Objectives: To systematically review the literature on effect of initiating urate lowering treatment (ULT) during an acute attack of gout on duration of index attack and persistence on ULT.

Methods: OVID (MEDLINE), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation during acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardised mean difference (SMD) and relative risk (RR) were used to pool continuous and categorical data. Meta-analysis was carried out using STATA v14. 

Results: 537 studies were selected. 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evidence from two high quality studies that early initiation of allopurinol did not increase pain severity at days 10 to 15 (SMDpooled (95%CI) 0.18(-0.58, 0.93)). Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with drop-outs (RRpooled (95%CI) 1.16(0.58, 2.31)).

Conclusion: There is moderate-quality evidence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT discontinuation. Larger studies are required to confirm these findings so that patients with acute gout can be initiated on ULT with confidence

A. Abhishek

Adrian Jones

D Khanna

EM Hill

Fatma Eminaga

Jonathan Le-Carratt

KM Jordan

PP Khanna

R Seth

RC Fraser

TH Taylor

W Zhang

X Feng

PubMed

Objectives: To systematically review the literature on effect of initiating urate lowering treatment (ULT) during an acute attack of gout on duration of index attack and persistence on ULT.Methods: OVID (MEDLINE), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation during acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardised mean difference (SMD) and relative risk (RR) were used to pool continuous and categorical data. Meta-analysis was carried out using STATA v14. Results: 537 studies were selected. 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evidence from two high quality studies that early initiation of allopurinol did not increase pain severity at days 10 to 15 (SMDpooled (95%CI) 0.18(-0.58, 0.93)). Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with drop-outs (RRpooled (95%CI) 1.16(0.58, 2.31)).Conclusion: There is moderate-quality evidence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT discontinuation. Larger studies are required to confirm these findings so that patients with acute gout can be initiated on ULT with confidence

Eminaga, Fatma

Le-Carratt, Jonathan

Jones, Adrian

Abhishek, A.

