The Use of Biologic and Targeted Synthetic Disease-Modifying Drugs in the Treatment of Psoriatic Arthritis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The topic faced in this review is interesting and has recently been systematically treated by authoritative international associations. However, many typing inaccuracies make the reading of the text difficult. Moreover, the complexity of  psoriatic arthritis and the difficult management of its therapy, with generally low levels of evidence to guide the therapeutic choice, are not discussed. According to this reviewer a discussion and a final message in the conclusion are necessary to let the readers know that, in spite of the great development of knowledge in the pathogenesis of PsA and the consequent setting up of tailored therapies, remission or minimal disease activity are goals not always easy to achieve. In fact, the pathogenesis of PsA is multifactorial, as rightly reported by the Authors, and even the treatment approach should be multifactorial, thus using not only drugs, but even changes in lifestyle, including the adoption of heathier, mediterranean, anti-inflammatory diet and physical activity, with weight loss and sleep increase in quantity and quality (Lubrano E, et al. RMD Open 2023;9:e003339. doi:10.1136/rmdopen-2023-003339).

Minor, generally formal, points:  line 42: "Figure 2" should be "Figure 4";  line 73: "focusing" should be "Focusing"; Table 2: this table refers to Table 1 of reference 53, thus this reference should be cited in the Table (from ref. 53 modified). Moreover, only the drugs approved for PsA should be included, according to this reviewer, whereas other drugs under study and not yet approved for PsA may only be reported in the text, but not in the Table. Finally, the Table is full of typing mistakes: conventional synthetic DMARDs should be put in the same, well visible position as biological and targeted synthetic DMARDs, like in the Table 1 of ref. 53. Moreover, among csDMARDs, Sulfasalazine is repeated 2-fold, whereas Leflunomide is lacking. Golimumab is FDA approved also for PsA. Guselkumab is wrongly spelled (Guseslkumab) and the same is for Tildakizumab which should be Tildrakizumab (at any rate, this should be cancelled in the Table, as well as Netakimab, Brodalumab, Deucravacitinib, which is FDA-approved for PsO and not yet for PsA as erroneously reported in the Table, and Brepocitinib and may only be discussed in the text). Figure 8 should be similar to Table 2, thus all the drugs mentioned above should be cancelled. Line 141: some examples of possible combination therapy should be suggested. Table 3: if this Table is completely reported from ref. 53 without modifications, the Authors should consider whether permission should be asked for reproduction and reported in the legend. Moreover, all the items should faithfully be reported and not in short version, like in items 1, 8 and 9. Finally, typing mistakes, like csDMARDs, which appears as scDMARDS in lines 156 and 160, "of" instead of "or" line 148, "on" instead of "one" line 155, "considered" instead of "commenced" line 156, "peripheral" instead of "peripheral arthritis" line 157, should be amended. Moreover, the level of evidence and grade of recommendation should be added in the Table or discussed in the text, in order the readers may understand that the highest grade of recommendation is rarely reached.

Even though the schematic algorithm of some recommendations with the Figure 9 may help readers to store the recommendations, not always Figure 9 seems to be a faithful representation of the ref. 53 recommendations. As an example, this seems to be the case for uveitis, for which anti-TNF monoclonal antibodies are recommended and not JAKi.

Even for Table 4 Authors should consider whether permission for reproduction from ref. 54 should be asked. Moreover, without a detailed legend, as in reference 54, the Table is absolutely not understandable, because "Superior" is not reported compared to what is meant. In addition,  "no date" for CTTLA4-Ig therapy in Axial Disease should be "no data". Line 223: "It would be important to avoid their use in" should be "Their use is contraindicated in".

Author Response

typing inaccuracies were addressed.

