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  • Michael Toprover1,2,* and
  • Michael H. Pillinger1,2

Reviewer 1: Geraldine M. McCarthy Reviewer 2: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The aim of this review is to discuss some of the controversies that exist in relation to the optimal management of gout patients, even with the benefit of existing guidelines.  In the second paragraph on page 1, the specific controversies to be discussed are enumerated. Item 3) uses the term 'goal urate levels' - 'target serum urate concentration' is a more conventional term for this. (This term is used again on page 4, line 5 in 'First-line agents for ULT'.).

The first topic relates to optimal prophylaxis when initiating ULT.  It is broadly noted that guidelines recommend initiation of prophylactic therapy for 3-6 months. A study by Stamp et al is discussed  in detail and interpreted as 'challenging' these recommendations. I believe that the study has in fact interrogated these recommendations as it is noted that participants receiving placebo had significantly more gout flares than those receiving placebo in the first 6 months of the study period. Although there was a rise in the number of gout flares when the colchicine/placebo was discontinued at the end of month 6, Stamp et al note that it is possible that the duration of anti-inflammatory prophylaxis beyond 6 months would be of benefit for at least some individuals. Also, it should be noted in the review that although there were numerically more  side effects in the colchicine group, these were not felt to be related to the drug. This overall paragraph should be rewritten to be more reflective of the points of view in the paper by Stamp et al.

In the last paragraph on page 2, the authors refer to concordant medical illnesses. I believe they mean concurrent medical illness as concordant refers to a 'state of agreement'. 

On page 3, last paragraph, the original phase 3 study by Becker et all comparing febuxostat and allopurinol is referred to and it is noted that colchicine prophylaxis was discontinued after 4 weeks. My understanding is that there was a two week washout period when colchicine was started and then continued for eight weeks. This is a total of 10 weeks colchicine therapy. Can the authors explain the note of only 4 weeks?

In relation to febuxostat, the authors should be more emphatic about their views on the persistence of the black box warning  despite the reassuring data from Mackenzie et al Lancet (ref 26). It might be helpful for the non-expert reader to get more specific guidance on the use of febuxostat in patients with a history of cardiovascular disease since so many patients with gout suffer from this class of co-morbidity.

Author Response

Comment 1: The aim of this review is to discuss some of the controversies that exist in relation to the optimal management of gout patients, even with the benefit of existing guidelines.  In the second paragraph on page 1, the specific controversies to be discussed are enumerated. Item 3) uses the term 'target serum urate concentration' - 'target serum urate concentration' is a more conventional term for this. (This term is used again on page 4, line 5 in 'First-line agents for ULT'.).

Response 1: Thank you for your suggestions, we have corrected target serum urate concentration to target serum urate concentration. (made 4 replacements for goal urate to target serum urate concentration)

Comment 2: The first topic relates to optimal prophylaxis when initiating ULT.  It is broadly noted that guidelines recommend initiation of prophylactic therapy for 3-6 months. A study by Stamp et al is discussed  in detail and interpreted as 'challenging' these recommendations. I believe that the study has in fact interrogated these recommendations as it is noted that participants receiving placebo had significantly more gout flares than those receiving placebo in the first 6 months of the study period. Although there was a rise in the number of gout flares when the colchicine/placebo was discontinued at the end of month 6, Stamp et al note that it is possible that the duration of anti-inflammatory prophylaxis beyond 6 months would be of benefit for at least some individuals. Also, it should be noted in the review that although there were numerically more  side effects in the colchicine group, these were not felt to be related to the drug. This overall paragraph should be rewritten to be more reflective of the points of view in the paper by Stamp et al.

