InstitutionalResearch and Ethics Review Committees of La Paz University Hospital.

Urate Lowering Therapy

The ULT regimen used at La Paz University Hospital was empiricallyestablished from the clinical experience gained over the last 25 years withmore than 300 patients with primary gout that came to our attention due

176 R. Bailen et al.

to acute gout flares. The regimen consists on allopurinol (50 mg/day, withincreases of 50 mg each of 6 months up to 300 mg/day) and colchicineprescribed as prophylaxis against acute arthritis[14] (0.5 mg/12-hour forthe first 6 months followed by 0.5 mg/day for the next 6 months). Theefficacy and safety of this ULT regimen was related to the serum uratedecrease at 3, 6, 9, and 12 months and to the incidence of acute goutflares. The primary efficacy endpoint was reduction of serum urate levels to<6.0 mg/dL at month 12. Every three months, each patient underwent aphysical examination, vital signs were recorded and serum urate and renalfunction were assessed. Acute arthritis flares were purposely questioned (“Didyou have any articular problem since last visit?”) on each visit and registered bya physician.

RESULTS

Patient’s Characteristics

Fifty nine patients (53 males, 95%) with primary gout were included inthe study. Ten patients did not receive ULT following the metabolic studyand 7 patients did not complete the 12-month follow up period, thus render-ing 42 patients that completed the 52-week treatment period. The mean agewas 59.3 (range, 38 to 84 years). The most frequent comorbidities were arte-rial 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, sexratio, racial distribution, mean baseline serum urate concentration, and his-tory or presence of tophi were similar in gout patients that had or had not re-ceived allopurinol (Table 1). The mean serum urate level was 8.4 mg/dL, and6 (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 diminished1.8, 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 MedicalAssociation)[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. Ofthese, 7 patients had never been treated with allopurinol. Four acute goutflares 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

Efficacy and Safety of a Urate Lowering Regimen in Primary Gout 177

TABLE 1 Baseline characteristics of gout patients

Gout With previous No previouspatients ULT ULT(n = 59) (n = 36) (n = 23)

Age (years) 59.3 ± 8.0 59.1 ± 9.6 59.6 ± 11.3Men (%) 55 (95%) 33 (92%) 22 (96%)Body mass index (Kg/m2) 29.5 ± 3.1 29.2 ± 3.9 29.8 ± 4.3Associated conditions(a)

Smokers (%) 8 (14%) 2 (6%) 6 (26%)Alcohol abuse (%) 18 (30%) 9 (25%) 9 (39%)

Clinical atherosclerosisStroke (%) 2 (3%) 1 (3%) 1 (4%)Coronary arterial disease (%) 1 (2%) 1 (3%) 0 (0%)Peripheral arterial disease (%) 0 (0%) 0 (0%) 0 (0%)Renal insufficiency (%) 3 (5%) 3 (8%) 0 (0%)Arterial hipertension (%) 48 (81%) 29 (81%) 19 (83%)Left ventricular hypertrophy (%) 14 (24%) 10 (28%) 4 (17%)Type 2 diabetes mellitus (%) 14 (24%) 12 (33%)(b) 2 (9%)(b)

Hyperlipidemia (%) 34 (58%) 25 (69%)(b) 9 (39%)(b)

Obesity (%) 25 (42%) 18 (50%) 7 (30%)Metabolic syndrome (%) 23 (40%) 16 (44%) 7 (30%)

Gout characteristicsEstimated age at onset (years) 46.4 ± 11.0 46.2 ± 11.5 46.5 ± 15.9Estimated duration (years) 13.2 ± 9.0 13.1 ± 9.4 12.2 ± 2.5