Moreover, the complexity ofpsoriatic arthritis and the difficult management of its therapy, with generally low levels of evidence to guide the therapeutic choice, are not discussed. According to this reviewer a discussion and a final message in the conclusion are necessary to let the readers know that, in spite of the great development of knowledge in the pathogenesis of PsA and the consequent setting up of tailored therapies, remission or minimal disease activity are goals not always easy to achieve. In fact, the pathogenesis of PsA is multifactorial, as rightly reported by the Authors, and even the treatment approach should be multifactorial, thus using not only drugs, but even changes in lifestyle, including the adoption of heathier, mediterranean, anti-inflammatory diet and physical activity, with weight loss and sleep increase in quantity and quality (Lubrano E, et al. RMD Open 2023;9:e003339. doi:10.1136/rmdopen-2023-003339).

-Acknowledged the importance of multifaceted treatment approach required to manage PsA (including lifestyle modification, weight loss etc) and included this in the summary

Minor, generally formal, points:line 42: "Figure 2" should be "Figure 4";

-Changed formatting points -line 42 to Figure 4

Table 2: this table refers to Table 1 of reference 53, thus this reference should be cited in the Table (from ref. 53 modified).

-Table 2 is now tablet 1 due to difficulty obtaining permission for caspar criteria

Moreover, only the drugs approved for PsA should be included, according to this reviewer, whereas other drugs under study and not yet approved for PsA may only be reported in the text, but not in the Table.

-We wanted to highlight both medications approved and in development both in table 1/figure 8 and also the main text.

Finally, the Table is full of typing mistakes: conventional synthetic DMARDs should be put in the same, well visible position as biological and targeted synthetic DMARDs, like in the Table 1 of ref. 53.

-Changed Table 1 to now have conventional DMARDs occupy a visible position like biologic and targeted synthetic dmards

Moreover, among csDMARDs, Sulfasalazine is repeated 2-fold, whereas Leflunomide is lacking.

-Duplicate sulfasalazine changed to leflunomide

Golimumab is FDA approved also for PsA.

-Removed asterick so Golimumab is now showing that it is approved for PsA

Guselkumab is wrongly spelled (Guseslkumab) and the same is for Tildakizumab which should be Tildrakizumab (at any rate, this should be cancelled in the Table, as well as Netakimab, Brodalumab, Deucravacitinib, which is FDA-approved for PsO and not yet for PsA as erroneously reported in the Table, and Brepocitinib and may only be discussed in the text). Figure 8 should be similar to Table 2, thus all the drugs mentioned above should be cancelled.

-Guselkumab spelling changed so that it is correctly spelled.

-Changed tilrakizumab to correct spelling in the table.

-Deucravacitinib was changed to FDA approved for PsO only.

Line 141: some examples of possible combination therapy should be suggested.

-Combination therapy example was added in Line 141 – Ustekinumab and etanercept as mentioned in reference 51.

Table 3: if this Table is completely reported from ref. 53 without modifications, the Authors should consider whether permission should be asked for reproduction and reported in the legend.

Moreover, all the items should faithfully be reported and not in short version, like in items 1, 8 and 9.

-Table 3 was removed.

Finally, typing mistakes, like csDMARDs, which appears as scDMARDS in lines 156 and 160,

-Changed scDMARD to csDMARD on line 160.

“on" instead of "one" line 155,

-on changed to one on line 155.

"considered" instead of "commenced" line 156,

-considered changed to commenced on line 156.

"peripheral" instead of "peripheral arthritis" line 157, should be amended.

-changed peripheral to peripheral arthritis on line 157.

Moreover, the level of evidence and grade of recommendation should be added in the Table or discussed in the text, in order the readers may understand that the highest grade of recommendation is rarely reached.

Even though the schematic algorithm of some recommendations with the Figure 9 may help readers to store the recommendations, not always Figure 9 seems to be a faithful representation of the ref. 53 recommendations. As an example, this seems to be the case for uveitis, for which anti-TNF monoclonal antibodies are recommended and not JAKi.

-table 3 was removed so could not address this in relation to figure 9.

Even for Table 4 Authors should consider whether permission for reproduction from ref. 54 should be asked.

-table 4 was also removed.

