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Pharmacogenetic Perspective for Optimal Gout Management

Future Pharmacol. 2022, 2(2), 135-152; https://doi.org/10.3390/futurepharmacol2020011

by Khalifa Y. Alrajeh

and Youssef M. Roman^*

Reviewer 1:

Pedro Dorado

Reviewer 2: Anonymous

Reviewer 3: Anonymous

Future Pharmacol. 2022, 2(2), 135-152; https://doi.org/10.3390/futurepharmacol2020011

Submission received: 27 February 2022 / Revised: 29 April 2022 / Accepted: 1 May 2022 / Published: 9 May 2022

(This article belongs to the Special Issue Feature Papers in Future Pharmacology)

Round 1

Reviewer 1 Report

The authors present an updated review of the evidence for the use of Pharmacogenomics in the pharmacotherapy of gout, in accordance with the CPIC, FDA, PharmGKB guidelines and scientific literature. However, there are some aspects that are not clear and are discussed below.

The abstract indicates that colchicine is related to different genes, including “rs6916345”, although it is a snp of some gene. Could you indicate which one?
Reference 2 is about the lack of adherence and this one could be updated since it is from 2008. Is there any more current? If so, the authors should include it.
The sentence about the prevalence of gout in FA (Filipino-Americans) I don´t understood as is written (lines 53-58). If the FAs have a prevalence of gout of 2.5%, which is higher than non-FAs (0.13%):

- Non-FA are the rest of non-Asians?, or are the rest of Asians except FAs?, or are they the rest of the populations?. It's hard to understand what the non-FA are.

- If the prevalence of gout in Asians is 2.7 times higher than the incidence in EUR, then it would be around 10.8%. Is it so?

- FAs are not Asian?

This should all be cleared up.

4 line 58. Change “high uric acid” to “hyperuricemia” or to “high levels of uric acid” or something similar.

The Table should be in the journal format.
Reference 62 is quite generic for the assertion in the paragraph (Lines 401-404). Additionally, losartan could be added. The sentence should be corrected, and more precise references added, for example:

Krasniqi V, Dimovski A, Domjanović IK, Bilić I, Božina N. How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity. Arh Hig Rada Toksikol. 2016 Mar;67(1):1-8. doi: 10.1515/aiht-2016-67-2754. PMID: 27092633.

Dorado P, Cavaco I, Cáceres MC, Piedade R, Ribeiro V, Llerena A. Relationship between CYP2C8 genotypes and diclofenac 5-hydroxylation in healthy Spanish volunteers. Eur J Clin Pharmacol. 2008 Oct;64(10):967-70. doi: 10.1007/s00228-008-0508-4. Epub 2008 Jun 12. PMID: 18548238.

Mukai Y, Senda A, Toda T, Eliasson E, Rane A, Inotsume N. The Role of CYP2C8 and CYP2C9 Genotypes in Losartan-Dependent Inhibition of Paclitaxel Metabolism in Human Liver Microsomes. Basic Clin Pharmacol Toxicol. 2016 Jun;118(6):408-14. doi: 10.1111/bcpt.12520. Epub 2015 Dec 28. PMID: 26551762.

Author Response

Reviewer 1

The authors present an updated review of the evidence for the use of Pharmacogenomics in the pharmacotherapy of gout, in accordance with the CPIC, FDA, PharmGKB guidelines, and scientific literature. However, there are some aspects that are not clear and are discussed below.

Authors’ response:

Thank you for your comments and suggestions, and we appreciate the time and effort put to better our manuscript. Our responses and actions taken, and the page and line numbers are inserted below each comment. In the manuscript file, you’ll see the highlighted paragraphs, indicating the changes made to reflect the responses to the reviewers.

The abstract indicates that colchicine is related to different genes, including “rs6916345”, although it is a snp of some gene. Could you indicate which one?

