Irregular Gout, Asymptomatic Hyperuricaemia and the Role of Treatment

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

It is a solid and conceptually rigorous historical review, highly erudite and well written, which traces with finesse the evolution of the notion of “irregular gout” from humoral medicine to contemporary debates on asymptomatic hyperuricemia. The text is richly documented, well structured chronologically, and convincingly links the history of medical ideas with modern pathophysiological data.

The article is particularly successful when it:

– shows how the concept of “irregular gout” functioned as a nosological catch-all,
– explains the transition toward a crystallopathic and inflammatory view of gout,
– and critically discusses the persistent hypothesis of a systemic toxicity of uric acid.

Very strong historical command: Sydenham, Cheyne, Cullen, Garrod, Ebstein, Haig, etc. are well integrated into a coherent narrative.

- Excellent articulation between history and modern pathophysiology (role of urate crystals, IL-1β, recent clinical trials).

- Balanced and critical discussion of asymptomatic hyperuricemia and negative trials (ALL-HEART, FREED).

- Rich, relevant, and well-chosen bibliography.

• Clear, pedagogical style, pleasant to read for a medically educated readership.

Points for improvement

- Objective and central message: the main argument would benefit from being stated more explicitly in the introduction (e.g., “we show that X aspects of ‘irregular gout’ can now be explained, whereas Y cannot”).

- Slight imbalance between:

– the historical section (very well developed and excellent),
– and the contemporary section (shorter, and somewhat more descriptive than synthetic).

Author Response

Objective and central message: the main argument would benefit from being stated more explicitly in the introduction (e.g., “we show that X aspects of ‘irregular gout’ can now be explained, whereas Y cannot”).

Thank you. I have added a paragraph to the beginning of the introduction which I hope is an improvement.

- Slight imbalance between:

– the historical section (very well developed and excellent),
– and the contemporary section (shorter, and somewhat more descriptive than synthetic).

Please bear in mind that this is a historical review, and the imbalance is inevitable. However, I take the point, and have added a few lines and some references to reviews of the contemporary situation - see pages 12 and 13. 

Reviewer 2 Report

Comments and Suggestions for Authors

This is a nice narrative review of the evolving understanding of the nature and implications of gout, from antiquity to the present. I have some minor comments to the authors:

1. I suggest a revision of the article's title. The authors should contextualise the term or provide a personal view of it to clarify for readers what the manuscript will contain.
2. I personally expected to read from Joseph Hollander and Daniel McCarty's work on finding MSU crystals in the synovial fluid and the importance of the polarised light microscope.
3. There are some orthographical or typographical errors throughout the manuscript (i.e. Page 1, paragraph 1, line 6; Page 2, paragraph 1, line 5; Page 3, transition from para 2 to 3; among others) that need to be revised
4. Figure 2 is a bit blurry, hard to read most of it, and needs to be improved.

Author Response

1. I suggest a revision of the article's title. The authors should contextualise the term or provide a personal view of it to clarify for readers what the manuscript will contain. Thanks for the suggestion. I have expanded the title accordingly, and I hope that this meets with the Reviewer's approval. 
2. I personally expected to read from Joseph Hollander and Daniel McCarty's work on finding MSU crystals in the synovial fluid and the importance of the polarised light microscope. This is a good point. I have changed the text on page 11 to bring this in.
3. There are some orthographical or typographical errors throughout the manuscript (i.e. Page 1, paragraph 1, line 6; Page 2, paragraph 1, line 5; Page 3, transition from para 2 to 3; among others) that need to be revised.......Thanks for spotting these - they have been corrected.
4. Figure 2 is a bit blurry, hard to read most of it, and needs to be improved.  I see the point. I cannot find any other version, so I have removed the figure.  I have lengthened the quote from his advertisements instead.