Moreover, without a detailed legend, as in reference 54, the Table is absolutely not understandable, because "Superior" is not reported compared to what is meant. In addition,  "no date" for CTTLA4-Ig therapy in Axial Disease should be "no data". Line 223: "It would be important to avoid their use in" should be "Their use is contraindicated in".

-Changed it would be important to avoid their use and adjusted sentence in line 223.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript titled “The use of biologic and targeted synthetic disease modifying drugs in the treatment of Psoriatic arthritis” provided an in-depth overview of the Psoriatic arthritis (PsA), covering its pathogenesis, clinical features, and treatment approaches. The article is well-structured and offers valuable insights into the current understanding and management of PsA. The authors thoroughly presented various aspects of PsA, including its introduction, pathogenesis, clinical features, treatment options and guidelines including 2023 EULAR recommendations. Various treatment options including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs are well described. The figures and tables are reasonably well presented to enhance the reader’s understanding. Overall, this article offers a comprehensive overview of psoriatic arthritis, incorporating up-to-date information and evidence-based recommendations. The reviewer has the following comments to the authors that need to be addressed.

1.     The article provides a wealth of information, however, it could benefit from more critical analysis of conflicting evidence or controversies in the field.

2.     Although the authors cited numerous clinical trials and studies to support their statements, addition of more information on emerging therapies and ongoing clinical trials could benefit the readers.

 3.     The article would benefit from incorporating additional insights into the patient experience and the impact of PsA on quality of life, providing a more holistic view of disease management. Additionally, a brief discussion of the economic implications of various treatment options, particularly the high costs associated with biologic therapies, could add significant value and context.

 4.     Psoriasis and Psoriatic arthritis are chronic autoimmune diseases characterized by persistent inflammation and oxidative stress. Curcumin based diarylheptanoids and isocoumarins, are known for their potent antioxidant properties, which are known to help mitigate oxidative imbalance associated with psoriatic arthritis. The reviewer recommends the authors cite relevant articles in the introduction that discuss the synthesis of these secondary plant metabolites and their potential therapeutic roles in managing oxidative stress-related conditions

https://aces.onlinelibrary.wiley.com/doi/full/10.1002/asia.202400380

https://www.sciencedirect.com/science/article/pii/S0223523416307243

 

 

 

Author Response

1. The article provides a wealth of information, however, it could benefit from more critical analysis of conflicting evidence or controversies in the field.

-Included a point that there is difference between different treatment guidelines depending on organization (eg.  ACR versus EULAR) amongst others, as some of these recommendations are based on low evidence.

2. Although the authors cited numerous clinical trials and studies to support their statements, addition of more information on emerging therapies and ongoing clinical trials could benefit the readers.

-Included some information on potential treatments on 6.6 and emerging therapies – eg.  filgotinib, and brepocitinib

3. The article would benefit from incorporating additional insights into the patient experience and the impact of PsA on quality of life, providing a more holistic view of disease management. Additionally, a brief discussion of the economic implications of various treatment options, particularly the high costs associated with biologic therapies, could add significant value and context.

-Included point that medication cost could impact treatment decisions.

4. Psoriasis and Psoriatic arthritis are chronic autoimmune diseases characterized by persistent inflammation and oxidative stress. Curcumin based diarylheptanoids and isocoumarins, are known for their potent antioxidant properties, which are known to help mitigate oxidative imbalance associated with psoriatic arthritis. The reviewer recommends the authors cite relevant articles in the introduction that discuss the synthesis of these secondary plant metabolites and their potential therapeutic roles in managing oxidative stress-related conditions

https://aces.onlinelibrary.wiley.com/doi/full/10.1002/asia.202400380

https://www.sciencedirect.com/science/article/pii/S0223523416307243.

-We did not include plant based metabolites and their role in managing oxidative stress related conditions for PsA as we felt this was outside the scope of the article.