Authors’ response and action taken:

Thank you for the question. The SNP, rs6916345, is an intergenic variant that occurs between genes in a candidate region (500-kbp) on chromosome 6. Since it is an intergenic variant, we did not specify the gene's name. Furthermore, this variant was predicted to be a modifier of RNU6-793P (i.e., RNA, U6 small nuclear 793, pseudogene). The information was added to the legend of Table 1. For more information, please check the supplementary documents for the Pharmacogemocis of the Efficacy and Safety of Colchicine in COLCOT study. “Direct Link: https://www.ahajournals.org/action/downloadSupplement?doi=10.1161%2FCIRCGEN.120.003183&file=proof_revised_Supplemental+material.pdf ”

Page: 1 Line: 30, Page: 6 Line: 473-474 & Table. 1

Reference 2 is about the lack of adherence and this one could be updated since it is from 2008. Is there any more current? If so, the authors should include it.

Authors’ response and action taken:

Thank you for the suggestion. A more recent reference was added and the action was taken with the pages and lines indicated below. The new reference was a systematic review and meta-analysis that was conducted in 2018 that measured the medication adherence among gouty patients in multiple countries, including the U.S.A. (Please, see reference #3: Scheepers LEJM, van Onna M, Stehouwer CDA, Singh JA, Arts ICW, Boonen A. Medication adherence among patients with gout: A systematic review and meta-analysis. Seminars in arthritis and rheumatism. 2018;47(5):689-702. doi:10.1016/J.SEMARTHRIT.2017.09.007)

Page: 2 Line: 52-53

The sentence about the prevalence of gout in FA (Filipino Americans) I don´t understood as is written (lines 53-58). If the FAs have a prevalence of gout of 2.5%, which is higher than non-FAs (0.13%):

- Non-FA are the rest of non-Asians? or are the rest of Asians except FAs?, or are they the rest of the populations?. It's hard to understand what the non-FA are.

- If the prevalence of gout in Asians is 2.7 times higher than the incidence in EUR, then it would be around 10.8%. Is it so?

- FAs are not Asian?

This should all be cleared up.

Authors’ response and action taken:

Thank you for your feedback, and we do agree with your comment. For clarity, the reported gout in Filipinos, in that particular study, was referenced to non-Filipino. This non-Filipino included Europeans, other Asian groups, and Pacific Islanders in the same dataset. We agree the term “non-FA” could be misinterpreted and misleading. Therefore, the comments were taken into consideration and accordingly modified the wording.

Page: 2 Line: 64-60.

line 58. Change “high uric acid” to “hyperuricemia” or to “high levels of uric acid” or something similar.

Authors’ response and action taken:

The comment was taken into consideration, and the term was corrected.

Page: 2 Line: 69.

The Table should be in the journal format.

Authors’ response and action taken:

The action was taken, and the table was modified to coincide with the journal format. It appears within the main text and close to its first citation and numbered following appearance (Table-1). The table also has a short explanatory title and caption (Legend) with a font size of 9. (https://www.mdpi.com/journal/futurepharmacol/instructions)

Table-1, line 135-144.

Reference 62 is quite generic for the assertion in the paragraph (Lines 401-404). Additionally, losartan could be added. The sentence should be corrected, and more precise references added, for example:

Authors’ response and action taken:

Thanks for your feedback. Losartan is also metabolized by the CYP2C9, Flurbiprofen, and diclofenac, warfarin, and tolbutamide are usually used as a probe with other drugs to characterize CYP2C9 phenotype. (Please, see Page: 5, Lines: 389-393) The recommended citations were also cited. (Please, see Page: 5, Lines: 392 & 404-405)

Page: 5, Lines: 389-393 & Page: 5, Lines: 392 & 404-405.

Reviewer 2 Report

See the attached file.

Comments for author File: Comments.pdf

Author Response

Reviewer 2

These authors have reviewed the pharmacogenetic relevance for drugs used to treat gout. Comments:

This summary of the pathophysiology and therapeutic agents reads like a textbook and not a critical review. In that regard, I found it less useful.

Authors’ response and action taken:

Thanks for your feedback. We revised the text of these sections. But notably, the main purpose of this narrative review is to summarize the most recent evidence for using pharmacogenetic in gout management as discussed in the CPIC guidelines, PharmGKB, FDA, and most recent publications. With the paucity of pharmacogenetic research in gout management, there is very limited literature to review. Indeed, the primary purpose of this review became an attempt to synthesize and report the current evidence and the highest level of evidence reported by the CPIC. Nonetheless, throughout the manuscript, we provided our critical appraisal of the limited literature such as the sample size, limitations of generalizability, sex-specific differences, and inconsistency of evidence; and we end with an overall conclusion about all evidence related to the topic covered.

