Interventions for tophi in gout

  • Review
  • Intervention

Authors


Abstract

Background

Tophi develop in untreated or uncontrolled gout. Their presence can lead to severe and potentially fatal complications. To date there have been no systematic reviews focused on the management of tophi in gout.

Objectives

To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout.

Search methods

We searched three databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE. We handsearched American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts from 2010 to 2011, references from included studies and trial registries. We completed the most recent search on 20 May 2013.

Selection criteria

All published randomised controlled trials (RCTs) or controlled clinical trials with quasi-randomised methods of allocating participants to treatment examining interventions for tophi in gout in adults. Possible interventions included urate-lowering pharmacological treatment (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase), surgical removal or other interventions such as haemodialysis.

Data collection and analysis

Two review authors extracted data from titles, abstracts and selected studies for detailed review, and extracted data and risk of bias independently. Major outcomes were number of participants with complete resolution of tophi, number of study participant withdrawals due to adverse events, joint pain reduction, function, quality of life, serum urate normalisation and total adverse events.

Main results

Only one study, at low risk of all biases, met the inclusion criteria. This was the pooled results from two RCTs (225 participants, 145 with tophi at baseline) randomised to one of three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Moderate-quality evidence from one study indicated that biweekly pegloticase 8 mg infusion reduced tophi in the subset of participants with tophi, but increased withdrawals due to adverse events in all participants, and monthly infusion appeared to result in less benefit.

Biweekly pegloticase treatment resulted in resolution of tophi in 21/52 participants compared with 2/27 who received placebo (risk ratio (RR) 5.45, 95% confidence intervals (CI) 1.38 to 21.54; number needed to treat for an additional beneficial outcome (NNTB) 3 (95% CI 2 to 6).

Eleven of 52 participants with monthly pegloticase treatment had complete resolution of one or more tophi compared with 2/27 who received placebo (RR 2.86, 95% CI 0.68 to 11.97).

Participant-reported pain relief of 30% or greater, function, quality of life, serum urate normalisation, were reported for all participants but not separately for those with tophi; therefore, we did not include the results.

Pegloticase administered biweekly resulted in more withdrawals due to adverse events compared with placebo (15/85 participants with pegloticase versus 1/43 participants with placebo; RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for an additional harmful outcome (NNTH) 7, 95% CI 4 to 17). Pegloticase administered monthly also resulted in more withdrawals due to adverse events than placebo (16/84 participants with pegloticase versus 1/43 participants with placebo; RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Most withdrawals were due to infusion reactions.

Total adverse events were high in all treatment groups: 80/85 participants administered pegloticase biweekly reported an adverse event compared with 41/43 from the placebo group (RR 0.99, 95% CI 0.91 to 1.07); 84/84 participants administered pegloticase monthly reported an adverse event versus 41/43 in the placebo group (RR 1.05, 95% CI 0.98 to 1.14). As 80% of adverse events were due to flares of gout, probably unrelated to the drug treatment per se, this may explain the high rate of adverse events in the placebo group - who were essentially untreated.

Authors' conclusions

This study showed pegloticase is probably beneficial in the management of tophi in gout, in terms of resolution of tophi, but with a high risk of adverse infusion reactions. However, there is a need for more RCT data considering other interventions, including surgical removal of tophi.

Résumé scientifique

Interventions contre les tophus dans la goutte

Contexte

Les tophus se développent chez les personnes atteintes de goutte non traitée ou incontrôlée. Leur présence peut entraîner des complications graves et potentiellement mortelles. Il n'y a pas eu à ce jour de revue systématique concernant spécifiquement le traitement des tophus dans la goutte.

Objectifs

Évaluer les avantages et les inconvénients de modalités non chirurgicales et chirurgicales de traitement des tophus dans la goutte.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans trois bases de données : le registre central Cochrane des essais contrôlés (CENTRAL), MEDLINE et EMBASE. Nous avons également effectué des recherches manuelles dans les résumés 2010 à 2011 de l’American College of Rheumatology (ACR) et de l'European League against Rheumatism (EULAR), dans les références des études incluses et dans des registres d'essais. La recherche la plus récente a été effectuée le 20 mai 2013.

Critères de sélection

Tous les essais publiés, soit essais contrôlés randomisés (ECR), soit essais cliniques contrôlés avec des méthodes d'affectation des participants au traitement quasi randomisées, examinant des interventions contre les tophus dans la goutte chez l'adulte. Les interventions possibles comprenaient les traitements pharmacologiques visant à abaisser le taux d'urate (par exemple benzbromarone, probénécide, allopurinol, febuxostat, pégloticase), l'ablation chirurgicale ou d'autres interventions telles que l'hémodialyse.

Recueil et analyse des données

Deux auteurs ont extrait les données des titres et des résumés et sélectionné des études en vue d'un examen détaillé, extrait les données et évalué le risque de biais de façon indépendante. Les principaux critères d'évaluation étaient le nombre de participants présentant une résolution complète de tophus, le nombre d'abandons en raison d'effets indésirables, la réduction des douleurs articulaires, les fonctions, la qualité de vie, la normalisation du taux sérique d'urate et le total des événements indésirables.

Résultats principaux

Une seule étude, à faible risque de tous biais, satisfaisait les critères d'inclusion. Elle regroupait les regroupés de deux ECR (225 participants, 145 avec tophus à l'inclusion) dont les sujets étaient randomisés en trois groupes : pégloticase en perfusion toutes les deux semaines, pégloticase en perfusion mensuelle (perfusion de pégloticase en alternance avec une perfusion de placebo toutes les deux semaines) et placebo. Des preuves de qualité modérée fournies par une étude indiquent que les perfusions de pégloticase à 8 mg toutes les deux semaines ont réduit les tophus dans le sous-ensemble de participants avec tophus, mais entraîné un nombre plus important d'abandons à cause d'effets indésirables chez tous les participants, tandis que les perfusions mensuelles semblent apporter un bénéfice moindre.

Le traitement par la pégloticase toutes les deux semaines a entraîné la résolution des tophus chez 21 participants sur 52, contre 2 sur 27 ayant reçu le placebo (risque relatif (RR) 5,45, intervalle de confiance (IC) à 95 % de 1,38 à 21,54 ; nombre de sujets à traiter pour observer bénéfice supplémentaire (NNTB) 3 (IC à 95 % de 2 à 6).

Onze des 52 participants traités par la pégloticase une fois par mois ont vu un ou plusieurs tophus disparaître complètement, contre 2 sur 27 ayant reçu le placebo (RR 2,86, IC à 95 % de 0,68 à 11,97).

La réduction de la douleur rapportée par les de 30 % ou plus, les fonctions, la qualité de vie et la normalisation du taux d'urate sérique ont été rapportées pour tous les participants, mais pas séparément pour ceux qui avaient des tophus ; par conséquent, nous n'avons pas inclus les résultats.

La pégloticase administrée toutes les deux semaines a donné lieu à un plus grand nombre d'abandons pour cause d'effets indésirables que le placebo (15 des 85 participants du groupe pégloticase contre 1 des 43 participants du groupe placebo ; RR 7,59, IC à 95 % de 1,04 à 55,55 ; nombre de sujets à traiter pour observer un préjudice supplémentaire (NNTH ) 7, IC à 95 % de 4 à 17). La pégloticase administrée une fois par mois a également entraîné un plus grand nombre d'abandons pour cause d'effets indésirables que le placebo (16 des 84 participants du groupe pégloticase contre 1 des 43 participants du groupe placebo ; RR 8,19, IC à 95 % de 1,12 à 59,71 ; NNTH 6, IC à 95 % de 4 à 14). La plupart des retraits étaient dus à des réactions à la perfusion.

Le total des événements indésirables était élevé dans tous les groupes de traitement : 80 des 85 participants du groupe pégloticase toutes les deux semaines ont signalé un événement indésirable contre 41 sur 43 dans le groupe placebo (RR 0,99, IC à 95 % de 0,91 à 1,07) ; 84 des 84 participants du groupe pégloticase une fois par mois ont signalé un événement indésirable contre 41 sur 43 dans le groupe placebo (RR 1,05, IC à 95 % de 0,98 à 1,14). Dans 80 % des cas, les événements indésirables étaient dus à des flambées de goutte, probablement sans lien avec le traitement médicamenteux par lui-même, ce qui peut expliquer le taux élevé d'événements indésirables dans le groupe placebo, qui ne recevait pour l'essentiel aucun traitement.

Conclusions des auteurs

Cette étude a montré que la pégloticase est probablement bénéfique dans le traitement des tophus dans la goutte, en termes de résolution des tophus, mais créait un risque élevé de réactions indésirables liées à la perfusion. Nous avons cependant besoin de davantage de données, fournies par des ECR incluant d'autres interventions, notamment l'ablation chirurgicale des tophus.

Resumen

Intervenciones para los tofos gotosos

Antecedentes

Los tofos se presentan en pacientes con gota sin tratar o no controlada. Su presencia puede dar lugar a complicaciones graves y potencialmente mortales. Hasta la fecha no ha habido ninguna revisión sistemática centrada en el tratamiento de los tofos gotosos.

Objetivos

Evaluar los efectos beneficiosos y perjudiciales de los tratamientos quirúrgicos y no quirúrgicos de los tofos gotosos.

Métodos de búsqueda

Se hicieron búsquedas en tres bases de datos: Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL), MEDLINE, EMBASE. Se hicieron búsquedas en los resúmenes del American College of Rheumatology (ACR) y de la European League against Rheumatism (EULAR), desde 2010 hasta 2011, en referencias de estudios incluidos y en registros de ensayos. Se completó la búsqueda más reciente el 20 de mayo de 2013.

Criterios de selección

Todos los ensayos controlados aleatorios (ECA) o los ensayos clínicos controlados con métodos cuasialeatorios para asignar a los participantes al tratamiento que hayan sido publicados y que examinaran intervenciones para los tofos gotosos en adultos. Las intervenciones posibles incluyeron tratamiento farmacológico para la disminución del urato (p.ej. benzbromarona, probenecid, alopurinol, febuxostat, pegloticase), extracción quirúrgica u otras intervenciones como la hemodiálisis.