Response 2: Thank you for your recommendations, we have rewritten the paragraph to more accurately reflect your suggestions. (However, a newer study looking at whether prophylaxis was necessary by Stamp and colleagues interrogated these recommendations (4). In a double-blind, placebo-controlled, non-inferiority study of 200 adults with gout who had at least one flare in the prior 6 months and met ACR criteria to start ULT, participants were started on allopurinol and randomized in a 1:1 fashion to either start 0.5mg colchicine daily or placebo. After 6 months, ULT was continued but prophylaxis (colchicine or placebo) was discontinued. Using a prespecified non-inferiority margin of 0.12 gout flares per month, the authors found that, during the first 6 months, the colchicine group had 0.35 gout flares per month compared with 0.61 flares per month in the placebo group. However, by 12 months there was no difference in the mean number of gout flares per month between the 2 groups, with a p value of 0.68.  At the same time, there were 11 serious adverse events in 7 participants of the colchicine group, versus 3 serious adverse events in 2 participants of the placebo group. Although there were numerically more side effects in the colchicine group, these were not felt to be related to the drug. In a follow-up assessment of the same study, Stamp and colleagues performed a multivariable analysis and found that the greatest risks of gout flares occurred in both those participants who had a gout flare in the month prior to starting allopurinol (odds ratio [OR] 2.65), and those who were started on 100mg of allopurinol, rather than 50mg (OR 3.21). Furthermore, when the prophylaxis was stopped at month 6, participants’ risks of developing another flare were higher among subjects in the colchicine group (OR 2.95), subjects who had at least one flare in the month prior to stopping study drug (OR 5.39) and subjects whose serum urate remained at greater than or equal to 0.36mmol/L (6mg/dL) (OR 2.85). Therefore, Stamp et al felt that duration of anti-inflammatory prophylaxis beyond 6 months would be of benefit for at least some individuals.

This study challenges the idea that colchicine prophylaxis should be started in every gout patient who is starting urate lowering therapy. Specifically, prophylaxis may be most useful in patients who have a higher flare burden, particularly preceding the initiation of the allopurinol. However, this study did not look at other ULTs, such as febuxostat, and so cannot be generalized to all ULTs.)

Comment 3: In the last paragraph on page 2, the authors refer to concordant medical illnesses. I believe they mean concurrent medical illness as concordant refers to a 'state of agreement'. 

Response 3: Thank you for pointing this out, we have changed concordant to concurrent.

Comment 4: On page 3, last paragraph, the original phase 3 study by Becker et all comparing febuxostat and allopurinol is referred to and it is noted that colchicine prophylaxis was discontinued after 4 weeks. My understanding is that there was a two week washout period when colchicine was started and then continued for eight weeks. This is a total of 10 weeks colchicine therapy. Can the authors explain the note of only 4 weeks?

Response 4: Thank you for pointing this out, we have corrected the paragraph to note that prophylaxis was taken for eight weeks before stopping.

Comment 5: In relation to febuxostat, the authors should be more emphatic about their views on the persistence of the black box warning  despite the reassuring data from Mackenzie et al Lancet (ref 26). It might be helpful for the non-expert reader to get more specific guidance on the use of febuxostat in patients with a history of cardiovascular disease since so many patients with gout suffer from this class of co-morbidity.

Response 5: Thank you for your suggestion, we have included a sentence at the end of the paragraph discussing our recommendations.

Reviewer 2 Report

Comments and Suggestions for Authors

Thanks for this great work aiming to analyze controversies in the management of gout. Please be sure to conclude each paragraph.