Repository@Nottingham

1 3Rheumatol IntDOI 10.1007/s00296-016-3579-zRheumatologyINTERNATIONAL OBSERVATIONAL RESEARCHDoes the initiation of urate‑lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature reviewFatma Eminaga1 · Jonathan Le‑Carratt1 · Adrian Jones1 · A. Abhishek1,2 Received: 18 June 2016 / Accepted: 12 October 2016 © The Author(s) 2016. This article is published with open access at Springerlink.comfindings so that patients with acute gout can be initiated on ULT with confidence.Keywords Acute gout · Urate-lowering treatment · Systematic reviewIntroductionGout is the commonest inflammatory arthritis and results from monosodium urate (MSU) crystal deposition. It is the only arthritis that has the potential of being cured if the serum uric acid is reduced to <360 µmol/L persistently with effective urate-lowering treatment (ULT) [1]. Guidelines for the management of gout recommend that patients con-tinue on ULT during a gout attack, but provide conflicting recommendations on whether ULT can be started during an acute attack [1–3]. For example, while the British Society for Rheumatology (BSR) and European League Against Rheumatism (EULAR) guidelines suggest commencing ULT 1–2 weeks after the acute attack has resolved, the 2012 American College of Rheumatology (ACR) guide-lines suggest that ULT may be started during an acute attack [1–3]. However, these recommendations are discord-ant, and the latest Cochrane review did not examine the effect of ULT initiation during an acute attack of gout on its duration and severity [4]. Thus, further research is required to examine whether ULT can be initiated during an acute gout attack, without unduly prolonging the index episode.The objectives of this study were to systematically review the literature to identify studies examining the effect of initiation of ULT during an acute gout attack on severity of the index episode, recurrent gout attacks, persistence on ULT and to conduct a meta-analysis to provide estimate of the effects.Abstract The aim of this study was to systematically review the literature on effect of initiating urate-lowering treatment (ULT) during an acute attack of gout on dura-tion of index attack and persistence on ULT. OVID (Med-line), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation dur-ing acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardized mean difference (SMD) and relative risk (RR) were used to pool continuous and cat-egorical data. Meta-analysis was carried out using STATA version 14. A total of 537 studies were selected. A total of 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evi-dence from two high-quality studies that early initiation of allopurinol did not increase pain severity at days 10–15 [SMDpooled (95 % CI) 0.18 (−0.58, 0.93)]. Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with dropouts [RRpooled (95 % CI) 1.16 (0.58, 2.31)]. There is moderate-quality evi-dence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT dis-continuation. Larger studies are required to confirm these Electronic supplementary material The online version of this article (doi:10.1007/s00296-016-3579-z) contains supplementary material, which is available to authorized users. * A. Abhishek  Abhishek.abhishek@nottingham.ac.uk1 Department of Medicine, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK2 Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham NG5 1PB, UK Rheumatol Int1 3MethodsLiterature searchMeSH terms were used to identify randomized controlled trials (RCTs) of ULT for gout in OVID (Medline) R 1946–week 4 October 2015, EMBASE (1974–week 44, 2015) and AMED (1985–October 2015). Reference lists of eligi-ble studies, ACR, EULAR, BSR guidelines and Cochrane systematic reviews of pharmacologic treatment of gout were hand searched. We restricted our search to studies in English. PubMed was searched using free text terms com-bining each ULT (allopurinol, febuxostat, benzbromarone and probenecid, etc.) and “acute gout” to identify any addi-tional studies.Inclusion criteriaInitiation of any ULT in patients with acute gout (either new diagnosis or long-standing gout) and ≥18 years in age.Exclusion criteriaUp-titration of ULT dose during an acute attack, ULT ini-tiation in the intercritical period, animal studies and confer-ence abstracts.Study selectionThe titles and abstracts of retrieved studies were inde-pendently reviewed by two reviewers. Full text articles were obtained if more information was required to decide eligibility.Quality assessmentTwo independent reviewers appraised the selected stud-ies for quality. Studies were evaluated using the Cochrane assessing risk of bias tool and Jadad score. Any disagree-ment was resolved after discussion with independent reviewer. The quality of evidence was assessed using the Cochrane collaborations’ GRADE tool.Data extractionData extraction was performed independently by two reviewers. Discrepancies were resolved after discussion with an independent reviewer. For each study, review-ers extracted data that were deemed to potentially impact efficacy outcomes, such as study population (percent men, mean age, disease duration, serum uric acid), study design (dose of ULT, initial treatment of gout attack, gout attack prophylaxis) and outcomes (total duration of gout attack, recurrent gout attacks, pain severity, ULT discontinuation). For continuous outcomes, data were pooled with the stand-ardized mean difference (SMD) of the final value across groups. For dichotomous data, the relative risk (RR) and 95 % confidence interval (CI) were calculated. Meta-anal-ysis was performed using the random effect model. I2 was calculated to assess heterogeneity. Meta-analysis was car-ried out using STATA version 14.ResultsThree studies were eligible to be included in this system-atic review (Fig. 1) [5–7]. Their details are in Table S1. Two of these studies were of high quality according to the Cochrane assessing risk of bias tool (Table 1). Data from only the first 28 days from one of the studies could be included [5] as that study compared the effect of azapropa-zone (a uricosuric anti-inflammatory drug) or regular indo-methacin followed by delayed initiation of allopurinol on day 28, on treatment of the acute attack of gout and in pre-venting recurrent gout attacks [5]. Patients initially rand-omized to indomethacin were required to discontinue indo-methacin and start allopurinol on day 28, which resulted in only part of the data being eligible for included in this systematic review.Duration of gout attackInformation on duration of gout attack was only pro-vided in one study and did not differ significantly between the allopurinol and placebo arms [17 (8.53) vs. 12.53 (7.73) days], p = 0.13 (intention to treat analysis) [7]. Authors of other studies were contacted, but were unable to provide any additional unpublished data on the duration of gout attack.Pain visual analogue score (VAS) by day 10Information on pain VAS on day 10 was published in one paper [6] and was obtained by contacting the authors of another study [7]. In the latter study, pain VAS was meas-ured between days 10 and 15 [7]. On pooling the data, there was no evidence to suggest that early initiation of ULT associated with pain; however, there was substantial heterogeneity, with I2 = 64 % (Fig. 2a). There was no evi-dence of a publication bias (Figure S1).Recurrent gout attacksThe comparison groups and end points were heteroge-neous and did not allow for pooling of data on recur-rent gout attacks. In the study comparing early versus Rheumatol Int 1 3delayed initiation of allopurinol, the number of patients with acute gout attacks was comparable in the early (7.7 %) and delayed (12 %) initiation arms at 28 days [6]. Only 1 patient commenced on allopurinol had a flare of acute gout in the Hill et al.’s [7] study; however, the other group was only given placebo, which would not be expected to trigger acute gout. In the study by Fraser et al. [5], there was one acute attack of gout in the first 28 days in those randomized to azapropazone, while there were 5 acute attacks of gout in those randomized to indomethacin.Dropouts/medication adherenceInformation on dropouts by day 28 [5, 6]–30 [7] was available for all three studies. Hill et al. [7] reported that the dropout rate was comparable by day 10 (1/16 allopu-rinol vs. 1/19 placebo). Meta-analysis of included studies showed that early ULT initiation did not associate with excessive dropouts (Fig. 2b). However, although the num-ber of studies was limited, there seemed to be publication bias for this outcome (Figure S1).Adverse eventsThe adverse event rates were comparable in those com-menced on ULT during an acute attack of gout (Table S2).Inflammation markersData on C-reactive protein and erythrocyte sedimentation rates in the follow-up period were only reported in one study and demonstrated a nonsignificant reduction in CRP and ESR at days 10 and 30 in those initiated on allopurinol during an acute attack of gout [6].DiscussionThis systematic review collected evidence from all RCTs of ULT initiation during acute gout attack published in the English language. We retrieved 3 trials, including 185 gout patients initiated on allopurinol [6, 7] or azapropazone [5] during a gout attack. Two trials were at low [6, 7] and one [5] at unclear risk of bias. However, the studies provide moderate-quality evidence due to small sample size [6, 7] or lack of suitable control group [5].Our findings imply that ULT initiated during an acute gout attack does not prolong the index attack. However, there was significant heterogeneity in the findings of the included studies [6, 7]. This may be due to the fact that the treatment of acute gout was not standardized in one study [7], and the disease characteristics of gout patients in the studies by Taylor et al. and Hill et al. were differ-ent. For example, patients in the study by Taylor et al. had Fig. 1  Flowchart summarizing study selection Rheumatol Int1 3milder disease (more likely to be presenting with gout for the first time) and did not have tophaceous gout, while those in the study by Hill et al. frequently had tophaceous gout [6, 7]. This suggests that the initiation of ULT dur-ing an acute attack of gout may be safer in patients with early stages of gout than in those with advanced topha-ceous gout.Apart from this, dropout rates in the early ULT initia-tion group and placebo or delayed ULT initiation groups were comparable, suggesting that ULT initiated during an acute gout attack is well tolerated. However, although not statistically significant, the dropout rates in early ULT initiation group were higher in one study in which allopurinol was started at 300 mg/day [6], compared to the study in which allopurinol was initiated at 100 mg/day as per the ACR and EULAR recommendations [7], suggesting that ULT should be initiated at a low dose and up-titrated gradually. The difference in dropout rates between the two studies is not likely to be due to treat-ment of acute attack of gout, as both NSAIDs and corti-costeroids are equally effective in treating acute attacks [8].A hospital-based retrospective study which examined the effect of initiation of ULT during an acute gout attack reported that patients commenced on ULT during an acute attack were significantly more likely to meet the SUA target earlier and less likely to have chronic kidney dis-ease in the long term [9]. However, the findings of this study may be biased due to its retrospective observational nature.Initiation of ULT during a gout attack can increase ULT prescription rates. This is as symptoms of gout are initially intermittent, and many patients do not return for ULT after the acute attack has resolved. Thus, early ini-tiation of ULT can improve overall gout treatment and reduce healthcare cost by avoiding further visits to initiate ULT.In summary, ULT initiated during an acute gout attack is well tolerated and does not prolong the index episode. However, there are several caveats to this study, namely, small sample size of included studies, heterogeneous study population and nonstandardized treatment of acute gout in one study and allopurinol initiation at a high dose in another study. Similarly, in the absence of individual patient data, and the fact that two of the three studies included in this systematic review did not report data on inflammatory markers during the follow-up period, we are unable to examine the relationship between (a) reduc-tion in serum uric acid levels and changes in pain VAS and (b) early initiation of ULT and reduction in inflamma-tion. Thus, further adequately powered studies that exam-ine the effect of initiating slow up-titrated ULT during an acute attack of gout on index attack duration and severity Table 1  Quality of included studies according to the risk of bias assessment tool and Jadad scoreRandom sequence generation (selection bias)Allocation conceal-ment (selection bias)Blinding of partici-pants and personnel (performance bias)Blinding of out-come assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reporting bias)Other biasesJadad scoreQuality of evidence (GRADE scheme)Hill++++−−−/−5/5MTaylor++++−−−/−5/5MFraser??++−−−/−4/5MRheumatol Int 1 3are needed before this strategy of ULT initiation can be widely implemented.Compliance with ethical standards Conflict of interest Dr A Abhishek has received research funding from AstraZeneca and Oxford Immunotec. Other authors do not report a conflict of interest.Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.Open Access This article is distributed under the terms of the Crea-tive Commons Attribution 4.0 International License (http://crea-tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Fig. 2  Forest plot showing effect of early initiation of ULT on a pain at day 10 (top panel) and b dropouts (lower panel) Rheumatol Int1 3References 1. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Cona-ghan P et al (2006) EULAR evidence based recommenda-tions for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 65:1312–1324 2. Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J et al (2007) British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the manage-ment of gout. Rheumatology 46:1372–1374 3. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T et al (2012) 2012 American College of Rheumatology guide-lines for management of gout. Part 2: therapy and antiinflam-matory prophylaxis of acute gouty arthritis. Arthritis Care Res 64:1447–1461 4. Seth R, Kydd AS, Buchbinder R, Bombardier C, Edwards CJ (2014) Allopurinol for chronic gout. Cochrane Database Syst Rev 10:CD006077 5. Fraser RC, Davis RH, Walker FS (1987) Comparative trial of azapropazone and indomethacin plus allopurinol in acute gout and hyperuricaemia. J R Coll Gen Pract 37:409–411 6. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA (2012) Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med 125(1126–34):e7 7. Hill EM, Sky K, Sit M, Collamer A, Higgs J (2015) Does start-ing allopurinol prolong acute treated gout? A randomized clini-cal trial. J Clin Rheumatol 21:120–125 8. Khanna PP, Gladue HS, Singh MK, FitzGerald JD, Bae S, Prakash S et al (2014) Treatment of acute gout: a systematic review. Sem Arthritis Rheum 44:31–38 9. Feng X, Li Y, Gao W (2015) Significance of the initiation time of urate-lowering therapy in gout patients: a retrospective research. Joint Bone Spine 82:428–431