Obtención y análisis de los datos

Dos autores de la revisión extrajeron los datos de los títulos, resúmenes y estudios seleccionados para la revisión detallada, y extrajeron los datos y el riesgo de sesgo de forma independiente. Los resultados principales fueron el número de participantes con resolución completa de los tofos, el número de retiros de participantes del estudio debido a los eventos adversos, la reducción de dolor de las articulaciones, la función, la calidad de vida, la normalización del urato sérico y los eventos adversos totales.

Resultados principales

Sólo un estudio, con bajo riesgo de todos los sesgos, cumplió los criterios de inclusión. El mismo incluyó los resultados agrupados de dos ECA (225 participantes, 145 con tofos al inicio) asignados al azar a uno de tres brazos; infusión de pegloticase cada dos semanas, infusión de pegloticase una vez al mes (infusión de pegloticase alternada con infusión de placebo cada dos semanas) y placebo. Las pruebas de calidad moderada de un estudio indicaron que la infusión de 8 mg de pegloticase cada dos semanas redujo los tofos en el subgrupo de participantes con tofos, aunque aumentó los retiros debido a eventos adversos en todos los participantes, y la infusión mensual pareció dar lugar a menos beneficios.

El tratamiento con pegloticase cada dos semanas dio lugar a la resolución de los tofos en 21/52 participantes en comparación con 2/27 que recibieron placebo (cociente de riesgos [CR] 5,45; intervalo de confianza [IC] del 95%: 1,38 a 21,54; número necesario a tratar para un resultado beneficioso adicional [NNTB] 3; IC del 95%: 2 a 6).

Once de 52 participantes que recibieron tratamiento con pegloticase una vez al mes presentaron la resolución completa de uno o más tofos en comparación con 2/27 que recibieron placebo (CR 2,86; IC del 95%: 0,68 a 11,97).

El alivio del dolor informado por el participante de un 30% o mayor, la función, la calidad de vida, la normalización del urato sérico, se informaron para todos los participantes pero no por separado para los que presentaban tofos; por lo tanto, no se incluyeron los resultados.

El pegloticase administrado cada dos semanas dio lugar a más retiros debido a eventos adversos en comparación con placebo (15/85 participantes con pegloticase versus 1/43 participantes con placebo; CR 7,59; IC del 95%: 1,04 a 55,55; número necesario a tratar para un resultado perjudicial adicional (NNTD) 7; IC del 95%: 4 a 17). El pegloticase administrado de forma mensual también dio lugar a más retiros debido a eventos adversos que el placebo (16/84 participantes con pegloticase versus 1/43 participantes con placebo; CR 8,19; IC del 95%: 1,12 a 59,71; NNTD 6; IC del 95%: 4 a 14). La mayoría de los retiros se debieron a reacciones a las infusiones.

Los eventos adversos totales fueron elevados en todos los grupos de tratamiento: 80/85 participantes que recibieron pegloticase cada dos semanas informaron un evento adverso en comparación con 41/43 del grupo de placebo (CR 0,99; IC del 95%: 0,91 a 1,07); 84/84 participantes que recibieron pegloticase de forma mensual informaron un evento adverso versus 41/43 en el grupo de placebo (CR 1,05; IC del 95%: 0,98 a 1,14). Debido a que un 80% de los eventos adversos fueron causados por los brotes de gota, y probablemente no se relacionaron con el tratamiento farmacológico per se, este hecho puede explicar la tasa alta de eventos adversos en el grupo de placebo - pacientes esencialmente sin tratar.

Conclusiones de los autores

Este estudio reveló que el pegloticase probablemente es beneficioso para el tratamiento de los tofos gotosos, en cuanto a la resolución de los tofos, aunque con un alto riesgo de reacciones adversas a las infusiones. Sin embargo, se necesitan más datos de ECA que consideren otras intervenciones, incluida la extracción quirúrgica de los tofos.

Plain language summary

Interventions for tophi in gout

Background: what are tophi and what interventions are used?

Gout is caused by urate crystals forming either within or around joints. Inflammation can lead to pain, redness, warmth and swelling of the affected joints, making the area difficult to touch or move. Some of the reasons why people get gout include their genetic make-up, being overweight, ingesting certain medications (e.g. cyclosporine), impaired kidney function and lifestyle habits such as drinking excessive amounts of alcohol and sugar-sweetened drinks. Tophi are nodules that develop in people with poorly treated or uncontrolled chronic gout. Tophi can become infected, cause pain and lead to a decrease in function. Tophi can be treated with urate-lowering drugs (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase), surgical removal or other interventions such as haemodialysis. Surgical interventions can be used where urgent removal is required, for example, for relief of nerve compression.

Study characteristics

This is a summary of a Cochrane review that shows interventions for the management of tophi. After searching for all relevant studies in May 2013, we found only one study (pooled results from two randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups)) that randomised 225 people to pegloticase (every two weeks (biweekly) or monthly) or placebo, in the management of chronic gout; 145 participants had tophi and 131 contributed outcome data.

Key results: what happens to people with tophi who are treated with biweekly or monthly pegloticase versus placebo

Resolution of tophi

- 33 more people out of 100 had resolution of one or more tophi after six months' treatment with pegloticase biweekly compared with placebo (33% absolute improvement).

- 14 more people out of 100 had resolution of one or more tophi after six months' treatment with pegloticase monthly compared with placebo (14% absolute improvement).

- 40 people out of 100 in the biweekly pegloticase group had resolution of one or more tophi.

- 21 people out of 100 in the monthly pegloticase group had resolution of one or more tophi.

- 7 people out of 100 in the placebo group had resolution of one or more tophi.

Other outcomes were for all participants, and not separated out for those people with tophi. Therefore, we have not reported them in this review. However, we reported on withdrawal due to adverse events for the total population. Most withdrawals were due to adverse reactions to drug infusion.

Withdrawal due to adverse events

- 16 more people out of 100 withdrew from treatment with biweekly pegloticase compared with placebo (16% more withdrawals).

- 17 more people out of 100 withdrew from treatment with monthly pegloticase compared to placebo (17% more withdrawals).

- 18 people out of 100 withdrew from treatment with biweekly pegloticase due to adverse events.

- 19 people out of 100 withdrew from treatment with monthly pegloticase due to adverse events.

- 2 people out of 100 withdrew from treatment with placebo due to adverse events.

Quality of evidence

Moderate-quality evidence indicated that pegloticase biweekly or monthly probably resolves one or more tophi. However, this has to be weighed up against high withdrawal rates from treatment due to adverse events, mostly due to an increase in infusion reactions. Pain reduction, quality of life, serum urate normalisation and function were not reported separately in people with tophi. The evidence was downgraded due to imprecise results. Further research may change these results.

We do not know if other interventions, including surgery, are effective, as we found no randomised controlled trials that assessed other interventions.

Résumé simplifié

Interventions contre les tophus dans la goutte

Contexte : Qu'est-ce que les tophus et quelles sont les interventions utilisées ?

La goutte est provoquée par des cristaux d'acide urique (urate) qui se forment à l'intérieur ou autour des articulations. L'inflammation peut provoquer une douleur, une rougeur, un échauffement et un gonflement des articulations affectées, qui deviennent sensibles au toucher ou difficiles à bouger. L'apparition de la goutte est en partie liée au patrimoine génétique, au surpoids, à la prise de certains médicaments (par exemple de ciclosporine), à des troubles de la fonction rénale et à des habitudes telles que l'abus d'alcool et de boissons sucrées. Les tophus sont des nodules qui se développent chez les personnes atteintes de goutte chronique mal traitée ou incontrôlée. Ils peuvent s'infecter, causer des douleurs et entraîner une réduction des fonctions. Les tophus peuvent être traités avec des médicaments réduisant le taux d'acide urique (par exemple la benzbromarone, le probénécide, l'allopurinol, le febuxostat, la pégloticase), par ablation chirurgicale ou par d'autres interventions telles que l'hémodialyse. La chirurgie peut être utilisée lorsqu'il est urgent d'éliminer un tophus, par exemple pour décompresser un nerf.

Caractéristiques des études

Ceci est un résumé d'une revue Cochrane décrivant les interventions pour le traitement des tophus. Après avoir recherché toutes les études pertinentes en mai 2013, nous avons trouvé une seule étude (regroupant les résultats de deux essais contrôlés randomisés [études cliniques dont les sujets sont répartis au hasard entre deux ou plusieurs groupes de traitement]) qui randomisait 225 personnes entre un groupe pégloticase (toutes les deux semaines ou une fois par mois) et un groupe placebo pour le traitement de la goutte chronique ; 145 participants avaient des tophus et 131 ont fourni des données sur les résultats.

Principaux résultats : que deviennent les sujets porteurs de tophus qui sont traités avec la pégloticase toutes les deux semaines ou une fois par mois, par rapport au placebo ?

Résolution des tophus

- 33 personnes de plus sur 100 ont vu un ou plusieurs tophus disparaître après six mois de traitement par la pégloticase toutes les deux semaines, par rapport au placebo (33 % d'amélioration absolue).

- 14 personnes de plus sur 100 ont vu un ou plusieurs tophus disparaître après six mois de traitement par la pégloticase une fois par moi, par rapport au placebo (14 % d'amélioration absolue).

- 40 personnes sur 100 dans le groupe pégloticase tous les quinze jours ont vu un ou plusieurs tophus disparaître.

- 21 personnes sur 100 dans le groupe pégloticase une fois par mois ont vu un ou plusieurs tophus disparaître.

- 7 personnes sur 100 dans le groupe placebo ont vu un ou plusieurs tophus disparaître.

Les autres critères d'évaluation concernaient tous les participants et les sujets ayant des tophus n'y ont pas été évalués séparément. Par conséquent, nous ne les avons pas rapportés dans cette revue. Cependant, nous avons rapporté un retrait en raison d'effets indésirables dans la population totale. La plupart des retraits étaient dus à des réactions indésirables liées à la perfusion de médicament.