Estimated number of acute gout flares (per year) 1.1 ± 1.2 1.0 ± 2.6 1.1 ± 2.1Renal lithiasis (%) 6 (8%) 4 (11%) 2 (9%)Tophi (%) 3 (5%) 3 (8%) 0 (0%)Upper limb involvement (%) 14 (24%) 7 (19%) 7 (0%)Lower limb involvement (%) 56 (95%) 34 (94%) 22 (96%)First MTP joint involvement (%) 35 (60%) 19 (53%) 16 (70%)Poliarticular involvement (%) 9 (15%) 7 (19%) 2 (9%)Baseline serum urate (purine free diet, mg/dL) 8.4 ± 1.1 8.7 ± 1.4(b) 7.9 ± 0.65(b)

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

(b) = p < 0.05

TABLE 2 Efficacy and safety of a urate lowering therapy regimen in primary gout patients

EfficacySerum urate <6.0 mg/dL at month 3 (%) 13(22%)Serum urate <6.0 mg/dL at month 12 (%) 38(68%)Percent change in serum urate concentration from baseline to

month 12 (mean % ± SD)43.5 ± 1.8

SafetyIncidence of gout flares (number of patients) 10(17%)Day 1 to month 2 (%) 1(2%)Month 3 (%) 3(5%)Month 4 to month 6 (%) 2(3%)Month 7 to month 9(%) 4(7%)Month 10 to month 12 (%) 0(0%)Articular pain (%) 7(12%)Diarrhea (%) 1(2%)

178 R. Bailen et al.

treated with NSAID and the colchicine dose was increased to 0.5 mg/12-hourfor 1 month. Seven patients reported articular pain, with no inflammationsigns; pain resolved in a few days without medication.

DISCUSSION

The ULT empirically used at La Paz University Hospital showed to be ef-fective and safe. Concerning efficacy, 38/59 (64%) of the patients achieved aserum urate level below 6 mg/dL at 12 months. This figure is notably higherthan 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 possibleexplanation to account for this difference is that being the administeredallopurinol dose identical (300 mg/day), their gouty patients had a bodymass 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 beensupposed that acute gout flares following ULT are due to urate crystal mobi-lization. A rapid lowering of serum urate concentration would increase theremoval of urate crystals. In contrast, it is conceivable that a slower rate ofserum urate reduction would diminish the removal of these deposits andthus cause less acute gout flares.

The most relevant finding of this study is that only 10/59 (17%) of thepatients had acute gout flares following the first year of ULT. Several studieshave reported acute gout flares in up to 80% of the patients for the first yearwhen ULT is started.[4] However, the reported studies differ from ours notonly in gout patients characteristics but also on the ULT regimens employedand on the prophylaxis used. Becker et al.[4] and Schumacher et al.[6] com-municated an incidence of acute gout flares (8 weeks from the start of ULT)with allopurinol of 21% and 23%, respectively, despite colchicine prophy-laxis. The corresponding figure in our study is 1/10 (10%). One explanationto account for this difference is the start dose of ULT, being 50 mg/day versus300 mg/day.[4,6] These studies reported to withheld gout flares prophylaxisafter month 2 of ULT initiation. We have treated many many (this is not amistake, but to emphasize the high amount of gout attacks that we have treated) acutearthritis episodes for the last 25 years and we have observed many acute goutflares with full allopurinol doses. Thus, we decided to prescribe colchicineprophylaxis for the first 12 months after the start of ULT. In fact, duringthe period from 2 to 12 months, we documented 9 acute gout flares among59 patients (15%). This figure contrast to an incidence of 64% reportedwithout gout prophylaxis in previous studies.[4,6] In addition to colchicineprophylaxis, another issue that may have contributed to this difference (15%versus 64%) is that 61% of our patients had received allopurinol therapy be-fore ULT was started. This contrast to the figure of 44% and 29% reportedin previous studies.[4,6] In this sense, it is remarkable that the CONFIRMStrial[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 naproxenprophylaxis. An additional difference is that only 5% of our gout populationhad tophi. This contrast with the higher prevalence of 25%[4] and 28%[6] inother studies with increased incidence of acute gout flares following ULT.It is widely known that tophaceous gout is much more prone to suffer goutattacks as compared to nontophaceous gout.