  1. Introduction: the reviewer is surprised that authors did not discuss the current blockade of proper management by PCPs in the US. Please add comments in the introduction section even though this point is discussed page 4.
  2.  Optimal prophylaxis: page 2, line XXXX: please do check whether prophylaxis can be done by prescribing steroids for several months. Or delete even though this point was discussed later (page 3, lines XX; ref 15-17).
  3. Please also consider to add paragraph on colchicine dosage, e.g., 0.5 mg vs 1 mg QD
    1. Nieboer L, Veenstra F, Verhoef L, den Broeder AA, Kwok WY, van Herwaarden N, Flendrie M. Similar gout flare incidence rates when using once- or twice-daily 0.5 mg colchicine prophylaxis after the start of xanthine oxidase inhibitors. Scand J Rheumatol. 2025 Aug 11:1-6.
  1. Optimal prophylaxis: page 3, last paragraph, duration of prophylaxis : please check for duration linked to the presence of clinical tophi, “ as long as clinical tophi are present”.
  1. ULT/Allopurinol: could a conclusion to first paragraph be: “start low, go slow”, namely 50 mg QD allopurinol with titration reducing both flares and skin reactions. References are provided to improve the section.
    1. Pascart T, Lioté F. Gout: state of the art after a decade of developments. Rheumatology (Oxford) 2019;58(1):27-44.
    2. Stamp LK, Horne A, Mihov B, Drake J, Haslett J, Chapman P, Frampton C, Dalbeth N. Predicting Gout Flares in People Starting Allopurinol Using the Start-Low Go-Slow Dose Escalation Strategy. Arthritis Care Res (Hoboken). 2024 Oct;76(10):1371-1378.
  1. Also consider to mention the maximal ALLO dosage, e.g., 800 mg QD in the US, 900 mg QD in Europe.
  1. ULT/Allopurinol: HLA B5*58:01 typing. Please consider also another recent article from the Nottingham group: Cipolletta E, Nakafero G, Rozza D, Mahil SK, Smith CH, Riley RD, Abhishek A. Development and validation of a prognostic model for predicting the risk of allopurinol-induced severe cutaneous adverse reactions: a retrospective new-user cohort study using linked primary care, hospitalisation, and mortality data. Lancet Rheumatol. 2025 Sep 4:S2665-9913(25)00165-1.
  1. ULT/FBX: please mention the cross reaction between AHS and Febu related hypersensitivity reaction
    1. Bardin T, Chalès G, Pascart T, Flipo RM, Korng Ea H, Roujeau JC, Delayen A, Clerson P. Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment. Joint Bone Spine. 2016;83(3):314-7.
  2. ULT/FBX: what the price’s difference between ALLO and FBX, including generics?
  1. UKT/FBX; it is mandatory to cite and discuss the FAST study from EU demonstrating no higher CV risk with mid-term use of FBX in people with gout at CV risk, as well as several other recent large studies. Indeed you quoted Mackenzie paper – ref 26 – but did not discuss the case.
    1. Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, Ralston SH, Walters M, Robertson M, De Caterina R, Findlay E, Perez-Ruiz F, McMurray JJV, MacDonald TM; FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. 2020 ;396(10264):1745-1757.
    2. Bardin T, Richette P. FAST: new look at the febuxostat safety profile. 2020 Nov 28;396(10264):1704-1705.
    3. Yang TL, Leu HB, Lin SJ, Horng JL, Shih CM. Cardiovascular outcomes of febuxostat and allopurinol: A long-term Taiwanese nationwide cohort study. J Formos Med Assoc. 2025 Jun 2:S0929-6646(25)00270-0.
    4. Chen J, Zhang Y, Wang Y, Chen L. Comparative efficacy and safety of febuxostat and allopurinol in chronic kidney disease stage 3-5 patients with asymptomatic hyperuricemia: a network meta-analysis. Ren Fail. 2025 Dec;47(1):2470478.
  1. Second-line ULT: GUCDD is an international journal, thus authors cannot reduce this paragraph on Probenecid available in the US. Please upgrade your paragraph on benzbromarone, safe and very potent available and affordable URAT-1 inhibitor. Many papers are available. Please make the point by providing the list (or map) of countries where this cheap drug is available. Liver safety could not be anymore a matter of concern.
    1. Lin TS, Lin YL, Hsu CH, Hsieh SC, Shau WY, Yang WS, Chen CL. A systematic review and network meta-analysis of cardiovascular safety of benzbromarone compared to febuxostat and allopurinol in patients with gout. Front Cardiovasc Med. 2025 Jul 10;12:1541307
    2. Xue X, Sun M, Yan F, Dalbeth N, He Y, Li X, Qi H, Chen Y, Yuan X, Li M, Ji A, Terkeltaub R, Li C. Superiority of Low-Dose Benzbromarone Add-On to Low-Dose Febuxostat Compared With Febuxostat Monotherapy in Gout With Combined-Type Hyperuricemia. Arthritis Care Res (Hoboken). 2024 May;76(5):703-711.
    3. W, Cui L, Terkeltaub R, Chen Y, Li X, Cheng X, Liu T, Dalbeth N, Li C. Risk of Hepatotoxicity in Patients With Gout Treated With Febuxostat or Benzbromarone: A Propensity Score-Matched Cohort Study. Arthritis Care Res (Hoboken). 2025 Sep;77(9):1149-1156.
  1. Dotinurad should be addressed since available in Japan, and in development in other countries
    1. Hosoya T, Sano T, Sasaki T, Fushimi M, Ohashi T. Clinical efficacy and safety of dotinurad, a novel selective urate reabsorption inhibitor, in Japanese hyperuricemic patients with or without gout: randomized, multicenter, double-blind, placebo-controlled, parallel-group, confirmatory phase 2 study. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):53-61.
  1. Hosoya T, Sano T, Sasaki T, Fushimi M, Ohashi T. Dotinurad versus benzbromarone in Japanese hyperuricemic patient with or without gout: a randomized, double-blind, parallel-group, phase 3 study. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):62-70.
  2. Sun J, Wang Y, Cheng Y, Guo D, Hu J, Liu D, Gao Z, Li C, Lu Y, Kong X, Liu Y, Jiang Z, Yi B, Zhang H, Xu B, Yu S, Kokan R, Ishikawa K, Kawakatsu M, Zhang Z. Efficacy and safety of dotinurad versus febuxostat for the treatment of gout: a randomised, multicentre, double-blind, phase 3 trial in China. Arthritis Rheumatol. 2025 May 26. doi: 10.1002/art.43261. Epub ahead of print
  1. New drugs: ref 28 and 29. Please do cite and discuss pegadricase/rapamycin, or nowadays named NASP.
    1. Baraf HSB, Khanna PP, Kivitz AJ, Strand V, Choi HK, Terkeltaub R, Dalbeth N, DeHaan W, Azeem R, Traber PG, Keenan RT. The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout. Rheumatology (Oxford). 2024 Apr 2;63(4):1058-1067.
    2. Kivitz A, DeHaan W, Azeem R, Park J, Rhodes S, Inshaw J, Leung SS, Nicolaou S, Johnston L, Kishimoto TK, Traber PG, Sands E, Choi H. Phase 2 Dose-Finding Study in Patients with Gout Using SEL-212, a Novel PEGylated Uricase (SEL-037) Combined with Tolerogenic Nanoparticles (SEL-110). Rheumatol Ther. 2023 Aug;10(4):825-847.
  1. This is a possible strategy. Additional narrative reviews are suggested:
    1. Modjinou DV, Krasnokutsky S, Gyftopoulos S, Pike VC, Karis E, Keenan RT, Lee K, Crittenden DB, Samuels J, Pillinger MH. Comparison of dual-energy CT, ultrasound and surface measurement for assessing tophus dissolution during rapid urate debulking. Clin Rheumatol. 2017 Sep;36(9):2101-2107.
    2. Schlesinger N, Pérez-Ruiz F, Lioté F. Mechanisms and rationale for uricase use in patients with gout. Nat Rev Rheumatol. 2023 Oct;19(10):640-649