Retrait en raison d'événements indésirables

- 16 personnes de plus sur 100 se sont retirées du groupe de traitement par la pégloticase tous les quinze jours par rapport au placebo (16 % de retraits en plus).

- 17 personnes de plus sur 100 se sont retirées du traitement par la pégloticase une fois par mois, par rapport au placebo (17 % de retraits en plus).

- 18 personnes sur 100 ont abandonné le traitement par la pégloticase toutes les deux semaines en raison d'événements indésirables.

- 19 personnes sur 100 ont abandonné le traitement par la pégloticase une fois par mois en raison d'événements indésirables.

- 2 personnes sur 100 ont abandonné le traitement avec le placebo en raison d'événements indésirables.

Qualité des preuves

Des preuves de qualité modérée indiquent que la pégloticase tous les quinze jours ou une fois par mois élimine probablement un ou plusieurs tophus. Cependant, cela doit être mis en balance avec les taux élevés de retraits de traitement en raison d'effets indésirables, principalement d'une augmentation des réactions à la perfusion. La réduction de la douleur, la qualité de vie, la normalisation du taux sérique d'urate et les fonctions n'ont pas été présentées séparément pour les sujets porteurs de tophus. La qualité des preuves a été rétrogradée en raison de résultats imprécis. Des recherches supplémentaires pourraient modifier ces résultats.

Nous ne savons pas si d'autres interventions, notamment chirurgicales, sont efficaces car nous n'avons pas trouvé d'essais contrôlés randomisés évaluant ces autres interventions.

Notes de traduction

Traduction réalisée par le Centre Cochrane Français

Ringkasan bahasa mudah

Intervensi untuk tophi pada gout

Latar belakang: Apakah tophi dan apakah intervensi yang digunakan?

Gout disebabkan oleh urat krstal yang terbentuk sama ada di dalam atau di sekitar sendi. Keradangan ini boleh menyebabkan rasa sakit, kemerahan dan bengkak pada sendi yang terlibat dan ini menyebabkan kawasan yang terlibat sukar untuk disentuh atau digerak. Antara sebab-sebab mengapa orang mengalami gout adalah termasuk faktor genetik, berat badan berlebihan, pengambilan ubat-ubatan tertentu (contohnya: cyclosporine), mempunyai fungsi buah pinggang yang terjejas dan gaya hidup seperti minum alkohol dan minuman bergula secara berlebihan. Tophi adalah nodul yang terbentuk dikalangan orang yang mempunyai gout kronik yang tidak dirawat atau terkawal. Tophi boleh dijangkiti, menyebabkan kesakitan dan seterusnya mengurangkan fungsi. Tophi boleh dirawat dengan ubat-ubatan yang mengurangkan asid urik (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase), pembedahan atau intervensi lain seperti hemodialisis. Pembedahan boleh dilakukan apabila pembuangan tophi diperlukan dengan segera, sebagai contoh, untuk melegakan pemampatan saraf.

Ciri-ciri kajian

Ini adalah ringkasan daripada ulasan Cochrane yang menunjukkan intervensi bagi pengurusan tophi. Selepas mencari semua kajian yang relevan sehingga Mei 2013, kami mendapati hanya satu kajian (keputusan dikumpulkan daripada dua kajian terkawal rawak (kajian klinikal dimana peserta dimasukkan kepada salah satu daripada dua atau lebih kumpulan rawatan secara rawak)) yang membahagikan 225 peserta secara rawak dalam kumpulan pegloticase (setiap dua minggu (dua kali seminggu) atau bulanan) atau plasebo, dalam pengurusan gout kronik. 145 orang peserta mempunyai tophi dan 131 orang perserta meyumbang pada data hasil.

Keputusan Utama: Apa yang berlaku kepada orang yang mempunyai tophi yang dirawat dengan pegloticase dua kali seminggu atau bulanan berbanding dengan plasebo?

Resolusi tophi

-Lebih 33 peserta daripada 100 peserta mempunyai resolusi satu atau lebih tophi selepas rawatan selama enam bulan dengan pegloticase dua kali seminggu berbanding dengan plasebo (peningkatan mutlak 33%).

-Lebih 14 peserta daripada 100 peserta mempunyai resolusi satu atau lebih tophi selepas rawatan selama enam bulan dengan pegloticase secara bulanan berbanding dengan plasebo (peningkatan mutlak 14%).

-Lebih 40 peserta daripada 100peserta dalam kumpulan pegloticase dua kali seminggu mempunyai resolusi satu atau lebih tophi.

-Lebih 21 peserta daripada 100 peserta dalam kumpulan pegloticase secara bulanan mempunyai resolusi satu atau lebih tophi.

-Lebih 7 peserta daripada 100 peserta dalam kumpulan plasebo mempunyai resolusi satu atau lebih tophi.

Hasil lain adalah untuk semua peserta, dan tidak memisahkan mereka yang mempunyai tophi. Oleh itu, kami tidak melaporkan hasil-hasil yang lain dalam ulasan ini. Walau bagaimanapun, kami melaporkan peserta yang menarik diri daripada kajian kerana kesan sampingan untuk seluruh kumpulan. Kebanyakan penarikan diri adalah disebabkan oleh kesan sampingan akibat infusi ubat.

Penarikan diri oleh peserta disebabkan kesan-kesan sampingan

-Lebih 16 peserta daripada 100 peserta menarik dri daripada rawatan dengan pegloticase dua kali seminggu berbanding dengan plasebo (penarikan diri 16%).

-Lebih 17 peserta daripada 100 peserta menarik dri daripada rawatan dengan pegloticase secara bulanan berbanding dengan plasebo (penarikan diri 17%).

-18 peserta daripada 100 peserta menarik dri daripada rawatan dengan pegloticase dua kali seminggu kerana kesan sampingan.

-19 peserta daripada 100peserta menarik dri daripada rawatan dengan pegloticase secara bulanan kerana kesan sampingan.

-2 peserta daripada 100 peserta menarik dri daripada rawatan dengan plasebo kerana kesan sampingan.

Kualiti bukti

Kualiti bukti yang sederhana menunjukkan bahawa rawatan pegloticase dua kali seminggu atau bulanan mungkin membantu resolusi satu atau lebih tophi. Walau bagaimanapun, ini perlu dipertimbangkan dengan kadar penarikan diri yang tinggi akibat daripada kesan sampingan, yang kebanyakannya disebabkan oleh peningkatan dalam tindak balas infusi. Kadar pengurangan kesakitan, kualiti hidup, normalisasi urat serum dan fungsi tidak dilaporkan secara berasingan untuk peserta dengan tophi. Bukti-bukti yang didapati diturunkan kualitinya kerana keputusan yang tidak tepat. Kajian-kajian yang lebih lanjut mungkin boleh mengubah keputusan tersebut.

Kami tidak mengetahui sama ada intervensi lain, termasuk pembedahan, adalah berkesan, kerana kami tidak mendapat ujian terkawal rawak yang menilai intervensi yang lain.

Catatan terjemahan

Diterjemahkan oleh Ng Chia Shyn (International Medical University).Disunting oleh MW Chan (Kolej Perubatan Pulau Pinang). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi Ng.ChiaShyn@student.imu.edu.my atau chanmw@pmc.edu.my

Resumen en términos sencillos

Intervenciones para los tofos gotosos

Antecedentes: ¿qué son los tofos y qué intervenciones se utilizan?

La gota es causada por cristales de urato que se forman dentro o alrededor de las articulaciones. La inflamación puede causar dolor, enrojecimiento, calor y edema en las articulaciones afectadas, lo que da lugar a dificultades al tocar o mover dichas áreas. Algunos de los motivos por los que los pacientes contraen gota incluyen la constitución genética, el sobrepeso, la ingestión de determinados fármacos (por ejemplo, ciclosporina), el deterioro de la función renal y los hábitos del estilo de vida como beber cantidades excesivas de alcohol y bebidas endulzadas con azúcar. Los tofos son nódulos que se desarrollan en los pacientes con gota crónica tratada de forma deficiente o no controlada. Los tofos pueden infectarse, causar dolor y dar lugar a una disminución en la función. Los tofos pueden ser tratados con fármacos para la disminución del urato (p.ej. benzbromarona, probenecid, alopurinol, febuxostat, pegloticase), extracción quirúrgica u otras intervenciones como la hemodiálisis. Las intervenciones quirúrgicas pueden usarse cuando se requiere la extracción urgente, p.ej. para el alivio de la compresión nerviosa.

Características de los estudios

Este resumen de una revisión Cochrane muestra las intervenciones para el tratamiento de los tofos. Después de realizar búsquedas de todos los estudios relevantes en mayo de 2013; se encontró sólo un estudio (resultados agrupados de dos ensayos controlados aleatorios [estudios clínicos en los que los pacientes son asignados al azar a uno de dos o más grupos de tratamiento]) que asignó al azar a 225 pacientes al pegloticase (cada dos semanas o una vez al mes) o al placebo, para el tratamiento de la gota crónica; 145 participantes tenían tofos y 131 contribuyeron con datos de resultado.

Resultados clave: lo que les sucede a los pacientes con tofos que son tratados con pegloticase cada dos semanas o una vez al mes versus placebo

Resolución de los tofos

- 33 pacientes más de cada 100 presentaron la resolución de uno o más tofos después de seis meses de tratamiento con pegloticase cada dos semanas en comparación con placebo (mejoría absoluta del 33%).

- 14 pacientes más de cada 100 presentaron la resolución de uno o más tofos después de seis meses de tratamiento con pegloticase una vez al mes en comparación con placebo (mejoría absoluta del 14%).

- 40 pacientes de cada 100 en el grupo pegloticase cada dos semanas presentaron la resolución de uno o más tofos.

- 21 pacientes de cada 100 en el grupo de pegloticase mensual presentaron la resolución de uno o más tofos.