One limitation of this observational study is that the number of pa-tients included was about a third of the patients studied by Becker[4] andSchumacher[6] and all were Caucasic. Another limitation is that ULT wasempirically established. In addition, we had not evaluated the impact of thisULT regimen on tophi reduction, since only 3 patients had mild topha-ceous gout,[10] and on the comorbidities associated to primary gout[17] andsecondary gout.[18] Obviously, a more valid comparison would have been inthe context of a randomized clinical trial with different titration regimensand/or acute flare prophylaxis.

In summary, a gradually titrated hypouricemic regimen for 6 months inpatients with primary gout appears to be effective and safe, with a markedreduction in the incidence of acute gout arthritis episodes as compared withULT starting at full maintenance doses with limited prophylaxis.[4–9] Furtherstudies are needed to asses whether a more intensive ULT to achieve theserum urate target in a reduced period may be cost-effective with minimumside effects.

REFERENCES

1. Terkeltaub, R.A. Gout. N. Engl. J. Med. 2003, 349, 1647–1655.2. Moreland, L.W. Febuxostat: treatment for hyperuricemia and gout? New Engl. J. Med. 2005, 353,

2505–2507.3. Terkeltaub, R. Update in gout: new therapeutic strategies and options. Nat. Rev. Rheumatol. 2010, 6,

30–98.4. Becker, M.A.; Schumacher, H.R.; Wortmann, R.L.; MacDonald, P.A.; Eustace, D.; Palo, W.A.; Streit,

J.; Joseph-Ridge, N. Febuxostat compared with allopurinol in patients with hyperuricemia and gout.N. Engl. J. Med. 2005, 353, 2450–2461.

5. Becker, M.A.; Schumacher, H.R.; Espinoza, L.R.; Wells, A.F.; MacDonald, P.; Lloyd, E.; Lademacher,C. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout:the CONFIRMS trial. Arthritis Res. Ther. 2010, 12, R63.

6. Schumacher, H.R.; Becker, M.A.; Wortmann, R.L.; MacDonald, P.A.; Hunt, B.; Streit, J.; Lademacher,C.; Joseph-Ridge, N.; Effects of febuxostat versus allopurinol and placebo in reduncing serum urate insubjects with hiperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-grouptrial. Arth. Rheum. 2008, 59, 1540–1548.

7. Zhang, W.; Doherty, M.; Bardin, T.; Pascual, E; Barskova, V.; Conaghan, P.; Gerster, J.; Jacobs, J.;Leeb, B.; Liote, F.; McCarthy, G.; Netter, P.; Nuki, G.; Perez-Ruiz, F.; Pignone, A.; Pimentao, J.; Punzi,L.; Roddy, E.; Uhlig, T.; Zimmermann-Gorska, I. EULAR evidence based recommendations for gout.Part II: management. Report of a task force of the EULAR Standing Committee for InternationalClinical Studies Including Therapeutics (ESCISIT). Ann. Rheum. Dis. 2006, 65, 1312–1324.

8. Reinders, M.K.; van Roon, E.N.; Jansen, T.L.; Delsing, J.; Griep, E.N.; Hoekstra, M.; Hoekstra, M.; vande Laar, M.A.; Brouwers, J.R. Efficacy and tolerability of urate-lowering drugs in gout: a randomisedcontrolled trial of benzbromarone versus probenecid after failure of allopurinol. Ann. Rheum. Dis.2009, 68, 51–56.

180 R. Bailen et al.

9. Reinders, M.K.; Haagsma, C.; Jansen, T.L.; van Roon, E.N.; Delsing, J.; van de Laar, M.A.; Brouwers,J.R. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout. Ann. Rheum. Dis.2009, 68, 892–897.