Author Response

Comments and Suggestions for Authors

Thanks for this great work aiming to analyze controversies in the management of gout. Please be sure to conclude each paragraph.

Thank you for your review

Comment 1: Introduction: the reviewer is surprised that authors did not discuss the current blockade of proper management by PCPs in the US. Please add comments in the introduction section even though this point is discussed page 4.

Response 1: Thank you for your suggestion, we have added comments in the introduction about divergence of guidelines (Notably, American College of Physicians guidelines do not recommend robust urate lowering and are more geared towards treating symptoms without monitoring or lowering urate.)

Comment 2: Optimal prophylaxis: page 2, line XXXX: please do check whether prophylaxis can be done by prescribing steroids for several months. Or delete even though this point was discussed later (page 3, lines XX; ref 15-17).

Response 2: Thank you for this comment, we have deleted the initial point about prophylaxis with prednisone, and kept the later point.

 Comment 3: Please also consider to add paragraph on colchicine dosage, e.g., 0.5 mg vs 1 mg QD

    1. Nieboer L, Veenstra F, Verhoef L, den Broeder AA, Kwok WY, van Herwaarden N, Flendrie M. Similar gout flare incidence rates when using once- or twice-daily 0.5 mg colchicine prophylaxis after the start of xanthine oxidase inhibitors. Scand J Rheumatol. 2025 Aug 11:1-6.

Response 3: Thank you for your suggestion and the study, we have added a paragraph discussing colchicine dosing (The optimal dosage of colchicine prophylaxis is also unclear. The ACR guidelines use the low dose colchicine 0.6mg available in the US, while the EULAR guidelines mention 0.5-1mg/day, to be adjusted according to renal function. A recent study by Nieboer et al appears to indicate that lower dose of colchicine may be sufficient. The authors performed a retrospective cohort study in 808 patients at three rheumatology centers in the Netherlands starting xanthine oxidase inhibitors for gout along with colchicine prophylaxis. They found that twice daily colchicine 0.5mg was not superior to once daily 0.5mg colchicine at preventing gout flares, with an adjusted incidence rate ratio of 0.93 (CI 0.80-1.09).  

