Convergence of Psoriatic Arthritis and Hyperuricemia: A Review of Emerging Data from This New Concept Called “Psout”

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I do not feel that the reason why this term would need to be defined as a distinct entity comes across in this article. It really needs to be justified why creating a new disease entity is valuable in this instance. Is there diagnostic or therapeutic impact to identifying someone as having “psout” as a distinct phenotype as opposed to recognizing that metabolic syndrome is common in psoriatic arthritis and that gout is a common comorbidity of this? Specific comments that I feel that authors need to address are below:

1.      With a new new term (“psout”) being the focus of this review, I feel that the authors need to justify more thoroughly why this would be an improvement over simply identifying psoriatic arthritis and gout as individual conditions that often overlap. It also would be important to give a clearer definition of what “psout” means. I understand that definitions have been vague thus far in the literature, but in order for a reader to understand the significance of all the information presented in this review, a definition would be very helpful.

2.      I don’t know that it was directly addressed that obesity is a risk factor for both psoriasis and gout, and that this could be an actual cause of the relationship between PsO and gout. Is the higher incidence of obesity and metabolic syndrome in PsA the reason why gout is more common? If so, perhaps the importance is really in identifying metabolic syndrome rather than identifying “psout” and recognizing gout as one of many comorbidities of this syndrome?

3.      Page 3, link 129-130 is missing a citation.

4.      The authors propose that defining “psout” provides the ability to avoid misinterpreting a gout attack as a PsA flare. However, they state that “psout” describes a wide spectrum of conditions ranging from hyperuricemia to defined gout. Again, I think it needs to be justified how adding a pretty vaguely-defined term to our vocabulary would improve diagnostic accuracy.

5.      Page 5, line 203-207 is missing a citation.

6.      The paragraph on dermatologic phenotypes (page 5) is difficult to follow. It seems to state that there is no data on this but that the authors feel it needs researched.

7.      I think the wide range of prevalences in Table 2 needs to be addressed. This suggests to me that “psout” is not really a clear phenotype, although limited by small study sizes.

8.      I am not sure that much is gained by the addition of Table 3 and would consider removing this. To me, this table highlighted that PsA and gout are distinct entities with very different treatments that are already well described, and that we should not be considering them to be part of an overlap syndrome.

Author Response

Comments and Suggestions for Authors

I do not feel that the reason why this term would need to be defined as a distinct entity comes across in this article. It really needs to be justified why creating a new disease entity is valuable in this instance. Is there diagnostic or therapeutic impact to identifying someone as having “psout” as a distinct phenotype as opposed to recognizing that metabolic syndrome is common in psoriatic arthritis and that gout is a common comorbidity of this? Specific comments that I feel that authors need to address are below:

1. With a new new term (“psout”) being the focus of this review, I feel that the authors need to justify more thoroughly why this would be an improvement over simply identifying psoriatic arthritis and gout as individual conditions that often overlap. It also would be important to give a clearer definition of what “psout” means. I understand that definitions have been vague thus far in the literature, but in order for a reader to understand the significance of all the information presented in this review, a definition would be very helpful.

We appreciate this comment and have now clarified the need for defining "psout" as a separate entity. The concept of psout is not just about the overlap of PsA and gout but about a broader spectrum where hyperuricemia plays a role in worsening PsA outcomes. Recognizing psout as a phenotype provides clinicians with a framework to consider hyperuricemia’s role in disease severity and comorbidities, leading to more tailored therapeutic strategies.

• Page 2 lines 58-69: ““Psout” is a recently established term proposed to describe the overlapping conditions ranging from hyperuricemic PsA (HU-PsA) to gout-associated PsA in the same patient[10]. This novel concept highlights the intersection of inflammatory and metabolic pathways in these two conditions. Psout is not merely an overlap of PsA and gout but represents a distinct entity where hyperuricemia plays a significant role in worsening PsA outcomes. Recognizing psout as a separate entity aids in optimizing diagnostic accuracy and treatment selection, as patients may require interventions targeting both inflammatory and metabolic pathways. It can also be seen as a psoriatic disease in which uric acid is playing a pathophysiological role. The growing number of publications about the concept of psout since its first description[10], few years ago in 2019, underscores the increasing interest and importance of this topic for the rheumatological community.”