Does the initiation of urate-lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review

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1 3Rheumatol Int (2016) 36:1747–1752DOI 10.1007/s00296-016-3579-zRheumatologyINTERNATIONAL OBSERVATIONAL RESEARCHDoes the initiation of urate‑lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature reviewFatma Eminaga1 · Jonathan Le‑Carratt1 · Adrian Jones1 · A. Abhishek1,2 Received: 18 June 2016 / Accepted: 12 October 2016 / Published online: 19 October 2016 © The Author(s) 2016. This article is published with open access at Springerlink.comfindings so that patients with acute gout can be initiated on ULT with confidence.Keywords Acute gout · Urate-lowering treatment · Systematic reviewIntroductionGout is the commonest inflammatory arthritis and results from monosodium urate (MSU) crystal deposition. It is the only arthritis that has the potential of being cured if the serum uric acid is reduced to <360 µmol/L persistently with effective urate-lowering treatment (ULT) [1]. Guidelines for the management of gout recommend that patients con-tinue on ULT during a gout attack, but provide conflicting recommendations on whether ULT can be started during an acute attack [1–3]. For example, while the British Society for Rheumatology (BSR) and European League Against Rheumatism (EULAR) guidelines suggest commencing ULT 1–2 weeks after the acute attack has resolved, the 2012 American College of Rheumatology (ACR) guide-lines suggest that ULT may be started during an acute attack [1–3]. However, these recommendations are discord-ant, and the latest Cochrane review did not examine the effect of ULT initiation during an acute attack of gout on its duration and severity [4]. Thus, further research is required to examine whether ULT can be initiated during an acute gout attack, without unduly prolonging the index episode.The objectives of this study were to systematically review the literature to identify studies examining the effect of initiation of ULT during an acute gout attack on severity of the index episode, recurrent gout attacks, persistence on ULT and to conduct a meta-analysis to provide estimate of the effects.Abstract The aim of this study was to systematically review the literature on effect of initiating urate-lowering treatment (ULT) during an acute attack of gout on dura-tion of index attack and persistence on ULT. OVID (Med-line), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation dur-ing acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardized mean difference (SMD) and relative risk (RR) were used to pool continuous and cat-egorical data. Meta-analysis was carried out using STATA version 14. A total of 537 studies were selected. A total of 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evi-dence from two high-quality studies that early initiation of allopurinol did not increase pain severity at days 10–15 [SMDpooled (95 % CI) 0.18 (−0.58, 0.93)]. Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with dropouts [RRpooled (95 % CI) 1.16 (0.58, 2.31)]. There is moderate-quality evi-dence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT dis-continuation. Larger studies are required to confirm these Electronic supplementary material The online version of this article (doi:10.1007/s00296-016-3579-z) contains supplementary material, which is available to authorized users. * A. Abhishek  Abhishek.abhishek@nottingham.ac.uk1 Department of Medicine, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK2 Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham NG5 1PB, UK1748 Rheumatol Int (2016) 36:1747–17521 3MethodsLiterature searchMeSH terms were used to identify randomized controlled trials (RCTs) of ULT for gout in OVID (Medline) R 1946–week 4 October 2015, EMBASE (1974–week 44, 2015) and AMED (1985–October 2015). Reference lists of eligi-ble studies, ACR, EULAR, BSR guidelines and Cochrane systematic reviews of pharmacologic treatment of gout were hand searched. We restricted our search to studies in English. PubMed was searched using free text terms com-bining each ULT (allopurinol, febuxostat, benzbromarone and probenecid, etc.) and “acute gout” to identify any addi-tional studies.Inclusion criteriaInitiation of any ULT in patients with acute gout (either new diagnosis or long-standing gout) and ≥18 years in age.Exclusion criteriaUp-titration of ULT dose during an acute attack, ULT ini-tiation in the intercritical period, animal studies and confer-ence abstracts.Study selectionThe titles and abstracts of retrieved studies were inde-pendently reviewed by two reviewers. Full text articles were obtained if more information was required to decide eligibility.Quality assessmentTwo independent reviewers appraised the selected stud-ies for quality. Studies were evaluated using the Cochrane assessing risk of bias tool and Jadad score. Any disagree-ment was resolved after discussion with independent reviewer. The quality of evidence was assessed using the Cochrane collaborations’ GRADE tool.Data extractionData extraction was performed independently by two reviewers. Discrepancies were resolved after discussion with an independent reviewer. For each study, review-ers extracted data that were deemed to potentially impact efficacy outcomes, such as study population (percent men, mean age, disease duration, serum uric acid), study design (dose of ULT, initial treatment of gout attack, gout attack prophylaxis) and outcomes (total duration of gout attack, recurrent gout attacks, pain severity, ULT discontinuation). For continuous outcomes, data were pooled with the stand-ardized mean difference (SMD) of the final value across groups. For dichotomous data, the relative risk (RR) and 95 % confidence interval (CI) were calculated. Meta-anal-ysis was performed using the random effect model. I2 was calculated to assess heterogeneity. Meta-analysis was car-ried out using STATA version 14.ResultsThree studies were eligible to be included in this system-atic review (Fig. 1) [5–7]. Their details are in Table S1. Two of these studies were of high quality according to the Cochrane assessing risk of bias tool (Table 1). Data from only the first 28 days from one of the studies could be included [5] as that study compared the effect of azapropa-zone (a uricosuric anti-inflammatory drug) or regular indo-methacin followed by delayed initiation of allopurinol on day 28, on treatment of the acute attack of gout and in pre-venting recurrent gout attacks [5]. Patients initially rand-omized to indomethacin were required to discontinue indo-methacin and start allopurinol on day 28, which resulted in only part of the data being eligible for included in this systematic review.Duration of gout attackInformation on duration of gout attack was only pro-vided in one study and did not differ significantly between the allopurinol and placebo arms [17 (8.53) vs. 12.53 (7.73) days], p = 0.13 (intention to treat analysis) [7]. Authors of other studies were contacted, but were unable to provide any additional unpublished data on the duration of gout attack.Pain visual analogue score (VAS) by day 10Information on pain VAS on day 10 was published in one paper [6] and was obtained by contacting the authors of another study [7]. In the latter study, pain VAS was meas-ured between days 10 and 15 [7]. On pooling the data, there was no evidence to suggest that early initiation of ULT associated with pain; however, there was substantial heterogeneity, with I2 = 64 % (Fig. 2a). There was no evi-dence of a publication bias (Figure S1).Recurrent gout attacksThe comparison groups and end points were heteroge-neous and did not allow for pooling of data on recur-rent gout attacks. In the study comparing early versus 1749Rheumatol Int (2016) 36:1747–1752 1 3delayed initiation of allopurinol, the number of patients with acute gout