Comment 4: Optimal prophylaxis: page 3, last paragraph, duration of prophylaxis : please check for duration linked to the presence of clinical tophi, “ as long as clinical tophi are present”.

Respone 4: We appreciate the reviewers comments, however, neither the EULAR nor most recent ACR guidelines on gout management discuss prophylaxis as it relates to tophi or remaining on prophylaxis as longas tophi are present, as prophylaxis seems to be focused more on flare prevention, rather than tophus resolution. The author could not find any recent studies that addressed this issue, but would be happy to add information if the reviewer knows of such a study. Thank you.

Comment 5: ULT/Allopurinol: could a conclusion to first paragraph be: “start low, go slow”, namely 50 mg QD allopurinol with titration reducing both flares and skin reactions. References are provided to improve the section.

    1. Pascart T, Lioté F. Gout: state of the art after a decade of developments. Rheumatology (Oxford) 2019;58(1):27-44.
    2. Stamp LK, Horne A, Mihov B, Drake J, Haslett J, Chapman P, Frampton C, Dalbeth N. Predicting Gout Flares in People Starting Allopurinol Using the Start-Low Go-Slow Dose Escalation Strategy. Arthritis Care Res (Hoboken). 2024 Oct;76(10):1371-1378.

Response 5: Thank you for your suggestion, have added a paragraph discussing this (Optimal allopurinol titration is another increasingly studied approach to better gout management. Rheumatology guidelines recommend starting at low doses of urate lowering therapy (≤100mg of allopurinol, ≤40mg of febuxostat etc.) And newer studies suggest that a “start low, go slow” approach, with using 50mg allopurinol and titrating in 50mg increments, may be best at prevent flares and side effects from titration.)

Comment 6: Also consider to mention the maximal ALLO dosage, e.g., 800 mg QD in the US, 900 mg QD in Europe.

Response 6: Thank you for your suggestion, we have added this to the allopurinol section (Allopurinol doses required to get to goal serum urate (i.e., <6mg/dL) are, on average, above, and can go as high as 800mg in the US, or 900mg in Europe.)

Comment 7: ULT/Allopurinol: HLA B5*58:01 typing. Please consider also another recent article from the Nottingham group: Cipolletta E, Nakafero G, Rozza D, Mahil SK, Smith CH, Riley RD, Abhishek A. Development and validation of a prognostic model for predicting the risk of allopurinol-induced severe cutaneous adverse reactions: a retrospective new-user cohort study using linked primary care, hospitalisation, and mortality data. Lancet Rheumatol. 2025 Sep 4:S2665-9913(25)00165-1.

Response 7: Thank you for the suggestion, we have included some text summarizing the study (An additional prognostic model was recently published by Cipolletta et al, using primary care, hospitalization, and mortality data from the UK Clinical Practice Research Datalink primary care database, wherein adults residing in England newly prescribed allopurinol were followed for 100 days to assess whether a severe cutaneous adverse reaction was recorded in hospitalization and mortality records. The authors found that age, chronic kidney disease stages 3, 4, and 5, an initial dose of 300mg or higher of allopurinol, South Asian ethnicity, and other Asian ethnicity were the risks associated with 100-day allopurinol-induced severe cutaneous adverse events. This model can better help providers in screening patients for risk of allopurinol reaction and best tailor therapy to avoid allopurinol in individuals at highest risk.) 

Comment 8: ULT/FBX: please mention the cross reaction between AHS and Febu related hypersensitivity reaction

Bardin T, Chalès G, Pascart T, Flipo RM, Korng Ea H, Roujeau JC, Delayen A, Clerson P. Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment. Joint Bone Spine. 2016;83(3):314-7.

Response 8: Thank you for this suggestion, we have added the following text when discussing febuxostat (There is some data that the risk of an allergic skin reaction is slightly increased in patients switched to febuxostat after having a cutaneous reaction to allopurinol, with Bardin et al finding a 9.1% risk of skin reaction to patients switched to febuxostat after a skin reaction to allopurinol, compared with only 2.5% of patients without a skin reaction to allopurinol developing a skin reaction to febuxostat.)