2. I don’t know that it was directly addressed that obesity is a risk factor for both psoriasis and gout, and that this could be an actual cause of the relationship between PsO and gout. Is the higher incidence of obesity and metabolic syndrome in PsA the reason why gout is more common? If so, perhaps the importance is really in identifying metabolic syndrome rather than identifying “psout” and recognizing gout as one of many comorbidities of this syndrome?

We agree that obesity is a common risk factor for both psoriasis and gout and contributes to their co-occurrence. However, recent data suggest that hyperuricemia may independently contribute to PsA severity. We have now stated that point in the manuscript.

• Page 3 lines 101-104: “Metabolic syndrome and obesity are, indeed, a shared risk factor for both psoriasis and gout, and it may partially explain the increased prevalence of hyperuricemia in PsA pa-tients. However, studies suggest that hyperuricemia itself may independently contribute to the severity of PsA, beyond metabolic syndrome alone [12].”

3. Page 3, line 129-130 is missing a citation.

We have now added the following reference to this statement: [24] Crișan TO, Cleophas MCP, Oosting M, Lemmers H, Toenhake-Dijkstra H, Netea MG, et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis 2016;75:755–62. https://doi.org/10.1136/annrheumdis-2014-206564.

4. The authors propose that defining “psout” provides the ability to avoid misinterpreting a gout attack as a PsA flare. However, they state that “psout” describes a wide spectrum of conditions ranging from hyperuricemia to defined gout. Again, I think it needs to be justified how adding a pretty vaguely-defined term to our vocabulary would improve diagnostic accuracy.

We acknowledge the need to strengthen the argument regarding how defining psout improves management accuracy. We have now modified the paragraph accordingly:

• Page 5 line 213-220: “The recently established term "psout" describes a wide spectrum of overlapping con-ditions ranging from hyperuricemic PsA (HU-PsA) to gout-associated PsA. The most ap-parent benefit of recognizing this condition for clinicians is the ability to avoid misclassifying a gout attack as a PsA flare, preventing unnecessary modifications in PsA treatment regimens. Recognizing the psout phenotype ensures that hyperuricemia is appropriately addressed alongside PsA treatment, reducing the risk of uncontrolled joint inflamma-tionmisinterpreting a gout attack as a PsA flare and that clinicians pay more attention to those patients with additional comorbidities.”

5. Page 5, line 203-207 is missing a citation.

We have now added an appropriate citation: [10] Felten R, Duret P-M, Gottenberg J-E, Spielmann L, Messer L. At the crossroads of gout and psoriatic arthritis: “psout.” Clin Rheumatol 2020;39:1405–13. https://doi.org/10.1007/s10067-020-04981-0.

6. The paragraph on dermatologic phenotypes (page 5) is difficult to follow. It seems to state that there is no data on this but that the authors feel it needs researched.

We recognize that the paragraph could have been clearer and have now revised it  accordingly for improved readability:

• Page 6 line 240-257: “Although there is limited data on whether specific psoriasis subtypes (vulgaris, scalp, guttate, nail, inverse or pustular) are more common in psout, some studies suggest that psoriasis vulgaris and scalp psoriasis may be more prevalent in hyperuricemic PsA patients [43]. Psoriasis vulgaris (in plaques) subtype seems to be the predominant form of psoriasis in HU-PsA patients, followed by psoriasis of the scalp, whereas guttate, nail, in-verse, or pustular palmo-plantar psoriasis subtypes are less frequently associated with HU [43]. One could hypothesize for the latter, a preferential association with “pure” im-mune-mediated PsA. However, these observations should be mitigated by the higher prevalence of psoriasis in plaques over other psoriasis subsets, which limits formulation of definitive conclusions. In addition, currently available data on psoriasis skin phenotypes in HU context are very limited and with no specific dermatological expertise as-sessment of the skin, since most studies are emanating from mono-centric retrospective rheumatological cohorts, introducing selection bias. Future studies are needed to deter-mine if hyperuricemia influences the severity of specific dermatologic phenotypes. Therefore, these findings highlight the need for dedicated studies exploring the dermatological phenotypes of psoriasis in PsA versus psout, which are currently lacking. Such studies examining psoriasis subtypes are critical to better characterize the diversity of phenotypes at the dermatological level.”

7. I think the wide range of prevalences in Table 2 needs to be addressed. This suggests to me that “psout” is not really a clear phenotype, although limited by small study sizes.