attacks was comparable in the early (7.7 %) and delayed (12 %) initiation arms at 28 days [6]. Only 1 patient commenced on allopurinol had a flare of acute gout in the Hill et al.’s [7] study; however, the other group was only given placebo, which would not be expected to trigger acute gout. In the study by Fraser et al. [5], there was one acute attack of gout in the first 28 days in those randomized to azapropazone, while there were 5 acute attacks of gout in those randomized to indomethacin.Dropouts/medication adherenceInformation on dropouts by day 28 [5, 6]–30 [7] was available for all three studies. Hill et al. [7] reported that the dropout rate was comparable by day 10 (1/16 allopu-rinol vs. 1/19 placebo). Meta-analysis of included studies showed that early ULT initiation did not associate with excessive dropouts (Fig. 2b). However, although the num-ber of studies was limited, there seemed to be publication bias for this outcome (Figure S1).Adverse eventsThe adverse event rates were comparable in those com-menced on ULT during an acute attack of gout (Table S2).Inflammation markersData on C-reactive protein and erythrocyte sedimentation rates in the follow-up period were only reported in one study and demonstrated a nonsignificant reduction in CRP and ESR at days 10 and 30 in those initiated on allopurinol during an acute attack of gout [6].DiscussionThis systematic review collected evidence from all RCTs of ULT initiation during acute gout attack published in the English language. We retrieved 3 trials, including 185 gout patients initiated on allopurinol [6, 7] or azapropazone [5] during a gout attack. Two trials were at low [6, 7] and one [5] at unclear risk of bias. However, the studies provide moderate-quality evidence due to small sample size [6, 7] or lack of suitable control group [5].Our findings imply that ULT initiated during an acute gout attack does not prolong the index attack. However, there was significant heterogeneity in the findings of the included studies [6, 7]. This may be due to the fact that the treatment of acute gout was not standardized in one study [7], and the disease characteristics of gout patients in the studies by Taylor et al. and Hill et al. were differ-ent. For example, patients in the study by Taylor et al. had Fig. 1  Flowchart summarizing study selection1750 Rheumatol Int (2016) 36:1747–17521 3milder disease (more likely to be presenting with gout for the first time) and did not have tophaceous gout, while those in the study by Hill et al. frequently had tophaceous gout [6, 7]. This suggests that the initiation of ULT dur-ing an acute attack of gout may be safer in patients with early stages of gout than in those with advanced topha-ceous gout.Apart from this, dropout rates in the early ULT initia-tion group and placebo or delayed ULT initiation groups were comparable, suggesting that ULT initiated during an acute gout attack is well tolerated. However, although not statistically significant, the dropout rates in early ULT initiation group were higher in one study in which allopurinol was started at 300 mg/day [6], compared to the study in which allopurinol was initiated at 100 mg/day as per the ACR and EULAR recommendations [7], suggesting that ULT should be initiated at a low dose and up-titrated gradually. The difference in dropout rates between the two studies is not likely to be due to treat-ment of acute attack of gout, as both NSAIDs and corti-costeroids are equally effective in treating acute attacks [8].A hospital-based retrospective study which examined the effect of initiation of ULT during an acute gout attack reported that patients commenced on ULT during an acute attack were significantly more likely to meet the SUA target earlier and less likely to have chronic kidney dis-ease in the long term [9]. However, the findings of this study may be biased due to its retrospective observational nature.Initiation of ULT during a gout attack can increase ULT prescription rates. This is as symptoms of gout are initially intermittent, and many patients do not return for ULT after the acute attack has resolved. Thus, early ini-tiation of ULT can improve overall gout treatment and reduce healthcare cost by avoiding further visits to initiate ULT.In summary, ULT initiated during an acute gout attack is well tolerated and does not prolong the index episode. However, there are several caveats to this study, namely, small sample size of included studies, heterogeneous study population and nonstandardized treatment of acute gout in one study and allopurinol initiation at a high dose in another study. Similarly, in the absence of individual patient data, and the fact that two of the three studies included in this systematic review did not report data on inflammatory markers during the follow-up period, we are unable to examine the relationship between (a) reduc-tion in serum uric acid levels and changes in pain VAS and (b) early initiation of ULT and reduction in inflamma-tion. Thus, further adequately powered studies that exam-ine the effect of initiating slow up-titrated ULT during an acute attack of gout on index attack duration and severity Table 1  Quality of included studies according to the risk of bias assessment tool and Jadad scoreRandom sequence generation (selection bias)Allocation conceal-ment (selection bias)Blinding of partici-pants and personnel (performance bias)Blinding of out-come assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reporting bias)Other biasesJadad scoreQuality of evidence (GRADE scheme)Hill++++−−−/−5/5MTaylor++++−−−/−5/5MFraser??++−−−/−4/5M1751Rheumatol Int (2016) 36:1747–1752 1 3are needed before this strategy of ULT initiation can be widely implemented.Compliance with ethical standards Conflict of interest Dr A Abhishek has received research funding from AstraZeneca and Oxford Immunotec. Other authors do not report a conflict of interest.Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.Open Access This article is distributed under the terms of the Crea-tive Commons Attribution 4.0 International License (http://crea-tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Fig. 2  Forest plot showing effect of early initiation of ULT on a pain at day 10 (top panel) and b dropouts (lower panel)1752 Rheumatol Int (2016) 36:1747–17521 3References 1. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Cona-ghan P et al (2006) EULAR evidence based recommenda-tions for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 65:1312–1324 2. Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J et al (2007) British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the manage-ment of gout. Rheumatology 46:1372–1374 3. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T et al (2012) 2012 American College of Rheumatology guide-lines for management of gout. Part 2: therapy and antiinflam-matory prophylaxis of acute gouty arthritis. Arthritis Care Res 64:1447–1461 4. Seth R, Kydd AS, Buchbinder R, Bombardier C, Edwards CJ (2014) Allopurinol for chronic gout. Cochrane Database Syst Rev 10:CD006077 5. Fraser RC, Davis RH, Walker FS (1987) Comparative trial of azapropazone and indomethacin plus allopurinol in acute gout and hyperuricaemia. J R Coll Gen Pract 37:409–411 6. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA (2012) Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med 125(1126–34):e7 7. Hill EM, Sky K, Sit M, Collamer A, Higgs J (2015) Does start-ing allopurinol prolong acute treated gout? A randomized clini-cal trial. J Clin Rheumatol 21:120–125 8. Khanna PP, Gladue HS, Singh MK, FitzGerald JD, Bae S, Prakash S et al (2014) Treatment of acute gout: a systematic review. Sem Arthritis Rheum 44:31–38 9. Feng X, Li Y, Gao W (2015) Significance of the initiation time of urate-lowering therapy in gout patients: a retrospective research. Joint Bone Spine 82:428–431