- siete pacientes de cada 100 en el grupo de placebo presentaron la resolución de uno o más tofos.

Otros resultados incluyeron información de todos los participantes, y no hubo datos por separado sobre los pacientes con tofos. Por lo tanto, no se han informado en esta revisión. Sin embargo, se informó sobre los retiros debido a eventos adversos para la población total. La mayoría de los retiros se debieron a reacciones adversas a la infusión del fármaco.

Retiro debido a eventos adversos

- 16 pacientes más de cada 100 se retiraron del tratamiento con pegloticase cada dos semanas en comparación con placebo (16% más retiros).

- 17 pacientes más de cada 100 se retiraron del tratamiento con pegloticase mensual en comparación con placebo (17% más retiros).

- 18 pacientes de cada 100 se retiraron del tratamiento con pegloticase cada dos semanas debido a los eventos adversos.

- 19 pacientes de cada 100 se retiraron del tratamiento con pegloticase mensual debido a los eventos adversos.

- dos pacientes de cada 100 se retiraron del tratamiento con placebo debido a los eventos adversos.

Calidad de la evidencia

Las pruebas de calidad moderada indicaron que el pegloticase cada dos semanas o una vez al mes probablemente resuelve uno o más tofos. Sin embargo, este hecho debe compararse con las tasas altas de retiros del tratamiento debido a los eventos adversos, principalmente debido a un aumento de las reacciones a las infusiones. La reducción del dolor, la calidad de vida, la normalización del urato sérico y la función no se informaron por separado en los pacientes con tofos. La calidad de las pruebas se disminuyó debido a los resultados imprecisos. La investigación adicional puede cambiar estos resultados.

No se conoce si otras intervenciones, incluida la intervención quirúrgica, son efectivas, debido a que no se encontró ningún ensayo controlado aleatorio que evaluara otras intervenciones.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

Summary of findings(Explanation)

Summary of findings for the main comparison. Pegloticase every two weeks (biweekly) compared with placebo for participants with tophi
  1. 1 Estimates are from a single study, and wide confidence intervals indicate imprecision.
    2 NNTB or NNTH not applicable when result is not statistically significant. Number needed to treat for dichotomous outcomes calculated using 1/risk difference.

Pegloticase every two weeks (biweekly) compared with placebo for participants with tophi
Patient or population: participants with tophi in gout
Settings:
Intervention: pegloticase every 2 weeks (biweekly)
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Biweekly pegloticase
Regression of tophi
Central reader blinded to treatment allocation using RECIST software
Follow-up: median 6 months
74 per 1000 404 per 1000
(104 to 1000)
RR 5.45
(1 to 22)
79
(1 study)
⊕⊕⊕⊝
moderate 1

Absolute improvement with pegloticase 33% (16% to 50%)

Relative change 445% (40% to 2060%)

NNTB 3 (2 to 6)2

Joint pain reduction - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi
Quality of life - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi
Serum urate normalisation - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi
Function - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi

Number of participant withdrawals due to adverse events
Participant files reviewed by committee blinded to treatment allocation

Follow-up: median 6 months

23 per 1000 177 per 1000
(24 to 1000)
RR 7.59
(1.04 to 55.55)
128
(1 study)
⊕⊕⊕⊝
moderate 1

Absolute increase in withdrawals with pegloticase 16% (8% to 28%)

Relative increase in withdrawals 660% (4% to 5455%)

NNTH 7 (4 to 16)

(Reported for all participants but not separately for those with tophi)

Total adverse events - not reported 953 per 1000

941 per 1000

(851 to 1000)

RR 0.99 (0.91 to 1.07)128 (1 study)⊕⊕⊕⊝
moderate 1

Absolute decrease in adverse events with pegloticase 1% (9% decrease to 7% increase)

Relative decrease 1% (-9% to 7%)

NNTH - not applicable

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Monthly pegloticase compared with placebo for tophi

Summary of findings 2. Monthly pegloticase compared with placebo for tophi
  1. 1 Estimates are from a single study, and wide confidence intervals indicate imprecision.

    2 NNTB or NNTH not applicable when result is not statistically significant. Number needed to treat for dichotomous outcomes calculated using 1/risk difference

Monthly pegloticase compared with placebo for tophi
Patient or population: participants with tophi in gout
Settings:
Intervention: monthly pegloticase
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Monthly pegloticase
Regression of tophi
Central reader blinded to treatment allocation with RECIST software
Follow-up: mean 6 months
74 per 1000 212 per 1000
(52 to 889)
RR 2.86
(0.7 to 12)
79
(1 study)
⊕⊕⊕⊝
moderate 1

Absolute improvement with pegloticase: 14% (1% worse to 29% improvement)

Relative change: 190% improvement (30% worse to 1100% improvement)

NNTB - not applicable2

Joint pain reduction - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi
Quality of life - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi
Serum urate normalisation - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi
Function - not reportedSee commentSee commentNot estimable-See commentReported for all participants but not separately for people with tophi

Number of participant withdrawals due to adverse events
Participant files reviewed by committee blinded to treatment allocation

Follow-up: mean 6 months

23 per 1000 190 per 1000
(166 to 1000)
RR 8.19
(1.12 to 59.71)
127
(1 study)
⊕⊕⊕⊝
moderate 1

Absolute increase in withdrawals with pegloticase: 17% (7% to 26%)

Relative change: 719% more withdrawals (12% to 5870% more)

NNTH 6 (4 to 14)2

(Reported for all participants but not separately for people with tophi)

Total adverse events 953 per 1000

1000 per 1000

(980 to 1000)

RR 1.05

(0.98 to 1.14)

127 (1 study)⊕⊕⊕⊝
moderate 1

Absolute increase with pegloticase: 5% (20% decrease to 12% increase)

Relative increase 5% (-20% to 14%)

NNTH - not applicable2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Gout is the most common type of inflammatory arthritis in men; it affects at least 1% of the population in western countries (Terkeltaub 2003). It is characterised by the formation of monosodium urate crystals in joints and other tissues. The crystals trigger release of pro-inflammatory cytokines leading to inflammation causing gouty arthritis. Gouty arthritis can progress to chronic, deforming and physically disabling disease through the development of disfiguring tophi, joint destruction and persistent pain (Schlesinger 2011).

Tophi are nodular masses of monosodium urate. The presence of tophi is common in people with untreated or inadequately controlled gout. Tophi can become infected, cause pain and lead to a decrease in function. Complications may also occur when tophi develop in unusual sites such as heart valves, carpal tunnel, larynx and spine.

Description of the intervention

The mainstay of management of tophi is through pharmacological interventions (i.e. urate-lowering therapy including purine and non-purine xanthine oxidase inhibitors (such as allopurinol and febuxostat), uricosuric agents (e.g. probenecid and benzbromarone) and uricases (e.g. pegloticase)). However, other interventions, such as surgical management, are also used in practice.

How the intervention might work

Tophi develop in people with poorly treated or uncontrolled gout. This is postulated to be due to persistently raised serum uric acid levels. Pharmacotherapy aims to reduce serum uric acid levels and thus leads to a reduction in tophi.

Surgical therapy may be used for direct removal of tophi, for example, where the presence of tophi have led to a decrease in function, or where there is urgent need for removal, for example, as a cause of spinal cord compression.

Other interventions may work by also reducing serum uric acid (e.g. haemodialysis).

Why it is important to do this review

The presence of tophi can lead to significant morbidity, and even mortality through potential complications. Despite this, there have been no systematic reviews to date determining the management of tophi separately from the management of gout.

Objectives

To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout.

Methods

Criteria for considering studies for this review

Types of studies

All published, randomised controlled trials (RCTs) or controlled clinical trials (CCTs) with pseudo-randomised methods of allocating people to treatment considering the management of tophi in gout. Although our original search included other types of studies, for the purpose of this review we will only include trials and pseudo-RCTs for assessment of treatment benefit.

Types of participants

All adults (aged 18 years or older) with a diagnosis of gout and the presence of one or more tophi. Where trials included gout with a subset of people with tophi, we reported on the people with tophi only.

Types of interventions

  • Pharmacotherapy (i.e. urate-lowering therapy including purine and non-purine xanthine oxidase inhibitors, uricosuric agents and uricases).

  • Any form of surgical removal (e.g. debridement, shaving, arthroscopic removal).

  • Other interventions.

Comparators were:

  • placebo;

  • no surgical or pharmacological intervention;

  • one pharmacological or surgical intervention versus another;

  • combination versus single intervention or another combination therapy.

Types of outcome measures

Major outcomes
  • Proportion of people with complete resolution.

  • Pain reduction.

  • Health-related quality of life.

  • Serum urate normalisation.

  • Function (i.e. activity limitation).

  • Study participant withdrawals due to adverse events (e.g. wound infection, failure to close or surgical complications, infusion reactions).

  • Total adverse events.

Minor outcomes
  • Proportion of people with recurrence.

  • Time to recurrence.

Search methods for identification of studies

Electronic searches

We searched the following databases using the search strategies detailed in the appendices. We completed the search in May 2013:

  1. the Cochrane Central Register of Controlled Trials (CENTRAL, via The Cochrane Library) on 20 May 2013 (Appendix 1);

  2. Ovid MEDLINE 1948 to May 2013 (Appendix 2);

  3. EMBASE 1980 to May 2013 (Appendix 3);

  4. trial registries: Clinical Trials.gov (www.clinicaltrials.gov, accessed 20 May 2013); the Australian & New Zealand Clinical Trial Registry (www.anzctr.org.au, accessed 20 May 2013); and the World Health Organization (WHO) Clinical Trials Registry Platform (www.who.int/ictrp/en/, accessed 20 May 2013) to identify potential ongoing studies.

We did not exclude studies based on language.

Searching other resources

We searched the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) conference abstracts from 2010 and 2011. We also conducted handsearches of references from included articles and relevant reviews to identify any additional studies not retrieved by the search strategies.