(Examples throughout the manuscript): Page: 4, Lines: 313-327; Page: 6, Lines: 443-445; Page: 6, Lines: 453-454; Page: 7, Lines: 467-468; Page: 8, Lines: 513-515 & Page: 8, Lines: 531-533.

Like most pharmacogenomic studies, there are always inconsistent data and disagreements with regards to conclusions rendered. The author should discuss controversy, review the primary literature, and opine on the strengths and weakness of the important and relevant articles.

Authors’ response and action taken:

The reviewer raises a good point. Briefly, we highlighted the inconsistencies in pharmacogenomic studies throughout the manuscript, so we can strengthen our review. Some of the inconsistencies of evidence were indeed discussed, such as the inconsistency in the association between the T allele (in ABCB1) and colchicine response. We also highlighted the conflicting results and hypothesized that this discordance could be due to inter-ethnic variations because the association was tested in Turkish and Israeli ethnicities. (Please see Colchicine section; Lines: 456-462). Moreover, we expanded on the broader issues of the conflicting results in pharmacogenetic studies in the newly added a new section titled “Pharmacogenetic challenges and opportunities in gout management”.

Page: 6 & 8, Lines: 456-469 & Page: 8, Lines: 534-558

Are there clinical practice guidelines by the appropriate medical bodies that have opined on the use of pharmacogenetic testing (beyond HLA-B*58-1)? Which genes and which study populations?

Authors’ response and action taken:

The only clinical practice guideline for pharmacogenetic testing is the CPIC guidelines, as it provides detailed information on what, who and when to test for various genes when using certain drugs. To answer the question, yes, there is another recommendation to use pharmacogenetic testing beyond HLA-B*5801. The FDA and CPIC recommend testing for G6PD status when using pegloticase in high-risk populations, including African, South European, Middle Eastern, South Asian. (See lines 328-335)

Page: 5, Lines: 357-358

How does one implement pharmacogenomic testing among GPs? Should there be targeted genotyping or whole genome sequencing?

Authors’ response and action taken:

Thanks for your comment. To address this question, we added a new section to the manuscript describing the challenges and opportunities of implementing pharmacogenetic in gout management, including some information about the barriers to implementation and means to overcome those barriers. Regarding genetic testing platforms, we believe that targeted genotyping of well-characterized actionable SNPs that carry clinical relevance beyond gout appears to be a logical first step to establishing the benefits of pharmacogenetic testing in gout management.

Page: 8, Lines: 549-551

A major issue is the absence of FDA-approved lab tests for any of these genes except the common SNPs. This should be discussed.

Authors’ response and action taken:

Thanks for your question. We agree with the comment above. To address this question, we added a new section to the manuscript describing the challenges and opportunities of implementing pharmacogenetic in gout management, including some information about barriers to implementation and reasons for inconsistency in the evidence for some pharmacogenetic tests.

Page: 8, Lines: 551-553

An economic analysis should also be reviewed to determine if testing is cost effective and under what circumstances. Are there reimbursements available? How do you educate a physicians, pharmacists, regulators, insurance companies, even patients as to the value of pharmacogenomics? Are there gout advocacy groups? Without solutions to all of the above, pharmacogenomics will simply be a research topic and have no influence on medical care.

Authors’ response and action taken:

Thanks for your questions. We agree with the comments mentioned above. The reviewer raises real-world questions about the challenges in implementing pharmacogenomics in practice. While these raised questions were not the primary scope of this paper, we added a section that addresses most of these questions. Addressing these topics in more detail, using our current paper, will derail the focus of our review article, which is to provide an update on the potential role of pharmacogenetics in improving gout treatment outcomes. We will be more than happy to be invited to submit a follow-up article to extensively address the challenges and opportunities in pharmacogenetics to move the needle in maximizing gout outcomes.

Page: 8, Lines: 553-558

Reviewer 3 Report

This is an interesting narrative review that brings an overview of how genetic factors influence the treatment of patients with gout.