Rheumatology International

Abhishek, Abhishek

Nottingham ePrints

Eminaga, Fatma and Le-Carratt, Jonathan and Jones, Adrian and Abhishek, Abhishek (2016) Does the initiation of urate lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review. Rheumatology International . ISSN 1437-160X Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/37912/7/art%253A10.1007%252Fs00296-016-3579-z.pdfCopyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions.This article is made available under the Creative Commons Attribution licence and may be reused according to the conditions of the licence.  For more details see: http://creativecommons.org/licenses/by/2.5/A note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk1 3Rheumatol IntDOI 10.1007/s00296-016-3579-zRheumatologyINTERNATIONAL OBSERVATIONAL RESEARCHDoes the initiation of urate‑lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature reviewFatma Eminaga1 · Jonathan Le‑Carratt1 · Adrian Jones1 · A. Abhishek1,2 Received: 18 June 2016 / Accepted: 12 October 2016 © The Author(s) 2016. This article is published with open access at Springerlink.comfindings so that patients with acute gout can be initiated on ULT with confidence.Keywords Acute gout · Urate-lowering treatment · Systematic reviewIntroductionGout is the commonest inflammatory arthritis and results from monosodium urate (MSU) crystal deposition. It is the only arthritis that has the potential of being cured if the serum uric acid is reduced to <360 µmol/L persistently with effective urate-lowering treatment (ULT) [1]. Guidelines for the management of gout recommend that patients con-tinue on ULT during a gout attack, but provide conflicting recommendations on whether ULT can be started during an acute attack [1–3]. For example, while the British Society for Rheumatology (BSR) and European League Against Rheumatism (EULAR) guidelines suggest commencing ULT 1–2 weeks after the acute attack has resolved, the 2012 American College of Rheumatology (ACR) guide-lines suggest that ULT may be started during an acute attack [1–3]. However, these recommendations are discord-ant, and the latest Cochrane review did not examine the effect of ULT initiation during an acute attack of gout on its duration and severity [4]. Thus, further research is required to examine whether ULT can be initiated during an acute gout attack, without unduly prolonging the index episode.The objectives of this study were to systematically review the literature to identify studies examining the effect of initiation of ULT during an acute gout attack on severity of the index episode, recurrent gout attacks, persistence on ULT and to conduct a meta-analysis to provide estimate of the effects.Abstract The aim of this study was to systematically review the literature on effect of initiating urate-lowering treatment (ULT) during an acute attack of gout on dura-tion of index attack and persistence on ULT. OVID (Med-line), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation dur-ing acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardized mean difference (SMD) and relative risk (RR) were used to pool continuous and cat-egorical data. Meta-analysis was carried out using STATA version 14. A total of 537 studies were selected. A total of 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evi-dence from two high-quality studies that early initiation of allopurinol did not increase pain severity at days 10–15 [SMDpooled (95 % CI) 0.18 (−0.58, 0.93)]. Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with dropouts [RRpooled (95 % CI) 1.16 (0.58, 2.31)]. There is moderate-quality evi-dence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT dis-continuation. Larger studies are required to confirm these Electronic supplementary material The online version of this article (doi:10.1007/s00296-016-3579-z) contains supplementary material, which is available to authorized users. * A. Abhishek  Abhishek.abhishek@nottingham.ac.uk1 Department of Medicine, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK2 Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham NG5 1PB, UK Rheumatol Int1 3MethodsLiterature searchMeSH terms were used to identify randomized controlled trials (RCTs) of ULT for gout in OVID (Medline) R 1946–week 4 October 2015, EMBASE (1974–week 44, 2015) and AMED (1985–October 2015). Reference lists of eligi-ble studies, ACR, EULAR, BSR guidelines and Cochrane systematic reviews of pharmacologic treatment of gout were hand searched. We restricted our search to studies in English. PubMed was searched using free text terms com-bining each ULT (allopurinol, febuxostat, benzbromarone and probenecid, etc.) and “acute gout” to identify any addi-tional studies.Inclusion criteriaInitiation of any ULT in patients with acute gout (either new diagnosis or long-standing gout) and ≥18 years in age.Exclusion criteriaUp-titration of ULT dose during an acute attack, ULT ini-tiation in the intercritical period, animal studies and confer-ence abstracts.Study selectionThe titles and abstracts of retrieved studies were inde-pendently reviewed by two reviewers. Full text articles were obtained if more information was required to decide eligibility.Quality assessmentTwo independent reviewers appraised the selected stud-ies for quality. Studies were evaluated using the Cochrane assessing risk of bias tool and Jadad score. Any disagree-ment was resolved after discussion with independent reviewer. The quality of evidence was assessed using the Cochrane collaborations’ GRADE tool.Data extractionData extraction was performed independently by two reviewers. Discrepancies were resolved after discussion with an independent reviewer. For each study, review-ers extracted data that were deemed to potentially impact efficacy outcomes, such as study population (percent men, mean age, disease duration, serum uric acid), study design (dose of ULT, initial treatment of gout attack, gout attack prophylaxis) and outcomes (total duration of gout attack, recurrent gout attacks, pain severity, ULT discontinuation). For continuous outcomes, data were pooled with the stand-ardized mean difference (SMD) of the final value across groups. For dichotomous data, the relative risk (RR) and 95 % confidence interval (CI) were calculated. Meta-anal-ysis was performed using the random effect model. I2 was calculated to assess heterogeneity. Meta-analysis was car-ried out using STATA version 14.ResultsThree studies were eligible to be included in this system-atic review (Fig. 1) [5–7]. Their details are in Table S1. Two of these studies were of high quality according to the Cochrane assessing risk of bias tool (Table 1). Data from only the first 28 days from one of the studies could be included [5] as that study compared the effect of azapropa-zone (a uricosuric anti-inflammatory drug) or regular indo-methacin followed by delayed initiation of allopurinol on day 28, on treatment of the acute attack of gout and in pre-venting recurrent gout attacks [5]. Patients initially rand-omized to indomethacin were required to discontinue indo-methacin and start allopurinol on day 28, which resulted in only part of the data being eligible for included in this systematic review.Duration of gout attackInformation on duration of gout attack was only pro-vided in one study and did not differ significantly between the allopurinol and placebo arms [17 (8.53) vs. 12.53 (7.73) days], p = 0.13 (intention to treat analysis) [7]. Authors of other studies were contacted, but were unable to provide any additional unpublished data on the duration of gout attack.Pain visual analogue score (VAS) by day 10Information on pain VAS on day 10 was published in one paper [6] and was obtained by contacting the authors of another study [7]. In the latter study, pain VAS was meas-ured between days 10 and 15 [7]. On pooling the data, there was no evidence to suggest that early initiation of ULT associated with pain; however, there was substantial heterogeneity, with I2 = 64 % (Fig. 2a). There was no evi-dence of a publication bias (Figure