Data collection and analysis

Selection of studies

Two review authors (MS, OV) independently reviewed all retrieved trials to identify the ones that fulfilled the criteria for inclusion in this systematic review. We retrieved all relevant articles in full-text for closer examination. We resolved disagreements about study inclusion or exclusion by consensus or by discussion with a third review author (CE) if needed. We translated studies into English where necessary.

Data extraction and management

Two independent review authors (MS, OV) extracted the following information from included trials using pre-determined data extraction forms:

  • study design;

  • characteristics of the study population (age, gender, number and distribution of tophi);

  • intervention used;

  • control interventions;

  • outcome measures;

  • timing of outcome assessment; and

  • methodological domains relevant to risk of bias assessment.

We resolved any differences in data extraction by referring back to the original articles and establishing consensus. We consulted a third review author (CE) to help resolve differences if necessary.

Assessment of risk of bias in included studies

We assessed the potential for bias in included studies using a 'Risk of bias' table (Higgins 2011). Two review authors (MS, OV) independently assessed the risk of bias for all included trials, and resolved any disagreements by consensus. We consulted a third review author (CE) to help resolve differences if necessary. We assessed the following methodological domains in conformity with The Cochrane Collaboration's recommendations.

  1. Random sequence generation: to determine if the method of generating the randomisation sequence was adequate to prevent biased allocation to interventions.

  2. Allocation concealment: to determine if adequate methods were used to conceal allocation to interventions.

  3. Blinding of participants, personnel and outcome assessors for each outcome measure.

  4. Incomplete outcome data.

  5. Selective outcome reporting.

  6. Other potential sources of bias, such as inappropriate administration of an intervention or insensitive instrument to measure outcome.

To determine the risk of bias of an included study, for each criterion we evaluated the presence of sufficient information and the likelihood of potential bias. We rated each criterion as 'low risk' of bias, 'high risk' of bias or 'unclear risk' of bias (either lack of information or uncertainty over the potential for bias).

We planned to compare the fixed-effect estimate against the random effects model. In the event of the possible presence of small sample bias in the published literature (i.e. in which the intervention effect was more beneficial in smaller studies), the random-effects estimate of the intervention is more beneficial than the fixed-effect estimate (Sterne 2011).

Measures of treatment effect

For dichotomous outcomes, we calculated the risk ratio (RR) with corresponding 95% confidence intervals (CIs) and numbers needed to treat for an additional beneficial (NNTB) or harmful (NNTH) outcome. We had planned to calculate mean difference and 95% CI for continuous outcomes measured on the same scale, or standardised mean difference and 95% CI for continuous outcomes reported on different scales. However, the included trials only reported dichotomous outcomes.

Unit of analysis issues

For the included study, we compared each treatment arm (i.e. pegloticase every two weeks (biweekly) and monthly pegloticase) with placebo in separate analyses. We also compared biweekly pegloticase with monthly pegloticase.

Dealing with missing data

We did not need to deal with missing data.

Assessment of heterogeneity

We planned to assess heterogeneity using subgroup analyses on effect of serum urate levels on tophus regression, or rate of tophi recurrence following surgical treatment. We included only one study in the review, hence we did not assess for heterogeneity.

Assessment of reporting biases

In order to determine whether reporting bias was present, we determined whether the protocol of the RCT was published before recruitment of participants of the study was started by searching trial registries for trial protocols. We evaluated whether selective reporting of outcomes was present (outcome reporting bias).

We were unable to explore the potential for reporting bias by funnel plots further due to lack of data.

Data synthesis

We planned to perform meta-analyses using a random-effects model, regardless of the results of the I2 statistic. We were unable to analyse the data in meta-analyses since we only included one study. We have presented analyses of outcomes for three comparisons from a single study in forest plots.

Presentation of key results

We produced a 'Summary of findings' tables using GRADEpro software. This table provides key information concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the most important participant-relevant outcomes (number of participants with complete resolution of tophi, number of study participant withdrawals due to adverse events, total adverse events, health-related quality of life, serum urate normalisation and function) as recommended by The Cochrane Collaboration (Schünemann 2011a).

The 'Summary of findings' table includes an overall grading of the evidence related to each of the main outcomes using the GRADE approach (Schünemann 2011b). In addition to the absolute and relative magnitude of effect provided in the 'Summary of findings' table, we calculated the NNTB or NNTH.

We were only able to extract data for dichotomous outcomes (proportion with tophi resolution; proportion who withdrew due to adverse events).

For dichotomous outcomes, we calculated the absolute risk difference using the risk difference statistic in Review Manager (RevMan 2011) and the result expressed as a percentage. The relative per cent change for dichotomous data was calculated as the RR - 1 and expressed as a percentage. The number needed to treat was calculated from the RR using 1/risk difference (RD).

Subgroup analysis and investigation of heterogeneity

There were insufficient studies to do planned subgroup analyses.

Sensitivity analysis

There were insufficient studies to do planned sensitivity analysis.

Results

Description of studies

Results of the search

Our preliminary searches found no RCTs examining interventions for tophi. Based on this, we extended the search to include systematic literature reviews, RCTs, CCTs, observational studies, case series and case reports. We have reported on other studies that we identified in our discussion.

We carried out the initial search on 22 October 2011 (Figure 1). This recovered 3206 articles. We excluded 3116 articles on review of title and abstract and 90 following full-text review.

Figure 1.

Study selection flow chart.

Only one article met the inclusion criteria for this review. We performed an updated search on 20 May 2013; we recovered 416 additional articles, none of which were RCTs that met the inclusion criteria.

Included studies

We included only one study in this systematic review (Sundy 2011). A total of 262 participants participated in the study and 225 participants were randomised. The primary efficacy end point was normalisation of plasma uric acid, and secondary efficacy end points included reduction in tophi, gout flares, and improvement in physical function and quality of life. One hundred and thirty-one participants had tophi at baseline; 52 in the pegloticase every two weeks (biweekly) group, 52 in the monthly pegloticase group and 27 in the placebo group.

Sundy 2011 reported on the pooled results of two replicate randomised, double-blind placebo-controlled trials. The aim of the study was to report on the efficacy and tolerability of pegloticase in people with chronic gout that was refractory to traditional urate-lowering therapy.

Participants were recruited from rheumatology practices across the USA, Canada and Mexico between June 2006 and October 2007. They were aged 18 years or older and met criteria for refractory gout:

  • baseline serum uric acid 8.0 mg/dL or greater;

  • contraindication to treatment with allopurinol or history of failure to normalise uric acid despite three months or more with maximal medically appropriate allopurinol dose (determined by the participant's physician);

  • at least one of the following:

    • three or more self reported gout flares during previous 12 to 18 months;

    • one or more tophi;

    • gouty arthropathy defined clinically or radiographically as joint damage due to gout.

Participants who were on urate-lowering therapy at the time of screening underwent a one-week washout period prior to entering study.

Two hundred and twenty-five participants were randomised to one of three arms: biweekly pegloticase infusion, monthly pegloticase infusion - pegloticase infusion alternating with placebo infusion every two weeks or placebo (also an infusion). Two hundred and twelve participants were included in primary analysis; 85 participants in biweekly pegloticase group, 84 in monthly pegloticase group and 43 in placebo group. Participants were analysed according to the group they were randomised to. Randomisation was performed by an automated interactive voice response system. Participants were given infusions of 250-mL 0.9% sodium chloride containing either pegloticase 8 mg or placebo every two weeks.

The primary efficacy point was proportion of uric acid responders; this was defined as maintaining a plasma uric acid level of less than 6.0 mg/dL for over 80% of the time during both months three and six. Secondary efficacy points included tophus regression. For this, standardised photographs of hands and feet and two other sites with tophi were taken. These were compared by a central reader who was unaware of treatment allocation.

Excluded studies

We assessed 90 articles in full text and excluded them based on population (Rozenberg 1995), study type (Chen 1999; Feher 2003; Flugel 1978; Hulsmeyer 2000; Kaarela 2009; Kitazawa 2006; Klotz 1981; Kropelin 1972; Kumar 2005; Kung 1991; Martin 1982; Marwaha 2010; McLean 2004; Piza-Katzer 1997; Ribeiro 2009; Richette 2007; Zuber 1996; Abrahamsson 1987; Abrams 2006; Baraf 2008; Barrett 2001; Baxter 2009; Becker 2009; Caldas 2007; Chang 2005; Chatterjee 2008; Dhote 1997; El Sandid 2004; Ertugrul 2000; Fiehn 2006; Frankel 1984; Funck-Brentano 2011; Graefen 1991; Griffin 2009; Hughes 2005;Johnson 1979; Kao 2000; Kemp 2010; Kerman 1993; Ko 1996; Kobayashi 2005; Kuo 2007; Landry 1986; Lapidus 1963; Lee 2003; Lee 2010; Li 2006; Lin 2009; Lui 2008; Mahmud 2005; Martínez-Villen 2007; Marwaha 2010; McGonagle 2007; Melloni 2004; Mockford 2003; Moolenburgh 2006; Morino 2007; Mrabet 2010; Nakazawa 2004; Niva 2006; Ntsiba 2010; Pai 1993; Pankhania 2006; Paquette 2000; Perez-Ruiz 2002; Pledger 1976; Raman 1981; Reineke 2009; Richette 2006; Schuind 2003; Sekiya 2010; Sener 2000; Shimizu 2008; Staub-Zahner 2007; Tan 2003; Tashiro 2002; Tausche 2011; Thavarajah 2011; Tran 2011; Uh 2011; Vetter 2008; Vogt 2005; Wakabayashi 1998; Weniger 2003; Woughter 1959; Yen 2002; Yetkin 1999; Migita 2001, and no intervention (Pouye 2006).

Risk of bias in included studies

Allocation

There was no selection bias; participants were randomly allocated to groups via an automated interactive voice response system. Numbers were stratified to get comparable numbers of participants with tophi within the groups.

