Inter-Critical Gout, Not Hyperuricemia or Asymptomatic Urate Crystal Deposition, Is Associated with Systemic Inflammation

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Great research with important results showing that history of gout flares, not just MSU deposition or a single serum urate are correlated with levels of inflammatory markers. One suggestion would be to better define intercritical gout, as in, at least how much time since their flare? If the flare was more recent, such as within a week or so, the data may be skewed, as inflammatory markers may remain elevated, or serum urate values may not represent true baseline.

Author Response

Comment 1: Great research with important results showing that history of gout flares, not just MSU deposition or a single serum urate are correlated with levels of inflammatory markers. One suggestion would be to better define intercritical gout, as in, at least how much time since their flare? If the flare was more recent, such as within a week or so, the data may be skewed, as inflammatory markers may remain elevated, or serum urate values may not represent true baseline.

Response 1: We thank the reviewer for their comment. Unfortunately information on the date of latest flare was not available. We have added the below sentence to the limitations of the study.

"Fourth, we did not ascertain the date of latest gout flare in the Biomarker of Gout and SOGAS studies. A more recent gout flare could have influenced the cytokine levels. " 

Reviewer 2 Report

Comments and Suggestions for Authors

The presented study is a well-written, interesting study into the differences in systemic inflammatory markers between patients with inter critical gout and people with normo-uricemia, asymptomatic hyperuricemia and MSU crystal deposition without gout flares.  

The aim was to examine the association between inter critical gout ans serum cytokine levels compared to three other states, mentioned above. The comparison of these four different groups side-by-side is a strength of the study. The cross-sectional design is a weakness, as it will give us little information about the dynamics of systemic inflammation in relation to the presence or absence of flares in the gout in the inter critical group. 

I have some minor comments to the study as presented: 

Methods 

• - The patients with inter critical gout (n=71). Please inform us of the use of anti-inflammatory drugs and ULT (Was it an exclusion criterium in the mentioned studies, the SOGAS and Biomarker of Gout studies?). 

• - Is information present on the number of flares in the last 12 months and on the timing between the last flare and the sampling? 

Discussion 

• - In the study, inflammation means 'systemic inflammation'. Suggestion to rephrase in line 150 

• - Question: When we measure systemic inflammation in gout patients, is it a result of local inflammation (a recent flare of persistent low-grade inflammation) or do gout patients also have a persistent systemic pro-inflammatory state? 

• - Question: More recently, there has been reported evidence of epigenetic changes in the innate immune system under the influence of hyperuricemia and the presence of MSU crystals. How do these findings compare to the results in the study?

Author Response

Comment 1: The patients with inter critical gout (n=71). Please inform us of the use of anti-inflammatory drugs and ULT (Was it an exclusion criterium in the mentioned studies, the SOGAS and Biomarker of Gout studies?). 

Response 1: The use of anti-inflammatory drugs and ULT did not form part of exclusion criteria. We have added this sentence to the methods section: Patients prescribed urate lowering treatment and/or anti-inflammatory drugs (e.g., NSAIDs, or colchicine) were eligible to be included in the abovementioned studies.

Comment 2: Is information present on the number of flares in the last 12 months and on the timing between the last flare and the sampling?

Response 2: We did not collect information on timing of gout flares. This has been added as a study limitation. Information on number of gout flares in the previous 12 months is now reported in the manuscript. The median (interquartile-range) number of gout flares was 3 (1-5).

Comment 3: In the study, inflammation means 'systemic inflammation'. Suggestion to rephrase in line 150.

Response 3: This has now been rephrased in line 154 and throughout as applicable. Please accept our apologies for this oversight.

 Comment 4: When we measure systemic inflammation in gout patients, is it a result of local inflammation (a recent flare of persistent low-grade inflammation) or do gout patients also have a persistent systemic pro-inflammatory state? 

Response 4: Thank you for asking this question. We have added the below sentence to the discussion:

Within the limits of data available to us, it is difficult to comment on whether the systemic inflammation observed in this study resulted from local inflammation or whether there was a persistent systemic pro-inflammatory state. We believe this question was addressed in a small study of where peripheral blood mononuclear cells (PBMCs) from gout patients in remission but with MSU crystal deposition showed activated inflammatory pathways, strengthened inflammatory cell-cell interactions, and elevated arachidonic acid metabolic activity [20]. A new reference has been added: Gu H, Yu H, Qin L, Yu H, Song Y, Chen G, Zhao D, Wang S, Xue W, Wang L, Ai Z, Xu B, Peng A. MSU crystal deposition contributes to inflammation and immune responses in gout remission. Cell Rep. 2023 Oct 31;42(10):113139]. 

Comment 5: More recently, there has been reported evidence of epigenetic changes in the innate immune system under the influence of hyperuricaemia and the presence of MSU crystals. How do these findings compare to the results in the study?

Response 5: Thank you. We have added a sentence to discuss this point in the discussion section: 

This observation is inconsistent with prior reports of immune priming induced by soluble and crystalline urate. Due to the cross-sectional nature of this study, our finding does not refute such an effect because people in whom there was immune priming by urate could have progressed to symptomatic gout, and therefore be excluded from the asymptomatic groups.