S1).Recurrent gout attacksThe comparison groups and end points were heteroge-neous and did not allow for pooling of data on recur-rent gout attacks. In the study comparing early versus Rheumatol Int 1 3delayed initiation of allopurinol, the number of patients with acute gout attacks was comparable in the early (7.7 %) and delayed (12 %) initiation arms at 28 days [6]. Only 1 patient commenced on allopurinol had a flare of acute gout in the Hill et al.’s [7] study; however, the other group was only given placebo, which would not be expected to trigger acute gout. In the study by Fraser et al. [5], there was one acute attack of gout in the first 28 days in those randomized to azapropazone, while there were 5 acute attacks of gout in those randomized to indomethacin.Dropouts/medication adherenceInformation on dropouts by day 28 [5, 6]–30 [7] was available for all three studies. Hill et al. [7] reported that the dropout rate was comparable by day 10 (1/16 allopu-rinol vs. 1/19 placebo). Meta-analysis of included studies showed that early ULT initiation did not associate with excessive dropouts (Fig. 2b). However, although the num-ber of studies was limited, there seemed to be publication bias for this outcome (Figure S1).Adverse eventsThe adverse event rates were comparable in those com-menced on ULT during an acute attack of gout (Table S2).Inflammation markersData on C-reactive protein and erythrocyte sedimentation rates in the follow-up period were only reported in one study and demonstrated a nonsignificant reduction in CRP and ESR at days 10 and 30 in those initiated on allopurinol during an acute attack of gout [6].DiscussionThis systematic review collected evidence from all RCTs of ULT initiation during acute gout attack published in the English language. We retrieved 3 trials, including 185 gout patients initiated on allopurinol [6, 7] or azapropazone [5] during a gout attack. Two trials were at low [6, 7] and one [5] at unclear risk of bias. However, the studies provide moderate-quality evidence due to small sample size [6, 7] or lack of suitable control group [5].Our findings imply that ULT initiated during an acute gout attack does not prolong the index attack. However, there was significant heterogeneity in the findings of the included studies [6, 7]. This may be due to the fact that the treatment of acute gout was not standardized in one study [7], and the disease characteristics of gout patients in the studies by Taylor et al. and Hill et al. were differ-ent. For example, patients in the study by Taylor et al. had Fig. 1  Flowchart summarizing study selection Rheumatol Int1 3milder disease (more likely to be presenting with gout for the first time) and did not have tophaceous gout, while those in the study by Hill et al. frequently had tophaceous gout [6, 7]. This suggests that the initiation of ULT dur-ing an acute attack of gout may be safer in patients with early stages of gout than in those with advanced topha-ceous gout.Apart from this, dropout rates in the early ULT initia-tion group and placebo or delayed ULT initiation groups were comparable, suggesting that ULT initiated during an acute gout attack is well tolerated. However, although not statistically significant, the dropout rates in early ULT initiation group were higher in one study in which allopurinol was started at 300 mg/day [6], compared to the study in which allopurinol was initiated at 100 mg/day as per the ACR and EULAR recommendations [7], suggesting that ULT should be initiated at a low dose and up-titrated gradually. The difference in dropout rates between the two studies is not likely to be due to treat-ment of acute attack of gout, as both NSAIDs and corti-costeroids are equally effective in treating acute attacks [8].A hospital-based retrospective study which examined the effect of initiation of ULT during an acute gout attack reported that patients commenced on ULT during an acute attack were significantly more likely to meet the SUA target earlier and less likely to have chronic kidney dis-ease in the long term [9]. However, the findings of this study may be biased due to its retrospective observational nature.Initiation of ULT during a gout attack can increase ULT prescription rates. This is as symptoms of gout are initially intermittent, and many patients do not return for ULT after the acute attack has resolved. Thus, early ini-tiation of ULT can improve overall gout treatment and reduce healthcare cost by avoiding further visits to initiate ULT.In summary, ULT initiated during an acute gout attack is well tolerated and does not prolong the index episode. However, there are several caveats to this study, namely, small sample size of included studies, heterogeneous study population and nonstandardized treatment of acute gout in one study and allopurinol initiation at a high dose in another study. Similarly, in the absence of individual patient data, and the fact that two of the three studies included in this systematic review did not report data on inflammatory markers during the follow-up period, we are unable to examine the relationship between (a) reduc-tion in serum uric acid levels and changes in pain VAS and (b) early initiation of ULT and reduction in inflamma-tion. Thus, further adequately powered studies that exam-ine the effect of initiating slow up-titrated ULT during an acute attack of gout on index attack duration and severity Table 1  Quality of included studies according to the risk of bias assessment tool and Jadad scoreRandom sequence generation (selection bias)Allocation conceal-ment (selection bias)Blinding of partici-pants and personnel (performance bias)Blinding of out-come assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reporting bias)Other biasesJadad scoreQuality of evidence (GRADE scheme)Hill++++−−−/−5/5MTaylor++++−−−/−5/5MFraser??++−−−/−4/5MRheumatol Int 1 3are needed before this strategy of ULT initiation can be widely implemented.Compliance with ethical standards Conflict of interest Dr A Abhishek has received research funding from AstraZeneca and Oxford Immunotec. Other authors do not report a conflict of interest.Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.Open Access This article is distributed under the terms of the Crea-tive Commons Attribution 4.0 International License (http://crea-tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Fig. 2  Forest plot showing effect of early initiation of ULT on a pain at day 10 (top panel) and b dropouts (lower panel) Rheumatol Int1 3References 1. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Cona-ghan P et al (2006) EULAR evidence based recommenda-tions for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 65:1312–1324 2. Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J et al (2007) British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the manage-ment of gout. Rheumatology 46:1372–1374 3. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T et al (2012) 2012 American College of Rheumatology guide-lines for management of gout. Part 2: therapy and antiinflam-matory prophylaxis of acute gouty arthritis. Arthritis Care Res 64:1447–1461 4. Seth R, Kydd AS, Buchbinder R, Bombardier C, Edwards CJ (2014) Allopurinol for chronic gout. Cochrane Database Syst Rev 10:CD006077 5. Fraser RC, Davis RH, Walker FS (1987) Comparative trial of azapropazone and indomethacin plus allopurinol in acute gout and hyperuricaemia. J R Coll Gen Pract 37:409–411 6. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA (2012) Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med 125(1126–34):e7 7. Hill EM, Sky K, Sit M, Collamer A, Higgs J (2015) Does start-ing allopurinol prolong acute treated gout? A randomized clini-cal trial. J Clin Rheumatol 21:120–125 8. Khanna PP, Gladue HS, Singh MK, FitzGerald JD, Bae S, Prakash S et al (2014) Treatment of acute gout: a systematic review. Sem Arthritis Rheum 44:31–38 9. Feng X, Li Y, Gao W (2015) Significance of the initiation time of urate-lowering therapy in gout patients: a retrospective research. Joint Bone Spine 82:428–431