We appreciate this observation. The wide range of prevalence estimates in Table 2 may be due to differences in hyperuricemia definitions, patient populations, and study methodologies. Future research should standardize diagnostic thresholds to improve comparability across studies. We have now added this statement below the Table 2.

• Page 11, line 353-355: “The wide range of prevalence may be due to differences in HU definitions, patient popula-tions, and study methodologies. Future research should standardize diagnostic thresh-olds to improve comparability across studies.“

8. I am not sure that much is gained by the addition of Table 3 and would consider removing this. To me, this table highlighted that PsA and gout are distinct entities with very different treatments that are already well described, and that we should not be considering them to be part of an overlap syndrome.

We have now consider revising or removing Table 3. While it was included to highlight the differences in treatment approaches, we acknowledge that it may not add significant value to the discussion. We have now removed it.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors provide a comprehensive depiction of the intersection of gout/HU and PsA/Pso with an update of current research findings and the clinical implications.

Some comments

- The use of the term ‘gout-associated PsA’ can be misleading as it suggests and established (causal) relationship. Perhaps the use of concurrent or co-existence could be clearer

- Pathophysiol section, 1^st par. The sentence ‘deposition of SU in joints and systemic effects of HU play a significant role in the inflammatory processes seen in both conditions’ could be misinterpreted. MSU in joints could play a role in inflammation if PsA and gout coexisted, but not in isolated PsA. The effect of HU in inflammation is at best controversial.

- Pathophysiol, last par. As the focus point of the review is Psout, the paragraph and the whole section would benefit of focusing on the findings relevant to psout and the clinical implications of the basic science findings.

- Section 4.2 Impact of HU on PsA, 2^nd and 3^rd par. The OR provided for some of these studies are univariate, but significance has been lost in multivariate, suggesting that some of these associations have confounding factors. For example, obesity is a risk factor for severity of Ps and the HU cohort is more obese. Consider toning down if only univariate association is present

- Section 4.3, 2^nd par. Is it known how many patients had MSU and how many had CPPD (relevant for understanding the results)?

- Add reference for Gancheva study in line 414

- The inclusion of HU in the treatment of CV risk is still controversial. While some consensus incorporate this (ref 58), European ESC guidelines do not. A balanced and nuanced presentation of this would be welcome in Section comorbidities, par 5 and especially in Section 6.2, where treatment of HU for patients with PsA is recommended.

- As treatment of PsA and gout remains essentially the treatment of each disease, section 6.2 should convey the need to treat all gout patients with ULT.

- Table 3, for gout, consider changing ‘not typically used’ to something like ‘no evidence of benefit’ as it currently gives the impression that it could be an option.

- Check that reference 59 is the correct reference for the URRAH CV mortality cut-off as it seems to center on the heart failure outcome.

Comments on the Quality of English Language

The manuscript wound benefit from minor English editings (for example line 391, first sentence). 

Author Response

Reviewer 2:

The authors provide a comprehensive depiction of the intersection of gout/HU and PsA/Pso with an update of current research findings and the clinical implications.

Some comments

1. The use of the term ‘gout-associated PsA’ can be misleading as it suggests and established (causal) relationship. Perhaps the use of concurrent or co-existence could be clearer

We agree that the term "gout-associated PsA" may imply causation. We have now adjusted our terminology to "co-existing gout and PsA" to avoid misleading implications, throughout the manuscipt.

2. Pathophysiol section, 1st par. The sentence ‘deposition of SU in joints and systemic effects of HU play a significant role in the inflammatory processes seen in both conditions’ could be misinterpreted. MSU in joints could play a role in inflammation if PsA and gout coexisted, but not in isolated PsA. The effect of HU in inflammation is at best controversial.

We have rephrased the sentence to clarify that MSU deposition plays a role in inflammation when gout and PsA coexist but not necessarily in isolated PsA.

• Page 3 lines 109-114: “The deposition of MSU crystals in joints and the systemic effects of hyperuricemia play significant roles in the inflammatory processes seen in both conditions. MSU crystals play a significant role in inflammation when gout and PsA co-exist, but their contribution in isolated PsA remains uncertain. While hyperuricemia may influence PsA severity, the direct role of MSU crystals in PsA without clinical gout remains controversial.”

3. Pathophysiol, last part. As the focus point of the review is Psout, the paragraph and the whole section would benefit of focusing on the findings relevant to psout and the clinical implications of the basic science findings.