10. Khanna, D.; Fitzgerald, J.D.; Khanna, P.P.; Bae, S.; Singh, M.K.; Neogi, T.; Pillinger, M.H.; Merill, J.;Lee, S.; Prakash, S.; Kaldas, M.; Gogia, M.; Perez-Ruiz, F.; Taylor, W.; Liote, F.; Choi, H.; Singh, J.A.;Dalbeth, N.; Kaplan, S.; Niyyar, V.; Jones, D.; Yarows, S.A.; Roessler, B.; Kerr, G.; King, C.; Levy, G.;Furst, D.E.; Edwards, N.L.; Mandell, B.; Schumacher, H.R.; Robbins M.; Wenger, N.; Terkeltaub, R.2012 American College of Rheumatology Guidelines for management of gout. Part 1: systematic nopharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arth. Care Res. 2012,64, 1431–1446.

11. Puig, J.G.; Torres, R.J.; de Miguel, E.; Sanchez, A.; Bailen, R.; Banegas, J.R. Uric acid excretionin normal subjects: a nomogram to assess the mechanisms underlying purine metabolic disorders.Metabolism. 2012, 61, 512–518.

12. Wallace, S.L.; Robinson, H.; Masi, A.T.; Decker, J.L.; McCarty, D.J.; Yu, T.F. Preliminary criteria forthe classification of the acute arthritis of primary gout. Arthritis Rheum. 1977, 20, 895–900.

13. Mancia, G.; De Backer, G.; Dominiczak, A.; Cifkova, R.; Fagard, R.; Germano, G.; Grassi, G.; Hea-gerty, A.M.; Kjeldsen, S.E.; Laurent, S.; Narkiewicz, K.; Ruilope, L.; Rynkiewicz, A.; Schmieder, R.E.;Boudier, H.A.; Zanchetti, A.; ESH-ESC task force on the management of arterial hypertension. J.Hypertens 2007, 25, 1751–1762.

14. Borstad, G.C.; Bryant, L.R.; Abel, M.P.; Scroggie, D.A.; Harris, M.D.; Alloway, J.A. Colchicine forprophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J. Rheumatol. 2004,31, 2429–2432.

15. Grundy, S.M.; Brewer, H.B.; Clleman, J.I.; Smith, S.C.; Lenfant, C.; American Heart Association,National Heart, Lung and Blood Institute. Definition of metabolic syndrome: report of the NationalHeart, Lung, and Blood Institute/American Heart Association conference on scientific issues relatedto definition. Circulation. 2004, 27, 433–438.

16. Khanna, D.; Fitzgerald, J.D.; Khanna, P.P.; Bae, S.; Singh, M.K.; Neogi, T.; Pillinger, M.H.; Merill, J.;Lee, S.; Prakash, S.; Kaldas, M.; Gogia, M.; Perez-Ruiz, F.; Taylor, W.; Liote, F.; Choi, H.; Singh, J.A.;Dalbeth, N.; Kaplan, S.; Niyyar, V.; Jones, D.; Yarows, S.A.; Roessler, B.; Kerr, G.; King, C.; Levy, G.;Furst, D.E.; Edwards, N.L.; Mandell, B.; Schumacher, H.R.; Robbins, M.; Wenger, N.; Terkeltaub, R.;American College of Rheumatology. 2012 American College of Rheumatology guidelines for man-agement of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approachesto hyperuricemia. Arthritis. Care Res. 2012, 64, 1431–1446.

17. Lopez-Jimenez, M.; Vigil-Medina, L.; Condes-Moreno, E.; Garcıa-Carretero, R.; Fernandez-Mejıas, C.Ruiz-Galiana, J. Uricemia and metabolic syndrome in patients with arterial hypertension. Rev. Clin.Esp. 2012, 212, 425–431.

18. Casado, J.; Montero, M.; Formiga, F.; Camafort, M.; Sanchez, C.; Muela, A.; Dıez, J.; Perez, J.I.;Grupo RICA. Renal function in patients with heart failure: prognostic value. Rev. Clin. Esp. 2012,212, 119–126.

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