Blinding

There was adequate blinding of outcome data (e.g. the use of a blinded central reader for tophi outcomes), and thus a low risk of detection bias. There was also blinding in terms of treatment (ensuring same number of infusions for all participants); however, blinding of staff during treatment, and thus the risk of performance bias, was unclear.

Incomplete outcome data

Incomplete outcome data were addressed where possible. Three participants were lost to follow-up. A total of 145 participants had tophi at baseline, of these, 131 were reported on in terms of complete resolution of tophi. The proportion of participants with tophi who dropped out was evenly distributed across treatment groups.

Selective reporting

The study protocol was registered with ClinicalTrials.gov in 2006. There were minimal changes made to the protocol. No selective reporting was noted. The work was funded by Savient Pharmaceuticals. The author-employees were responsible for study concept and design, and sponsor-employees were responsible for data collection and storage. However, we have no evidence to suggest there was selective reporting of data.

Other potential sources of bias

We noted no other potential sources of bias, such as inappropriate administration of an intervention or insensitive instrument to measure outcome.

Effects of interventions

See: Summary of findings for the main comparison Pegloticase every two weeks (biweekly) compared with placebo for participants with tophi; Summary of findings 2 Monthly pegloticase compared with placebo for tophi

We present only the outcomes that were reported separately for the subgroup of participants with tophi at baseline (resolution of tophi). All other outcomes were reported for total participants with no separate reporting for people with tophi. Thus, we were unable to report the effect of pegloticase on other outcomes in the participants with tophi. However, we have reported on withdrawal due to adverse events and total adverse events for the total participants.

Resolution of tophi

More participants in the pegloticase every two weeks (biweekly) group had complete resolution of one or more tophi compared with participants in the placebo group (21/52 with biweekly pegloticase versus 2/27 with placebo; RR 5.45, 95% CI 1 to 22; NNTB 3, 95% CI 2 to 6; Analysis 1.1) (Summary of findings for the main comparison).

More participants in the monthly pegloticase group had complete resolution of one or more tophi compared with participants in the placebo group (11/52 with monthly pegloticase versus 2/27 with placebo; RR 2.86, 95% CI 0.7 to 12.0; NNTB 8, 95% CI 4 to 91; Analysis 2.1) (Summary of findings 2).

In addition, comparison of the two pegloticase group found that more participants in the biweekly pegloticase arm had complete resolution of one or more tophi compared with participants in the monthly pegloticase group (RR 1.91, 95% CI 1.03 to 3.55; Analysis 3.1).

Other outcomes

As pain, function, serum acid normalisation and quality of life data were only presented for the total population in the trial, and not for the subgroup with tophi at baseline, we could not report these outcomes.

Withdrawal due to adverse events

Pegloticase administered biweekly resulted in more withdrawals due to adverse events than placebo (15/85 with biweekly pegloticase versus 1/43 with placebo; RR 7.59, 95% CI 1.04 to 55.55; NNTH 5, 4 to 17; Analysis 1.2) (Summary of findings for the main comparison).

Pegloticase administered monthly also resulted in more withdrawals due to adverse events than placebo (16/84 with monthly pegloticase versus 1/43 with placebo; RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14; Analysis 2.2) (Summary of findings 2).

A similar proportion of participants in the biweekly and monthly pegloticase arms withdrew due to adverse events (RR 0.93, 95% CI 0.49 to 1.75; Analysis 3.2).

Infusion reactions were the most common reason for study discontinuation with both biweekly and monthly pegloticase (22/85 with biweekly pegloticase versus 2/43 with placebo; RR 5.56, 95% CI 1.37 to 22.57; NNTH 2; 35/84 with monthly pegloticase group versus 2/43 with placebo; RR 8.96, 95% CI 2.26 to 35.49; NNTH 2).

Of note, one ACR hotline update advised measurement of routine serum uric acid level prior to each pegloticase infusion in order to identify people at increased risk of infusion reaction. This study noted that 79% of participants who had an infusion reaction in the development of pegloticase antibody, did so after loss of urate-lowering response (i.e. rising uric acid levels). Two deaths during the treatment period were attributed to cardiovascular adverse events (cardiac arrest, arrhythmia) in the biweekly group. The third death was due to renal failure in the monthly pegloticase group.

Adverse events

Pegloticase administered biweekly resulted in similar numbers of participants with any adverse event to placebo (80/85 with biweekly pegloticase treatment versus 41/43 with placebo; RR 0.99, 95% CI 0.91 to 1.07) (Summary of findings for the main comparison).

Pegloticase administered monthly also resulted in similar numbers of participants with any adverse event to placebo (84/84 with monthly pegloticase versus 41/43 with placebo; RR 1.05, 95% CI 0.98 to 1.14) (Summary of findings 2).

The top three most common adverse events were gout flares, infusion reactions and headaches; 80% of adverse events were due to flares of gout. This may explain the high rate of adverse events in the placebo groups that were essentially untreated.

More participants in the biweekly and monthly pegloticase group had infusion reactions compared with participants in the placebo group (22/85 with biweekly pegloticase versus 2/43 with placebo; RR 5.56, 95% CI 1.37 to 22.57; NNTH 2; 35/84 with monthly pegloticase group versus 2/43 with placebo; RR 8.96, 95% CI 2.26 to 35.49; NNTH 2).

We were unable to perform the subgroup or sensitivity analyses as only one study met the inclusion criteria for this review.

Discussion

Summary of main results

Only one study met our inclusion criteria for this review for interventions for tophi in gout. The study showed that the pegloticase every two weeks (biweekly) dose of 8 mg was beneficial in reduction of tophi. Monthly pegloticase was also beneficial but to a lesser degree. Relative risk of withdrawals due to adverse events appeared to be similar in the biweekly and monthly pegloticase groups. Our review also shows that further RCT data are needed to examine specifically interventions for tophi.

Overall completeness and applicability of evidence

We have included the only RCT evidence for interventions for tophi that is published at present. We found no RCT data for other interventions or for non-pharmacological interventions such as surgery.

We extended our search to include studies other than RCTs for management of tophi. We will discuss them here.

Pharmacotherapy

Becker 2009 reported the results of fEbuXostat/allopurinol Comparative Extension Long-term study (EXCEL). This was an open-label extension of two phase III double-blind trials. These compared febuxostat (80 and 120 mg) versus allopurinol (100 or 300 daily, higher dose used if serum creatinine less than 1.5 mg/dL). Outcome was measured by percentage reduction in number of tophi and reduction in size or disappearance of index tophus. At baseline, 214 participants had palpable tophi. The high-dose febuxostat (120mg) group appeared to fare better in terms of complete resolution of primary tophi. The study also noted that overall, long-term maintenance of goal serum uric acid led to a reduction in tophi.

Perez-Ruiz 2002 reported on a prospective observational study comparing allopurinol alone, benzbromarone alone and allopurinol plus benzbromarone on tophi resolution. All participants had one or more tophi at baseline. There was no placebo arm to act as comparator. Outcome was reduction in size of target tophus. The participants in the combination group appeared to fare best with a mean rate of reduction until tophus resolution of 1.53 mm/month (standard deviation 0.45). However, the mean time to resolution in this group was the longest at 27.8 months (standard deviation 1.21). Participants with more severe tophaceous gout were given combination therapy, which may explain this finding (Table 1).

Table 1. Pharmacological studies
  1. No: number.

Study Study type No of participants (no of drop-outs) Duration Intervention Comparator Overall risk of bias

Becker 2009

USA

Canada

Open-label extension1086 (168)3 yearsFebuxostat 80 or 120 mgAllopurinolHigh

Perez-Ruiz 2002

Spain

Cohort (prospective observational)70 (7)6 monthsAllopurinol 200 mg daily plus benzbromarone 50 mg dailyAllopurinol maximum 300 mg daily alone or benzbromarone maximum 200 mg daily aloneHigh

We retrieved 14 case-series and reports that compared pharmacological interventions. There were few negative outcomes reported. Objective measures of outcome included pictoral (photographs taken before and after intervention) and size/physical measurement. Not all of the studies reported objective measures of outcome (Table 2).

Table 2. Pharmacological interventions - case-series and reports
  1. CT: computed tomography; No: number; QoL: quality of life; sUA: serum uric acid.

Intervention No of case-series/reports Total no of participants Positive outcomes Negative outcomes Objective measure of outcome?

Interleukin-1 inhibitor (anakinra)

Tran 2011; McGonagle 2007

24

Pain reduction

sUA reduction

0Pictoral resolution of tophi (2)

Febuxostat

Tausche 2011; Uh 2011

22

sUA reduction

Improved QoL

Reduction in tophi

0Pictoral

Allopurinol

Mrabet 2010; Chatterjee 2008; Raman 1981; Shimizu 2008

44

Improved function

Reduction in tophi

sUA reduction

No resolution of tophi (1 case)

Pictoral (1)

CT image (1)

Probenecid and steroid injections

Niva 2006

11

Improved function

Pain reduction

-None

Rasburicase

Baxter 2009; Richette 2006; Vogt 2005

312

Improved function

Reduction in tophi

sUA reduction

Acute attacks of arthritis (1)Physical measurement (12 participants)

Pegloticase

Baraf 2008

12

sUA reduction

Resolution of tophi

-Size of tophi

Infliximab

Fiehn 2006

11Pain reduction-None

Surgical interventions

We found 40 case-series and reports for surgical interventions for tophi. These compared decompression/laminectomy, excision/debridement and soft-tissue shaving. All reported positive outcomes. However, none of the studies employed objective outcome measures (Table 3).

Table 3. Surgical interventions
  1. No: number.

Intervention No of case-series/reports Total no of participants Positive outcomes Negative outcomes Objective measure of outcome?