Comment 9: ULT/FBX: what the price’s difference between ALLO and FBX, including generics?

Response 9: Thank you for this suggestion, we have added a sentence discussing this. (While febuxostat cost per pill is higher than allopurinol, and initial studies showed that allopurinol was a cheaper option than febuxostat, febuxostat appears to be more cost effective due to increased treatment success.

Comment 10: UKT/FBX; it is mandatory to cite and discuss the FAST study from EU demonstrating no higher CV risk with mid-term use of FBX in people with gout at CV risk, as well as several other recent large studies. Indeed you quoted Mackenzie paper – ref 26 – but did not discuss the case.

    1. Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, Ralston SH, Walters M, Robertson M, De Caterina R, Findlay E, Perez-Ruiz F, McMurray JJV, MacDonald TM; FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. 2020 ;396(10264):1745-1757.
    2. Bardin T, Richette P. FAST: new look at the febuxostat safety profile. 2020 Nov 28;396(10264):1704-1705.
    3. Yang TL, Leu HB, Lin SJ, Horng JL, Shih CM. Cardiovascular outcomes of febuxostat and allopurinol: A long-term Taiwanese nationwide cohort study. J Formos Med Assoc. 2025 Jun 2:S0929-6646(25)00270-0.
    4. Chen J, Zhang Y, Wang Y, Chen L. Comparative efficacy and safety of febuxostat and allopurinol in chronic kidney disease stage 3-5 patients with asymptomatic hyperuricemia: a network meta-analysis. Ren Fail. 2025 Dec;47(1):2470478.

 Response 10: Thank you for the suggestion and studies offered, we have expanded the paragraph to discuss the FAST trial and mention the Tiawanese study. (Therefore, several follow-up studies have been done, including the FAST trial, a similar trial in Europe which evaluated a population at similarly higher cardiovascular risk, but had much fewer loss to follow-up and better accounted for patients being on appropriate cardiac therapy. The authors of the FAST trial found no increased risk of adverse cardiovascular outcomes in the febuxostat compared with allopurinol arm. Multiple other studies have since shown a similar lack of increased risk in patients taking febuxostat compared with allopurinol, including a Taiwanese nationwide study. Despite this evidence--the black box warning in the US remains, creating an area of concern for many providers, particularly given the high rates of cardiovascular disease in gout patients at baseline.)

Comment 11: Second-line ULT: GUCDD is an international journal, thus authors cannot reduce this paragraph on Probenecid available in the US. Please upgrade your paragraph on benzbromarone, safe and very potent available and affordable URAT-1 inhibitor. Many papers are available. Please make the point by providing the list (or map) of countries where this cheap drug is available. Liver safety could not be anymore a matter of concern.

    1. Lin TS, Lin YL, Hsu CH, Hsieh SC, Shau WY, Yang WS, Chen CL. A systematic review and network meta-analysis of cardiovascular safety of benzbromarone compared to febuxostat and allopurinol in patients with gout. Front Cardiovasc Med. 2025 Jul 10;12:1541307
    2. Xue X, Sun M, Yan F, Dalbeth N, He Y, Li X, Qi H, Chen Y, Yuan X, Li M, Ji A, Terkeltaub R, Li C. Superiority of Low-Dose Benzbromarone Add-On to Low-Dose Febuxostat Compared With Febuxostat Monotherapy in Gout With Combined-Type Hyperuricemia. Arthritis Care Res (Hoboken). 2024 May;76(5):703-711.
    3. W, Cui L, Terkeltaub R, Chen Y, Li X, Cheng X, Liu T, Dalbeth N, Li C. Risk of Hepatotoxicity in Patients With Gout Treated With Febuxostat or Benzbromarone: A Propensity Score-Matched Cohort Study. Arthritis Care Res (Hoboken). 2025 Sep;77(9):1149-1156.

Response 11: Thank you for the suggestion, we have updated the paragraph about benzbromarone as follows: (Benzbromarone, another uricosuric agent, is registered in 20 countries throughout Asia, South America, Europe and New Zealand and has been widely withdrawn from many markets due to potential hepatotoxicity risks. However, newer data indicates that the risks of liver disease may have been overestimated, with several studies showing that it is as effective as allopurinol and febuxostat, and potentially less hepatotoxic. Therefore, in those countries where it is available, it should be considered a safe option for ULT in gout patients, with proper monitoring of liver function.)