We appreciate this suggestion and have now refined the section. To enable the readers to make the link between shared inflammatory pathways, we found valuable to add such basic sciences background. As suggested, in order to now focus more on psout-specific mechanisms rather than general inflammatory processes, we have added a last sentence to this last part.

• Page 5 lines 199-201: “In psout, the interplay of IL-1β, TNF-α, IL-23 and IL-17 signaling pathways may exacer-bate joint inflammation, highlighting the need for tailored management.”

4. Section 4.2 Impact of HU on PsA, 2^nd and 3^rd   The OR provided for some of these studies are univariate, but significance has been lost in multivariate, suggesting that some of these associations have confounding factors. For example, obesity is a risk factor for severity of PsA and the HU cohort is more obese. Consider toning down if only univariate association is present.

We acknowledge that most studies found significant associations only in univariate analysis. We have now added a sentence after the Table 2 to reflect this point.

• Page 11 lines 356-358: “These studies have linked HU to increased PsA severity or comorbidities; however, these associations are largely univariate and could lose significance in multivariate analyses, as confounding factors may play a role.”

5. Section 4.3, 2nd par. Is it known how many patients had MSU and how many had CPPD (relevant for understanding the results)?

We have now clarified this point by adding the rate of MSU or CPPD identified in the patient cohorts.

• Page 11 line 382: “They found that 23.7% PsA patients had detectable crystals, predominantly MSU (67.6%) and calcium pyrophosphate crystals (21.6%)”

6. Add reference for Gancheva study in line 414

The reference has now been added: [61] Gancheva R, Kundurzhiev T, Sheitanov I, Petranova Tz, Kolarov Zl, Yankova P, et al. The Prevalence of Asymptomatic Hyperuricemia in Patients with or Without Psoriatic Arthritis is Associated with a Similar Cardiovascular Risk. Acta Medica Bulgarica 2022;49:12–8. https://doi.org/10.2478/amb-2022-0024.

7. The inclusion of HU in the treatment of CV risk is still controversial. While some consensus incorporate this (ref 58), European ESC guidelines do not. A balanced and nuanced presentation of this would be welcome in Section comorbidities, par 5 and especially in Section 6.2, where treatment of HU for patients with PsA is recommended.

We agree that this remains a controversial area. We have now provided a balanced discussion, including the differing views from European ESC guidelines.

• Page 13 lines 456-459: “The role of ULT in CV risk reduction remains debated. While some consensus guidelines support its use, others, such as the European ESC guidelines [61], do not. A nuanced approach considering individual patient risk factors is warranted.”

8. As treatment of PsA and gout remains essentially the treatment of each disease, section 6.2 should convey the need to treat all gout patients with ULT.

We have explicitly stated the need to treat all gout patients with urate-lowering therapy (ULT), aligning with established guidelines.*

• Page 13 lines 487-489: “All gout patients should be treated with ULT, in line with established guidelines. In psout, ULT may also offer potential benefits for PsA severity and cardiovascular risk, though further studies are needed.”

9. Table 3, for gout, consider changing ‘not typically used’ to something like ‘no evidence of benefit’ as it currently gives the impression that it could be an option.

Based on another reviewer’s comment, we have now consider revising or removing Table 3. While it was included to highlight the differences in treatment approaches, we acknowledge that it may not add significant value to the discussion. We have now removed it.

10. Check that reference 59 is the correct reference for the URRAH CV mortality cut-off as it seems to center on the heart failure outcome.

We thank the reviewer for his/her vigilance. We have now modified the reference for the right one: Virdis A, Masi S, Casiglia E, Tikhonoff V, Cicero AFG, Ungar A, et al. Identification of the Uric Acid Thresholds Predicting an Increased Total and Cardiovascular Mortality Over 20 Years. Hypertension 2020;75:302–8. https://doi.org/10.1161/HYPERTENSIONAHA.119.13643.

Comments on the Quality of English Language

The manuscript wound benefit from minor English editings (for example line 391, first sentence).

We have now conducted a minor language edit to improve clarity and address specific instances (e.g., line 391).

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

My comments have been addressed.

Comments on the Quality of English Language

There are some misspellings in the revised sections that need corrections. Mostly words that are incorrectly hyphenated or missing spaces between.

Reviewer 2 Report

Comments and Suggestions for Authors

All comments have been adequately adressed.