Decompression/laminectomy

Barrett 2001; Chang 2005; Dhote 1997; El Sandid 2004; Kao 2000; Ko 1996; Kuo 2007; Lin 2009; Mahmud 2005; Martínez-Villen 2007; Ntsiba 2010; Pankhania 2006; Pledger 1976; Tan 2003; Thavarajah 2011; Yen 2002

1621

Improved function

Reduction in pain

Postoperative flare of gout in 2 casesNone

Excision/amputation/debridement

Abrams 2006; Ertugrul 2000; Kerman 1993; Kobayashi 2005; Lapidus 1963; Sener 2000; Yetkin 1999; Lee 2010; Li 2006; Lui 2008; Martin 1982; Melloni 2004; Mockford 2003; Morino 2007; Pai 1993; Paquette 2000; Reineke 2009; Schuind 2003; Tashiro 2002; Vetter 2008; Wakabayashi 1998; Weniger 2003; Woughter 1959

2327

Pain reduction

Improved function

No evidence of local recurrence

Superficial wound dehiscence in 1 caseNone

Soft-tissue shaving procedure

Lee 2003

117

Improved function

Pain reduction

Skin loss (2 cases)

Gastrointestinal bleed leading to death (1 case)

none

Other interventions

The only other single intervention found in our literature search was haemodialysis. This was in one participant with chronic renal failure who was started on haemodialysis for congestive heart failure, and incidentally was noted to have a reduction of tophi. No objective measure of outcome was noted.Migita 2001

Combination therapies

There were 13 studies which reported on combination therapies. These also had few negative outcomes.

Although there are some objective measures of outcome in this group, we could not determine whether combination was superior to single surgical, pharmacological or other therapy due to lack of head to head trials (Table 4).

Table 4. Combination therapies
  1. No: number; sUA: serum uric acid.

Intervention No of case-series/reports Total no of participants Positive outcomes Negative outcomes Objective measure of outcome?

Rasburicase plus allopurinol

Moolenburgh 2006

11

Reduction in tophi

sUA reduction

Flare after each infusionSize

Benzbromarone plus allopurinol

Caldas 2007

11

Resolution of tophi

Improved function

0Pictoral

Anakinra plus haemodialysis

Funck-Brentano 2011

11

Resolution of tophi

Improved function

0Pictoral

Benzbromarone plus allopurinol, arthroscopic removal

Staub-Zahner 2007

11Improved function0None

Debridement, vacuum-assisted dressing and allopurinol

Kemp 2010

11No recurrence of tophi0None

Excision/debridement/joint replacement and allopurinol

Abrahamsson 1987; Frankel 1984; Graefen 1991; Griffin 2009; Hughes 2005; Landry 1986; Nakazawa 2004; Sekiya 2010

88

Reduction in pain

Improved function

Postoperative ischaemic ulceration (1)

Recurrence of tophi (1)

None

Quality of the evidence

The overall quality of evidence was moderate for resolution of tophi, withdrawals due to adverse events and total adverse events after treatment with pegloticase. We assessed study limitations, indirectness, consistency and publication bias. The results were based on one study, and we downgraded the evidence because of imprecision. Other important outcomes were not measured in participants with tophi: pain, quality of life, serum urate normalisation and function, thus we do not know the effect of treatment on these outcomes. The quality of evidence is summarised in Summary of findings for the main comparison and Summary of findings 2.

Savient Pharmaceuticals, as the manufacturer of pegloticase, sponsored the study. However, there was no evidence that this has led to selective data reporting.

Other pharmacological or surgical interventions have not been assessed in RCTs.

Potential biases in the review process

We used a sensitive search strategy and included searching of grey literature to identify as many studies as possible. However, we acknowledge that the time lag between the completion of the search and the publication of the review may be a potential source of bias.

Two review authors independently extracted titles, abstracts and data, minimising errors and bias in the review process.

We did not report data on pain, function, serum acid normalisation and quality of life as these were only presented for the total population in the trial, and not for the subgroup with tophi at baseline.

Agreements and disagreements with other studies or reviews

To our knowledge there has been no published systematic literature reviews or meta-analyses examining interventions for tophi in gout in isolation. There is one previous Cochrane systematic review on pegloticase in chronic gout (Anderson 2010). However, the study did not report on tophi outcomes.

Authors' conclusions

Implications for practice

Sundy 2011 showed that pegloticase is probably beneficial in the management of tophi in gout. The main reason for withdrawal from treatment was infusion reactions.

Further randomised controlled trial (RCT) evidence is needed for all other urate-lowering therapies such as allopurinol. Analyses of lowering serum uric acid and its effect on the rate of reduction of tophi would also be useful.

We found several case series and reports describing non-pharmacological therapies for management of tophi. These included surgical interventions such as decompression and debridement, and other interventions such as haemodialysis. However, there was also no RCT evidence for this. Thus, it was difficult to draw conclusions about the benefit of these treatments against pharmacological treatments.

Implications for research

Currently there is insufficient RCT evidence to show which intervention is preferable for treating tophi in gout. Future research could include RCTs examining non-pharmacological interventions for tophi. Outcomes such as withdrawal due to adverse events, quality of life and function could be included specifically for people with tophi (Anderson 2010).

Sundy 2011 have suggested that measurement of serum uric acid prior to infusion may identify people likely to have developed antibodies and, therefore, at risk of reaction. Future research could also examine this in people with tophi.

Acknowledgements

The authors thank Louise Falzon, former Trials Search Co-ordinator of the Cochrane Musculoskeletal Group, for assisting with the design of the search strategy.

Data and analyses

Download statistical data

Comparison 1. Pegloticase every two weeks (biweekly) versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proportion with tophi resolution1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2 Withdrawal due to adverse events1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3 Total adverse events1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Pegloticase every two weeks (biweekly) versus placebo, Outcome 1 Proportion with tophi resolution.

Analysis 1.2.

Comparison 1 Pegloticase every two weeks (biweekly) versus placebo, Outcome 2 Withdrawal due to adverse events.

Analysis 1.3.

Comparison 1 Pegloticase every two weeks (biweekly) versus placebo, Outcome 3 Total adverse events.

Comparison 2. Pegloticase monthly versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proportion with tophi resolution1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2 Withdrawal due to adverse events1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3 Total adverse events1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Pegloticase monthly versus placebo, Outcome 1 Proportion with tophi resolution.

Analysis 2.2.

Comparison 2 Pegloticase monthly versus placebo, Outcome 2 Withdrawal due to adverse events.

Analysis 2.3.

Comparison 2 Pegloticase monthly versus placebo, Outcome 3 Total adverse events.

Comparison 3. Pegloticase every two weeks (biweekly) versus pegloticase monthly
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proportion with tophi resolution1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2 Withdrawals due to adverse events1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 Pegloticase every two weeks (biweekly) versus pegloticase monthly, Outcome 1 Proportion with tophi resolution.

Analysis 3.2.

Comparison 3 Pegloticase every two weeks (biweekly) versus pegloticase monthly, Outcome 2 Withdrawals due to adverse events.

Appendices

Appendix 1. CENTRAL search strategy

#1MeSH descriptor Gout explode all trees
#2gout*:ti,ab
#3tophi:ti,ab
#4tophaceous:ti,ab
#5tophus:ti,ab
#6(#1 OR #2 OR #3 OR #4 OR #5)

Appendix 2. MEDLINE search strategy

1gout$.tw. AND co.fs
2tophus.tw
3tophi.tw
4tophaceous.tw
5exp GOUT/co [Complications]
61 OR 2 OR 3 OR 4 OR 5
7"randomi?ed controlled trial".pt
8"controlled clinical trial".pt
9randomi?ed.ab
10placebo.ab
11"drug therapy".fs
12randomly.ab
13trial.ab
14groups.ab
157 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14
16(animals NOT (humans AND animals)).sh
1720 NOT 21
186 AND 17
19exp COHORT STUDIES/
20cohort$.tw.
21"controlled clinical trial".pt
22exp CASE-CONTROL STUDIES/
23(case$ AND control$).tw
24(case$ AND series).tw
25"case reports".pt
26(case$ adj2 report$).tw
27(case$ adj2 stud$).tw
28EPIDEMIOLOGIC METHODS/
2919 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28
306 AND 29
3118 OR 30

Appendix 3. EMBASE search strategy

1gout$.tw. AND co.fs
2tophus.tw
3tophi.tw
4tophaceous.tw
5exp GOUT/co [Complications]
61 OR 2 OR 3 OR 4 OR 5
7RANDOMIZED CONTROLLED TRIAL/
8CLINICAL TRIAL/
9RANDOMIZATION/
10SINGLE BLIND PROCEDURE/
11DOUBLE BLIND PROCEDURE/
12CROSSOVER PROCEDURE/
13PLACEBO/
14"Randomi?ed controlled trial$".tw
15Rct.tw
16"Random allocation".tw
17"Randomly allocated".tw
18"Allocated randomly".tw
19(allocated adj2 random).tw
20"Single blind$".tw
21"Double blind$".tw
22((treble OR triple) adj1 blind$).tw
23Placebo$.tw
24PROSPECTIVE STUDY/
257 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24
26CASE STUDY/
27"Case report".tw
28ABSTRACT REPORT/ OR LETTER/
2926 OR 27 OR 28
3025 not 29
31exp COHORT ANALYSIS/
32exp LONGITUDINAL STUDY/
33exp PROSPECTIVE STUDY/
34exp FOLLOW UP/
35cohort$.tw
36exp CASE CONTROL STUDY/
37(case$ AND control$).tw
38exp CASE STUDY/
39(case$ AND series).tw
40CASE REPORT/
41(case$ adj2 report$).tw
42(case$ adj2 stud$).tw
4331 OR 32 OR 33 OR 34 OR 35 OR 36 OR 37 OR 38 OR 39 OR 40 OR 41 OR 42
446 AND 30
456 AND 43
4644 OR 45

What's new

DateEventDescription
25 June 2014AmendedCMSG ID A074-R

Contributions of authors

MS wrote the current version of the protocol.

CE, CB and OV provided comments and suggestions on draft versions of the protocol.

All review authors approved the current version.

Declarations of interest

None known.

Sources of support

Internal sources

  • University Hospital Southampton NHS Foundation Trust, UK.

    In-kind support

  • University of Toronto, Canada.