Reviewer 3 Report

Comments and Suggestions for Authors

An extensive review on the various treatment approach in psoriatic arthritis (PsA), ranging from tradition DMARDs, to b(biological) DMARDs (TNF, IL-17 & IL12/23 inhibitors) and ts(targeted synthetic) DMARDs (PDE4 & JAKi).

The article is well written with up to date information including EULAR guidelines summarised in 3 Tables, 9 Figures and 132 references. Some minor suggestions from this reviewer:

1.  An abstract would be informative (Page 1) listing out the main points in the review.

2.  Page 10, a section on glucocorticoid (ie, Prednisolone) why it is far from ideal as a standard treatment in PsA. Also side effects of MTX/leflunomide, ie, avoidance during pregnancy, whereas sulfasalazine and TNFi are relatively low risk.

3.  A table listing all the abbreviations would be useful for the readers, especially those without the necessary internal medicine/rheumatology exposure, ie, cs(conventional synthetic) DMARDs.

Minor – Page formatting, ie, line 147, 209, 408/9; Page 9, line 174, Table 4 should change to Table 3.

 

Author Response

1. An abstract would be informative (Page 1) listing out the main points in the review.

-Abstract included on page 1 listing the main points in the review

2. Page 10, a section on glucocorticoid (ie, Prednisolone) why it is far from ideal as a standard treatment in PsA. Also side effects of MTX/leflunomide, ie, avoidance during pregnancy, whereas sulfasalazine and TNFi are relatively low risk.

-Added comments on side effects of MTX/leflunomide and avoidance during pregnancy, and that TNFi could be used in pregnancy.

3. A table listing all the abbreviations would be useful for the readers, especially those without the necessary internal medicine/rheumatology exposure, ie, cs(conventional synthetic) DMARDs.

-Included comment on glucocorticoid use and why this should not be standard treatment

-All abbreviations were mentioned within the text of the article

Minor – Page formatting, ie, line 147, 209, 408/9; Page 9, line 174, Table 4 should change to Table 3.

-Additional table 3 and 4 were removed, and some of the page formatting was adjusted.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors have substantially complied with my remarks.

However, I keep thinking that leaving in the Table 1 and Figure 8 drugs not approved for PsA may be misleading and may confound the readers. Moreover, a final Discussion with Conclusions, not a Summary which looks like an Abstract, to enable readers to understand how to begin therapy and in what sequence to proceed with other drugs in the event of initial failure, may really improve the quality of this review.

Finally, the Authors, following my suggestion, have included in the final Summary the need for a multifactorial approach to treatment, but I think that such an indication should be accompanied by a fit reference. This may be different from the one suggested by me, provided that the indicated reference come from a well-known and cited  scientific journal. 

Author Response

Reviewer additional suggestions:

The Authors have substantially complied with my remarks.

However, I keep thinking that leaving in the Table 1 and Figure 8 drugs not approved for PsA may be misleading and may confound the readers. Moreover, a final Discussion with Conclusions, not a Summary which looks like an Abstract, to enable readers to understand how to begin therapy and in what sequence to proceed with other drugs in the event of initial failure, may really improve the quality of this review.

Finally, the Authors, following my suggestion, have included in the final Summary the need for a multifactorial approach to treatment, but I think that such an indication should be accompanied by a fit reference. This may be different from the one suggested by me, provided that the indicated reference come from a well-known and cited  scientific journal. 

 

Comments:

-Took out the drugs not approved from PsA from table 1. They remain in Figure 8 as they are potential treatment targets and we wanted to highlight that.

-Changed Summary to Discussions. Added a brief section on how to begin therapy and sequence etc as outlined in Figure 9.

-Included the reference which was suggested by the reviewer: Lubrano E, Scriffignano S, de Vlam K, et al. Triple jump for the optimal management of psoriatic arthritis: diet, sleep and exercise – a review. RMD Open 2023;9:e003339. doi:10.1136/ rmdopen-2023-003339. PMID:37648398; PMCID: PMC10471880

Author Response File: Author Response.pdf