Does the initiation of urate lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review

Nottingham eTheses

1 3
Rheumatol Int (2016) 36:1747–1752
DOI 10.1007/s00296-016-3579-z
Rheumatology
INTERNATIONAL 
OBSERVATIONAL RESEARCH
Does the initiation of urate‑lowering treatment during an acute 
gout attack prolong the current episode and precipitate recurrent 
attacks: a systematic literature review
Fatma Eminaga1 · Jonathan Le‑Carratt1 · Adrian Jones1 · A. Abhishek1,2 
Received: 18 June 2016 / Accepted: 12 October 2016 / Published online: 19 October 2016 
© The Author(s) 2016. This article is published with open access at Springerlink.com
findings so that patients with acute gout can be initiated on 
ULT with confidence.
Keywords Acute gout · Urate-lowering treatment · 
Systematic review
Introduction
Gout is the commonest inflammatory arthritis and results 
from monosodium urate (MSU) crystal deposition. It is 
the only arthritis that has the potential of being cured if the 
serum uric acid is reduced to <360 µmol/L persistently with 
effective urate-lowering treatment (ULT) [1]. Guidelines 
for the management of gout recommend that patients con-
tinue on ULT during a gout attack, but provide conflicting 
recommendations on whether ULT can be started during an 
acute attack [1–3]. For example, while the British Society 
for Rheumatology (BSR) and European League Against 
Rheumatism (EULAR) guidelines suggest commencing 
ULT 1–2 weeks after the acute attack has resolved, the 
2012 American College of Rheumatology (ACR) guide-
lines suggest that ULT may be started during an acute 
attack [1–3]. However, these recommendations are discord-
ant, and the latest Cochrane review did not examine the 
effect of ULT initiation during an acute attack of gout on its 
duration and severity [4]. Thus, further research is required 
to examine whether ULT can be initiated during an acute 
gout attack, without unduly prolonging the index episode.
The objectives of this study were to systematically 
review the literature to identify studies examining the effect 
of initiation of ULT during an acute gout attack on severity 
of the index episode, recurrent gout attacks, persistence on 
ULT and to conduct a meta-analysis to provide estimate of 
the effects.
Abstract The aim of this study was to systematically 
review the literature on effect of initiating urate-lowering 
treatment (ULT) during an acute attack of gout on dura-
tion of index attack and persistence on ULT. OVID (Med-
line), EMBASE and AMED were searched to identify 
randomized controlled trials (RCTs) of ULT initiation dur-
ing acute gout attack published in English language. Two 
reviewers appraised the study quality and extracted data 
independently. Standardized mean difference (SMD) and 
relative risk (RR) were used to pool continuous and cat-
egorical data. Meta-analysis was carried out using STATA 
version 14. A total of 537 studies were selected. A total 
of 487 titles and abstracts were reviewed after removing 
duplicates. Three RCTs were identified. There was evi-
dence from two high-quality studies that early initiation 
of allopurinol did not increase pain severity at days 10–15 
[SMDpooled (95 % CI) 0.18 (−0.58, 0.93)]. Data from three 
studies suggested that initiation of ULT during an acute 
attack of gout did not associate with dropouts [RRpooled 
(95 % CI) 1.16 (0.58, 2.31)]. There is moderate-quality evi-
dence that the initiation of ULT during an acute attack of 
gout does not increase pain severity and risk of ULT dis-
continuation. Larger studies are required to confirm these 
Electronic supplementary material The online version of this 
article (doi:10.1007/s00296-016-3579-z) contains supplementary 
material, which is available to authorized users.
 * A. Abhishek 
 Abhishek.abhishek@nottingham.ac.uk
1 Department of Medicine, Nottingham University Hospitals 
NHS Trust, Nottingham NG7 2UH, UK
2 Academic Rheumatology, Clinical Sciences Building, 
University of Nottingham, Nottingham NG5 1PB, UK
1748 Rheumatol Int (2016) 36:1747–1752
1 3
Methods
Literature search
MeSH terms were used to identify randomized controlled 
trials (RCTs) of ULT for gout in OVID (Medline) R 1946–
week 4 October 2015, EMBASE (1974–week 44, 2015) 
and AMED (1985–October 2015). Reference lists of eligi-
ble studies, ACR, EULAR, BSR guidelines and Cochrane 
systematic reviews of pharmacologic treatment of gout 
were hand searched. We restricted our search to studies in 
English. PubMed was searched using free text terms com-
bining each ULT (allopurinol, febuxostat, benzbromarone 
and probenecid, etc.) and “acute gout” to identify any addi-
tional studies.
Inclusion criteria
Initiation of any ULT in patients with acute gout (either 
new diagnosis or long-standing gout) and ≥18 years in age.
Exclusion criteria
Up-titration of ULT dose during an acute attack, ULT ini-
tiation in the intercritical period, animal studies and confer-
ence abstracts.
Study selection
The titles and abstracts of retrieved studies were inde-
pendently reviewed by two reviewers. Full text articles 
were obtained if more information was required to decide 
eligibility.
Quality assessment
Two independent reviewers appraised the selected stud-
ies for quality. Studies were evaluated using the Cochrane 
assessing risk of bias tool and Jadad score. Any disagree-
ment was resolved after discussion with independent 
reviewer. The quality of evidence was assessed using the 
Cochrane collaborations’ GRADE tool.
Data extraction
Data extraction was performed independently by two 
reviewers. Discrepancies were resolved after discussion 
with an independent reviewer. For each study, review-
ers extracted data that were deemed to potentially impact 
efficacy outcomes, such as study population (percent men, 
mean age, disease duration, serum uric acid), study design 
(dose of ULT, initial treatment of gout attack, gout attack 
prophylaxis) and outcomes (total duration of gout attack, 
recurrent gout attacks, pain severity, ULT discontinuation). 
For continuous outcomes, data were pooled with the stand-
ardized mean difference (SMD) of the final value across 
groups. For dichotomous data, the relative risk (RR) and 
95 % confidence interval (CI) were calculated. Meta-anal-
ysis was performed using the random effect model. I2 was 
calculated to assess heterogeneity. Meta-analysis was car-
ried out using STATA version 14.
Results
Three studies were eligible to be included in this system-
atic review (Fig. 1) [5–7]. Their details are in Table S1. 
Two of these studies were of high quality according to the 
Cochrane assessing risk of bias tool (Table 1). Data from 
only the first 28 days from one of the studies could be 
included [5] as that study compared the effect of azapropa-
zone (a uricosuric anti-inflammatory drug) or regular indo-
methacin followed by delayed initiation of allopurinol on 
day 28, on treatment of the acute attack of gout and in pre-
venting recurrent gout attacks [5]. Patients initially rand-
omized to indomethacin were required to discontinue indo-
methacin and start allopurinol on day 28, which resulted 
in only part of the data being eligible for included in this 
systematic review.
Duration of gout attack
Information on duration of gout attack was only pro-
vided in one study and did not differ significantly between 
the allopurinol and placebo arms [17 (8.53) vs. 12.53 
(7.73) days], p = 0.13 (intention to treat analysis) [7]. 
Authors of other studies were contacted, but were unable to 
provide any additional unpublished data on the duration of 
gout attack.
Pain visual analogue score (VAS) by day 10
Information on pain VAS on day 10 was published in one 
paper [6] and was obtained by contacting the authors of 
another study [7]. In the latter study, pain VAS was meas-
ured between days 10 and 15 [7]. On pooling the data, 
there was no evidence to suggest that early initiation of 
ULT associated with pain; however, there was substantial 
heterogeneity, with I2 = 64 % (Fig. 2a). There was no evi-
dence of a publication bias (Figure S1).
Recurrent gout attacks