    In-kind support

External sources

  • No sources of support supplied

Differences between protocol and review

We included studies with a subset of people with tophi. We reported only on the participants with tophi.

We replaced the primary outcomes with a list of seven major outcomes in the review, to match the seven included in the 'Summary of findings' tables, and the remaining outcomes are called 'minor outcomes', rather than secondary outcomes.

We defined other sources of bias in the methods of the review after the protocol was published, specifically inappropriate administration of an intervention or insensitive instrument to measure outcome.

Subgroup analysis and investigation of heterogeneity

We had anticipated there may be differences in outcomes for the following subgroups.

  • High serum urate (greater than 0.36 mmol/L) versus low serum urate (0.36 mmol/L or less).

Thus, we planned to extract the outcome (proportion with resolution of tophi) separately for the participants with high serum urate and participants with low serum urate from each trial. We planned to compare the magnitudes of effect to assess possible differences in response to treatment between the subgroups. However, the outcomes were not reported by subgroup for participants with tophi.

Sensitivity analysis

Where sufficient studies existed, we had planned sensitivity analyses to assess:

  • the effect of including inadequate or unclear treatment allocation (including studies with quasi-randomised designs);

  • the effect of including unblinded or inadequately blinded study participants;

  • the effect of including unblinded or inadequately blinded outcome assessors.

Notes

Comparison of pegloticase every two weeks (biweekly) versus monthly pegloticase was the least clinically significant. We did not include this in the plain language summary or abstract due to word constraints.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Sundy 2011

MethodsStudy design: pooled results of 2 double-blind 3-arm randomised controlled trials
Participants

Number of participants enrolled: 262

Number of participants randomised: 225

Number of participants in primary analysis: 212 (85 in pegloticase every 2 weeks (biweekly) group, 84 in monthly pegloticase group, 43 in placebo group)

Setting: 56 rheumatology practices across USA, Canada and Mexico from June 2006 to October 2007

Number of baseline tophi: 155 (52 in biweekly pegloticase group, 64 in monthly pegloticase group, 29 in placebo group)

Trial 1 (trial C0405):

Mean age (± standard deviation); 58.2 ± 15 years in biweekly pegloticase group, 55.1 ± 13 in monthly pegloticase group, 57.2 ± 13 in placebo group

Male sex (%): 30 (69.8%) in biweekly pegloticase group, 35 (85.4%) in monthly pegloticase group, 15 (75%) in placebo group

Trial 2 (trial C0406):

Mean age (± standard deviation): 54.3 ± 16 years in biweekly pegloticase group, 53.9 ± 14 in monthly pegloticase group, 53.8 ± 11 in placebo group

Male sex (%): 38 (91.5%) in biweekly pegloticase group, 34 (79.1%) in monthly pegloticase group, 21 (91.3%) in placebo group

Inclusion criteria:

  • aged ≥ 18 years

  • baseline serum uric acid ≥ 8.0 mg/dL

  • contraindication to treatment with allopurinol or history of failure to normalise uric acid despite ≥ 3 months with maximal medically appropriate allopurinol dose (determined by physician treating the participant)

  • ≥ 1 of the following:

    • ≥ 3 self reported gout flares during previous 12-18 months

    • ≥ 1 tophi

    • gouty arthropathy defined clinically or radiographically as joint damage due to gout

Exclusion criteria:

  • glucose 6-phosphate dehydrogenase deficiency

  • prior treatment with uricase-containing agent

  • pregnancy

  • unstable angina

  • uncontrolled hypertension (> 150/95 mmHg)

  • cardiac arrhythmias

  • uncompensated congestive heart failure

  • renal dialysis

  • solid-organ transplant

Interventions

Intervention (85 participants): pegloticase 8 mg every 2 weeks, given as 2-hour intravenous infusion in 250 mL 0.9% sodium chloride

Comparator (84 participants): pegloticase 8 mg monthly; infusion was delivered every 2 weeks, pegloticase alternating with placebo

Placebo (43 participants): saline infusion without pegloticase given every 2 weeks

25 weeks of treatment, with 25 weeks of follow-up for all groups

Outcomes

Primary outcome:

  • proportion of plasma uric acid responders in each pegloticase group versus placebo

Secondary outcomes (which included tophus resolution) were reported at weeks 13, 19 and 25 (final visit):

  • proportion of plasma urate responders (plasma uric acid < 6.0 mg/dL for ≥ 80% of the time during months 3 and 6

  • tophus resolution (assessed by comparison of serial photographs of hands, feet and up to 2 other sites by central reader blinded to treatment allocation using computer-assisted quantitative measurement

  • reduction in proportion of participants with gout flare (reported by participant at time of occurrence and confirmed by investigator at interview,

  • numbers of flares per participant during months 1-3 and 4-6

  • reduction in tender and swollen joint count assessed by investigator

  • participant-reported changes in pain measured with Health Assessment Questionnaire pain scale (0-100 mm, where 0 = no pain)

  • physical function and quality of Life measured with HAQ-DI (20 questions regarding various physical activities including activities of daily living were scored from 0 = 'no difficulty', to 3 = 'unable to do without help or use of aids'. The individual scores were meaned, with weighting for use of help, to obtain a final score of 0-3.34) and 36-item Short Form (12 domains spanning physical and mental components)

  • withdrawals due to adverse events, adverse and serious adverse events

Notes

Savient Pharmaceuticals, producers of pegloticase, sponsored the study

We extracted data for complete resolution of tophi and withdrawal due to adverse events

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAutomated interactive voice response system was used to allocate participants randomly to treatment. Participants were stratified to ensure comparable numbers of participants with tophi within each group
Allocation concealment (selection bias)Low riskAutomated interactive voice response system was used to allocate to treatment
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of personnel was not reported
Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Central reader blinded to treatment allocation for tophus measurement

Computer-assisted quantitative Ax by Response Evaluation Criteria for Solid Tumours (RECIST) used to assess tophi response

Participants completed Health Assessment Questionnaire and 36-item Short Form questionnaires. Files were assessed by committee blinded to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe proportion of participants excluded from primary analysis was equivalent across groups (2/43 participants in biweekly pegloticase group, 2/44 in monthly pegloticase group, 2/22 in placebo group). However, we were unable to assess if this was also true for the subgroup of people with tophi
Selective reporting (reporting bias)Low riskReported both positive and negative outcomes (i.e. adverse events), and how this could affect treatment. All outcomes listed in the trial protocol were reported fully
Other biasUnclear riskStudy authors received consulting fees, institution has received royalties, etc. and study was funded by Savient Pharmaceuticals. However, there was no evidence of selective reporting due to this. Subgroup with tophi at baseline was similar to the rest of the trial participants.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Abrahamsson 1987Incorrect study type
Abrams 2006Incorrect study type
Baraf 2008Incorrect study type
Barrett 2001Incorrect study type
Baxter 2009Incorrect study type
Becker 2009Incorrect study type
Caldas 2007Incorrect Study type
Chang 2005Incorrect study type
Chatterjee 2008Incorrect study type
Chen 1999Incorrect study type
Dhote 1997Incorrect study type
El Sandid 2004Incorrect study type
Ertugrul 2000Incorrect study type
Feher 2003Incorrect study type
Fiehn 2006Incorrect study type
Flugel 1978Incorrect study type
Frankel 1984Incorrect study type
Funck-Brentano 2011Incorrect study type
Graefen 1991Incorrect study type
Griffin 2009Incorrect study type
Hughes 2005Incorrect study type
Hulsmeyer 2000Incorrect study type
Johnson 1979Incorrect study type
Kaarela 2009Incorrect study type
Kao 2000Incorrect study type
Kemp 2010Incorrect study type
Kerman 1993Incorrect study type
Kitazawa 2006Incorrect study type
Klotz 1981Incorrect study type
Ko 1996Incorrect study type
Kobayashi 2005Incorrect study type
Kropelin 1972Incorrect study type
Kumar 2005Incorrect study type
Kung 1991Incorrect study type
Kuo 2007Incorrect study type
Landry 1986Incorrect study type
Lapidus 1963Incorrect study type
Lee 2003Incorrect study type
Lee 2010Incorrect study type
Li 2006Incorrect study type
Lin 2009Incorrect study type
Lui 2008Incorrect study type
Mahmud 2005Incorrect study type
Martin 1982Incorrect study type
Martínez-Villen 2007Incorrect study type
Marwaha 2010Incorrect study type
McGonagle 2007Incorrect study type
McLean 2004Incorrect study type
Melloni 2004Incorrect study type
Migita 2001Incorrect study type
Mockford 2003Incorrect study type
Moolenburgh 2006Incorrect study type
Morino 2007Incorrect study type
Mrabet 2010incorrect study type
Nakazawa 2004Incorrect study type
Niva 2006Incorrect study type
Ntsiba 2010Incorrect study type
Pai 1993Incorrect study type
Pankhania 2006Incorrect study type
Paquette 2000Incorrect study type
Perez-Ruiz 2002Incorrect study type
Piza-Katzer 1997Incorrect study type
Pledger 1976Incorrect study type
Pouye 2006No intervention
Raman 1981Incorrect study type
Reineke 2009Incorrect study type
Ribeiro 2009Incorrect study type
Richette 2006Incorrect study type
Richette 2007Incorrect study type
Rozenberg 1995Incorrect population
Schuind 2003Incorrect study type
Sekiya 2010Incorrect study type
Sener 2000Incorrect study type
Shimizu 2008Incorrect study type
Staub-Zahner 2007Incorrect study type
Tan 2003Incorrect study type
Tashiro 2002Incorrect study type
Tausche 2011Incorrect study type
Thavarajah 2011Incorrect study type
Tran 2011Incorrect study type
Uh 2011Incorrect study type
Vetter 2008Incorrect study type
Vogt 2005Incorrect study type
Wakabayashi 1998Incorrect study type
Weniger 2003Incorrect study type
Woughter 1959Incorrect study type
Yen 2002Incorrect study type
Yetkin 1999Incorrect study type
Zuber 1996Incorrect study type

Ancillary