It doesn't make much sense to have two sections between the background section and the methods section. Perhaps the authors could rewrite the information under the " Epidemiology of Hyperuricemia and Gout " and " Genetics of Hyperuricemia and Gout " section so that it is organized and sequential within the Introduction section.

The aim of this review is not clear. Although, in the methods, section authors mention the purpose of the work …A clear objective of the study should be added to the end of the Background/Introduction section. The methods section should be reserved for describing the methodology used and all the procedures followed to search the articles, extract information from them, and define the inclusion and exclusion criteria and relevant information to be extracted from the included articles.

Line 69 – “Hyperuricemia (HU), the precursor to gout …” please change for “Hyperuricemia (HU), a risk factor for gout ….”

During the manuscript, the authors mention several times that "several studies ...", yet then only cite one study. Please review this throughout the manuscript. Some examples are:

Lines 92-94 – “… extensive population genetic studies, particularly genome-wide associate-92 action studies (GWAS), have identified significant genetic polymorphisms in the UA dis-93 position pathway.¹⁷“The authors mention that there are extensive population studies, however, they only cite one. Please add more references to this statement.
“Hence, multiple studies investigated the interplay between BCRP protein and the intestinal disposition of allopurinol and renal elimination of oxypurinol.²⁷” If there are multiple studies … authors should add more than one citation.

Why was the extensive information about benzbromarone added to the new version of the manuscript? Authors refer that this drug was withdrawn from the United States market, by FDA. In what year? Is it in the market in Europe or any country in the ICH region? If yes add some information about that.

Please do not use abbreviations in the titles. Change the titles “NSAIDs” to “Non-steroidal anti-inflammatory drugs”; and “IL-1 Inhibitors” to “Interleukin-1 (IL-1) Inhibitors”.

“… CYP2C9 is a major metabolizing enzyme accounting for > 25% of metabolic clearance of NSAIDs, losartan, warfarin, fluvastatin, and tolbutamide.77 In vivo, losartan78, diclofenac, flurbiprofen, and tolbutamide are commonly utilized as probe drugs for CYP2C9 phenotyping assays.” This sentence is under the title “NSAIDs”, and the use of examples of other drugs than NSAIDs could bring some confusion.

In the conclusions section, the authors should focus on the information they presented throughout the article. For example, in the conclusion they give great focus to tests, however, during the rest of the manuscript they are barely mentioned.

Author Response

Reviewer 3

This is an interesting narrative review that brings an overview of how genetic factors influence the treatment of patients with gout.

Thanks so much for the feedback and for taking the time to review our work.

Thanks for the suggestion. We do agree with the reviewer’s suggestion. We reorganized the paragraphs to improve the manuscript follow. Please see page 2 lines 17-27.

Thanks for the feedback. We agree with the reviewer's comment, and we added a clear aim to this review by the end of the background section. Please see page 2 lines 14-16

Line 69 – “Hyperuricemia (HU), the precursor to gout …” please change for “Hyperuricemia (HU), a risk factor for gout ….”

The change was made and highlighted. Thanks for the suggestion. Please see page 2 line 38

During the manuscript, the authors mention several times that "several studies ...", yet then only cite one study. Please review this throughout the manuscript. Some examples are:

Lines 92-94 – “… extensive population genetic studies, particularly genome-wide associate-92 action studies (GWAS), have identified significant genetic polymorphisms in the UA dis-93 position pathway.¹⁷“The authors mention that there are extensive population studies, however, they only cite one. Please add more references to this statement.
“Hence, multiple studies investigated the interplay between BCRP protein and the intestinal disposition of allopurinol and renal elimination of oxypurinol.²⁷” If there are multiple studies … authors should add more than one citation.

Thanks so much for the comment and observation. We agree with the reviewer, and we acknowledge that was our fault. We corrected this mistake throughout the manuscript.

Thanks so much for your comment. Yes! BBR is removed from the US market, but it remains widely used in many Asian countries. We adjusted the language to reflect the reviewer's comment. It's important to mention that BBR could potentially be one of those drugs that can be reintroduced to the US market, should we conduct more pharmacogenetic research. Therefore, this section was added to the manuscript. Please see page 9 lines 1-2

Please do not use abbreviations in the titles. Change the titles “NSAIDs” to “Non-steroidal anti-inflammatory drugs”; and “IL-1 Inhibitors” to “Interleukin-1 (IL-1) Inhibitors”.