The comparison groups and end points were heteroge-
neous and did not allow for pooling of data on recur-
rent gout attacks. In the study comparing early versus 
1749Rheumatol Int (2016) 36:1747–1752 
1 3
delayed initiation of allopurinol, the number of patients 
with acute gout attacks was comparable in the early 
(7.7 %) and delayed (12 %) initiation arms at 28 days 
[6]. Only 1 patient commenced on allopurinol had a flare 
of acute gout in the Hill et al.’s [7] study; however, the 
other group was only given placebo, which would not 
be expected to trigger acute gout. In the study by Fraser 
et al. [5], there was one acute attack of gout in the first 
28 days in those randomized to azapropazone, while 
there were 5 acute attacks of gout in those randomized 
to indomethacin.
Dropouts/medication adherence
Information on dropouts by day 28 [5, 6]–30 [7] was 
available for all three studies. Hill et al. [7] reported that 
the dropout rate was comparable by day 10 (1/16 allopu-
rinol vs. 1/19 placebo). Meta-analysis of included studies 
showed that early ULT initiation did not associate with 
excessive dropouts (Fig. 2b). However, although the num-
ber of studies was limited, there seemed to be publication 
bias for this outcome (Figure S1).
Adverse events
The adverse event rates were comparable in those com-
menced on ULT during an acute attack of gout (Table S2).
Inflammation markers
Data on C-reactive protein and erythrocyte sedimentation 
rates in the follow-up period were only reported in one 
study and demonstrated a nonsignificant reduction in CRP 
and ESR at days 10 and 30 in those initiated on allopurinol 
during an acute attack of gout [6].
Discussion
This systematic review collected evidence from all RCTs 
of ULT initiation during acute gout attack published in the 
English language. We retrieved 3 trials, including 185 gout 
patients initiated on allopurinol [6, 7] or azapropazone [5] 
during a gout attack. Two trials were at low [6, 7] and one 
[5] at unclear risk of bias. However, the studies provide 
moderate-quality evidence due to small sample size [6, 7] 
or lack of suitable control group [5].
Our findings imply that ULT initiated during an acute 
gout attack does not prolong the index attack. However, 
there was significant heterogeneity in the findings of the 
included studies [6, 7]. This may be due to the fact that 
the treatment of acute gout was not standardized in one 
study [7], and the disease characteristics of gout patients 
in the studies by Taylor et al. and Hill et al. were differ-
ent. For example, patients in the study by Taylor et al. had 
Fig. 1  Flowchart summarizing 
study selection
1750 Rheumatol Int (2016) 36:1747–1752
1 3
milder disease (more likely to be presenting with gout for 
the first time) and did not have tophaceous gout, while 
those in the study by Hill et al. frequently had tophaceous 
gout [6, 7]. This suggests that the initiation of ULT dur-
ing an acute attack of gout may be safer in patients with 
early stages of gout than in those with advanced topha-
ceous gout.
Apart from this, dropout rates in the early ULT initia-
tion group and placebo or delayed ULT initiation groups 
were comparable, suggesting that ULT initiated during 
an acute gout attack is well tolerated. However, although 
not statistically significant, the dropout rates in early 
ULT initiation group were higher in one study in which 
allopurinol was started at 300 mg/day [6], compared to 
the study in which allopurinol was initiated at 100 mg/
day as per the ACR and EULAR recommendations [7], 
suggesting that ULT should be initiated at a low dose 
and up-titrated gradually. The difference in dropout rates 
between the two studies is not likely to be due to treat-
ment of acute attack of gout, as both NSAIDs and corti-
costeroids are equally effective in treating acute attacks 
[8].
A hospital-based retrospective study which examined 
the effect of initiation of ULT during an acute gout attack 
reported that patients commenced on ULT during an acute 
attack were significantly more likely to meet the SUA 
target earlier and less likely to have chronic kidney dis-
ease in the long term [9]. However, the findings of this 
study may be biased due to its retrospective observational 
nature.
Initiation of ULT during a gout attack can increase 
ULT prescription rates. This is as symptoms of gout are 
initially intermittent, and many patients do not return for 
ULT after the acute attack has resolved. Thus, early ini-
tiation of ULT can improve overall gout treatment and 
reduce healthcare cost by avoiding further visits to initiate 
ULT.
In summary, ULT initiated during an acute gout attack 
is well tolerated and does not prolong the index episode. 
However, there are several caveats to this study, namely, 
small sample size of included studies, heterogeneous 
study population and nonstandardized treatment of acute 
gout in one study and allopurinol initiation at a high dose 
in another study. Similarly, in the absence of individual 
patient data, and the fact that two of the three studies 
included in this systematic review did not report data on 
inflammatory markers during the follow-up period, we 
are unable to examine the relationship between (a) reduc-
tion in serum uric acid levels and changes in pain VAS 
and (b) early initiation of ULT and reduction in inflamma-
tion. Thus, further adequately powered studies that exam-
ine the effect of initiating slow up-titrated ULT during an 
acute attack of gout on index attack duration and severity Ta
bl
e 
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1751Rheumatol Int (2016) 36:1747–1752 
1 3
are needed before this strategy of ULT initiation can be 
widely implemented.
Compliance with ethical standards 
Conflict of interest Dr A Abhishek has received research funding 
from AstraZeneca and Oxford Immunotec. Other authors do not report 
a conflict of interest.
Ethical approval This article does not contain any studies with 
human participants or animals performed by any of the authors.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://crea-
tivecommons.org/licenses/by/4.0/), which permits unrestricted use, 
distribution, and reproduction in any medium, provided you give 
appropriate credit to the original author(s) and the source, provide a 
link to the Creative Commons license, and indicate if changes were 
made.
Fig. 2  Forest plot showing effect of early initiation of ULT on a pain at day 10 (top panel) and b dropouts (lower panel)
1752 Rheumatol Int (2016) 36:1747–1752
1 3
References
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ghan P et al (2006) EULAR evidence based recommenda-
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lines for management of gout. Part 2: therapy and antiinflam-
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Objectives: To systematically review the literature on effect of initiating urate lowering treatment (ULT) during an acute attack of gout on duration of index attack and persistence on ULT.\ud
Methods: OVID (MEDLINE), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation during acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardised mean difference (SMD) and relative risk (RR) were used to pool continuous and categorical data. Meta-analysis was carried out using STATA v14. \ud
Results: 537 studies were selected. 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evidence from two high quality studies that early initiation of allopurinol did not increase pain severity at days 10 to 15 (SMDpooled (95%CI) 0.18(-0.58, 0.93)). Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with drop-outs (RRpooled (95%CI) 1.16(0.58, 2.31)).\ud
Conclusion: There is moderate-quality evidence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT discontinuation. Larger studies are required to confirm these findings so that patients with acute gout can be initiated on ULT with confidence

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Does the initiation of urate lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review

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