Comment 12: Dotinurad should be addressed since available in Japan, and in development in other countries

    1. Hosoya T, Sano T, Sasaki T, Fushimi M, Ohashi T. Clinical efficacy and safety of dotinurad, a novel selective urate reabsorption inhibitor, in Japanese hyperuricemic patients with or without gout: randomized, multicenter, double-blind, placebo-controlled, parallel-group, confirmatory phase 2 study. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):53-61.
  1. Hosoya T, Sano T, Sasaki T, Fushimi M, Ohashi T. Dotinurad versus benzbromarone in Japanese hyperuricemic patient with or without gout: a randomized, double-blind, parallel-group, phase 3 study. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):62-70.
  2. Sun J, Wang Y, Cheng Y, Guo D, Hu J, Liu D, Gao Z, Li C, Lu Y, Kong X, Liu Y, Jiang Z, Yi B, Zhang H, Xu B, Yu S, Kokan R, Ishikawa K, Kawakatsu M, Zhang Z. Efficacy and safety of dotinurad versus febuxostat for the treatment of gout: a randomised, multicentre, double-blind, phase 3 trial in China. Arthritis Rheumatol. 2025 May 26. doi: 10.1002/art.43261. Epub ahead of print

Response 12: Thank you for your suggestions, we have included a paragraph on dotinurad (Dotinurad, a novel selective urate reabsorption inhibitor, which is currently approved in Japan and being studied in other countries may help to further increase urate lowering options, as it appears as effective or more effective than currently approved XOI’s, as well as effective and tolerable in patients with CKD.)

Comment 13: New drugs: ref 28 and 29. Please do cite and discuss pegadricase/rapamycin, or nowadays named NASP.

    1. Baraf HSB, Khanna PP, Kivitz AJ, Strand V, Choi HK, Terkeltaub R, Dalbeth N, DeHaan W, Azeem R, Traber PG, Keenan RT. The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout. Rheumatology (Oxford). 2024 Apr 2;63(4):1058-1067.
    2. Kivitz A, DeHaan W, Azeem R, Park J, Rhodes S, Inshaw J, Leung SS, Nicolaou S, Johnston L, Kishimoto TK, Traber PG, Sands E, Choi H. Phase 2 Dose-Finding Study in Patients with Gout Using SEL-212, a Novel PEGylated Uricase (SEL-037) Combined with Tolerogenic Nanoparticles (SEL-110). Rheumatol Ther. 2023 Aug;10(4):825-847.

Response 13: Thank you for the suggestion, we have expanded on our discussion of SEL-212: (A newer uricase, SEL-212, which combines the uricase, pegadricase, with a rapamycin-containing nanoparticle, ImmTORTM is also being studied as an alternative to pegloticase. It benefits from the combination with ImmTOR acting to decrease the risk of loss of tolerance due to anti-drug antibodies, thereby allowing twice-monthly infusions, without the need for an oral immunosuppressive agent. When compared with pegloticase, SEL-212 was found to be comparable in efficacy and tolerability with pegloticase without the need for oral immunosuppression.)

Comment 14. This is a possible strategy. Additional narrative reviews are suggested:

    1. Modjinou DV, Krasnokutsky S, Gyftopoulos S, Pike VC, Karis E, Keenan RT, Lee K, Crittenden DB, Samuels J, Pillinger MH. Comparison of dual-energy CT, ultrasound and surface measurement for assessing tophus dissolution during rapid urate debulking. Clin Rheumatol. 2017 Sep;36(9):2101-2107.
    2. Schlesinger N, Pérez-Ruiz F, Lioté F. Mechanisms and rationale for uricase use in patients with gout. Nat Rev Rheumatol. 2023 Oct;19(10):640-649

Response 14: Thank you for these suggested studies, as their authors discuss the debulking therapy that we have included in our paper, we have added them as citations to that section, though feel that our discussion of debulking therapy is already an adequate summary of the suggestions mentioned in the above papers.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript has been perfectly modified and corrected accordingly to suggestions. Thanks to the authors.