Thanks for the suggestions. We adjusted the titles.

Thanks for the comment. This information was added because of a previous reviewer. However, we agree with this reviewer's comment. We modified the language to be more concise and minimize confusion. Please see page 10 lines 34-37

Thanks for your comment. We revised the conclusion to be more consistent with what was presented. Nonetheless, genetic testing was mentioned in different sections of our manuscripts hence it was mentioned in the conclusion. Please see page 14 lines 5-14

Round 2

Reviewer 1 Report

The authors have responded to the questions raised and have made the changes appropriately. However, it is necessary to make some more changes, which are detailed below.

Page: 2 Line: 64-60. The new paragraph remains unclear and confusing. If the percentage of the gout in EUR population is 4%, it is not understood that later it is said that the Filipino group is higher, being only 2.5%. I recommend that the authors simply describe the percentages of the prevalence in each population studied without making comparisons.

All Latin words such as "in vivo" (page 5) should be italicized. Also, the genes (such as “CYP2C9 genotype” in page 4, first paragraph). Review the entire document.

Author Response

Reviewer 1

The authors have responded to the questions raised and have made the changes appropriately. However, it is necessary to make some more changes, which are detailed below.

We thank you for taking the time to review our work again. We do appreciate the feedback to improve our manuscript.

Page: 2 Line: 64-60. The new paragraph remains unclear and confusing. If the percentage of the gout in EUR population is 4%, it is not understood that later it is said that the Filipino group is higher, being only 2.5%. I recommend that the authors simply describe the percentages of the prevalence in each population studied without making comparisons.

Thanks for the comment. To explain this statement further, we simplified this sentence to reflect where that data came from. The data you are inquiring about was from an old study, so it may appear confusing without the newly added information. To avoid this issue further, we indicated that the incidence reported was from an outdated study that was conducted in the state of Hawaii. Please see the changes on page 2 lines 35-37

All Latin words such as "in vivo" (page 5) should be italicized. Also, the genes (such as "CYP2C9 genotype" on page 4, first paragraph). Review the entire document

Thanks for the comment. We agree that all genes should be italicized, and we ensured that all genes in our manuscript are italicized. Regarding “In vitro” or “In vivo”, we agree that they could be italicized; however, we recognize that certain journals have specific requirements. Nonetheless, we italicized Latin words. Please see page 10 line 36

Reviewer 2 Report

The authors have revised the manuscript but it still does not read as a critical review but more of a textbook of information.

Author Response

Reviewer 2

The authors have revised the manuscript but it still does not read as a critical review but more like a textbook of information.

Thank you so much for reviewing our work again. We also appreciate the feedback. We believe that we have made substantive changes to our manuscript since the first iteration to improve the readability of our article. It's worthy to mention that there is not much pharmacogenetic research in the field of gout. We also believe that our review is one of the few, if not the only review, to comprehensively compile the current genetic evidence for urate-lowering therapies. Therefore, our manuscript was designed to educate the audience about pharmacogenomics as well as evaluate the evidence; hence our manuscript may read, in some parts, as a textbook chapter.

Reviewer 3 Report

Overall the authors responded to the comments posted in the first round. I have only a few minor comments, mainly regarding the designation/organization of the different sections, but the organization of the sections should be adapted to the journal and decided in agreement with the editorial board.

Here are my comments:

Remove the first sentence of the methods section. The objective of the study is already at the end of the introduction.

The section “Literature Review Methods” could be changed to “Material and Methods”. I suggest the following sections for authors' and editor consideration:

Introduction

Material and Methods

Main findings

Epidemiology of Hyperuricemia and Gout

….

Conclusions

Future Perspectives

Lines 22-24 “The primary objective of this narrative review is to synthesize the most contemporary levels of evidence of 23 pharmacogenetics in gout pharmacotherapy.” Change for something like: “Information was extracted to synthesize the most contemporary levels of evidence of pharmacogenetics in gout pharmacotherapy”

Author Response

We sincerely thank reviewer 3 for continuing to provide constructive feedback.

We modified the title from Literature Review Methods to Methods. We also changed the wording to reflect the reviewer's comment. Please see page 2 lines 17-23

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