Pyoderma Gangrenosum: A Review of Updates in Diagnosis, Pathophysiology and Management

Round 1

Reviewer 1 Report

Dear authors

Thanks for addressing this interesting topic; however recent reviews made this one less interesting

I have a few things to add for the knowledge of the authors and possible future papers

1)Diagnosis--There are currently three diagnostic criteria for PG and not only the Delphi consensus. A recent paper in JID 2021 compared all of them and PARACELSUS diagnostic tool performed better than the other ones. Among clinical PG experts in US and Europe, adopting PARACELSUS might be the future trend.

3)Pathophysiology--The T cell hypothesis is very interesting and more research will come from this. However, most people agree PG is an autoinflammatory skin disorder and then stimulation of the adaptive immune system is a consequence of the activation of the innate immune system. There other citations by Marzano's group and Dr Ortega's group have not been included covering this topic. 

Not all PGs come from around pilosebaceous units, as some PG have been described on scars(there is a report in the main indian journal) and there is also a report(several years ago) on the plantar surface of a patient--It is important to highlight there is no PG affecting the nipple.

Author Response

Dear Editorial Staff of Multidisciplinary Scientific Journal,

We would like to thank you for taking the time to review our work and for providing us with valuable feedback which helped to greatly increase the quality of information included in our review. Below, please find the comments of each reviewer followed by our responses to their revisions and comments. Our goal is to provide accurate, evidence- based information and to construct a review that is up to the standards of your journal and we thank you for the opportunity to publish our work and for your expertise in reviewing our work and for making sure that the latest, most evidence- based information was included.

Reviewer 1:

Dear authors

Thanks for addressing this interesting topic; however recent reviews made this one less interesting

I have a few things to add for the knowledge of the authors and possible future papers

1)Diagnosis--There are currently three diagnostic criteria for PG and not only the Delphi consensus. A recent paper in JID 2021 compared all of them and PARACELSUS diagnostic tool performed better than the other ones. Among clinical PG experts in US and Europe, adopting PARACELSUS might be the future trend.

3)Pathophysiology--The T cell hypothesis is very interesting and more research will come from this. However, most people agree PG is an autoinflammatory skin disorder and then stimulation of the adaptive immune system is a consequence of the activation of the innate immune system. There other citations by Marzano's group and Dr Ortega's group have not been included covering this topic. 

Not all PGs come from around pilosebaceous units, as some PG have been described on scars (there is a report in the main indian journal) and there is also a report (several years ago) on the plantar surface of a patient--It is important to highlight there is no PG affecting the nipple.

Response to Reviewer 1:

We would like to thank you for taking the time to review our work and for your revisions to our paper. This information is important in understanding the diagnosis and pathophysiology of PG and will be incorporated into the review and we thank you for sharing your knowledge with us.

1.Diagnosis – under the section labeled “Diagnosis”, in the 4^th and 5^th paragraphs, please find the addition of the information that you suggested regarding the PARACELSUS criteria and, interpretation of the data from the study by Haag et al comparing the three diagnostic criteria available for PG (Su, Delphi and PARACELSUS criteria).

2.Pathophysiology – thank you very much for your feedback in this section. After reading your suggestions and doing further literature searches, please find under the section labeled “pathophysiology” in the first, third and fourth paragraphs the addition of the information you recommended regarding the autoinflammatory nature of PG, the citation of Dr. Marzano and Dr. Ortega’s work regarding the pathophysiology of PG and, the additional theory that the pathogenesis of the disease is rooted in stimulation of both the innate and adaptive immune systems. We also included a case report of PG ulcer formation on the plantar aspect of the first MTP joint of a patient and, a case report of the formation of PG over a hypertrophic scar to beg the point that not all PG lesions are a result of destruction of pilosebaceous units. Your input in this section is greatly appreciated as it led us to really delve into the literature and learn additional interesting information about the pathophysiology of pyoderma gangrenosum.

Thank you for your time and consideration. We look forward to hearing from you.

Best,

Maria Skopis, DO

Ayse Bag-Ozbek, MD

Reviewer 2 Report

The authors presented a manuscript entitled: Pyoderma Gangrenosum: A Review of Updates in Diagnosis, Pathophysiology and Management. The issue is interesting given the little knowledge regarding this disease. The manuscript is well presented, and I think that it would be of interest for the readers of the Multidisciplinary Scientific Journal.

Author Response

Dear Editorial Staff of Multidisciplinary Scientific Journal,

We would like to thank you for taking the time to review our work and for providing us with valuable feedback which helped to greatly increase the quality of information included in our review. Below, please find the comments of each reviewer followed by our responses to their revisions and comments. Our goal is to provide accurate, evidence- based information and to construct a review that is up to the standards of your journal and we thank you for the opportunity to publish our work and for your expertise in reviewing our work and for making sure that the latest, most evidence- based information was included.

Reviewer 2:

The authors presented a manuscript titled: Pyoderma Gangrenosum: A Review of Updates in Diagnosis, Pathophysiology and Management. The issue is interesting given the little knowledge regarding this disease. The manuscript is well presented, and I think that it would be of interest for the readers of the Multidisciplinary Scientific Journal.

Response to Reviewer 2:

Thank you very much for your kind words. We are glad that you enjoyed reading our work and found it interesting. We hope to confer a better understanding of pyoderma gangrenosum to the readers of the Multidisciplinary Scientific Journal through this review by presenting the latest evidence regarding the pathophysiology, diagnosis and treatment of PG.

Thank you for your time and consideration.

Best,

Maria Skopis, DO

Ayse Bag Ozbek, MD

Reviewer 3 Report

I suggest to include some pictures – although there is a lack of established, specific histologic criteria to diagnose pyoderma gangrenosum and histology is nonspecific, the authors can show some clinical and histological pictures.

Cyclosporin, not ciclosporin

You should mention the possibility of biological treatment with Infliximab:

• Generalized Pyoderma Gangrenosum Associated with Ulcerative Colitis: Successful Treatment with Infliximab and Azathioprine.

Chatzinasiou F, Polymeros D, Panagiotou M, Theodoropoulos K, Rigopoulos D.Chatzinasiou F, et al. Acta Dermatovenerol Croat. 2016 Apr;24(1):83-5.

• Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet's syndrome: a comprehensive review and disease classification criteria.

Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M.Marzano AV, et al. Clin Rev Allergy Immunol. 2013 Oct;45(2):202-10. doi: 10.1007/s12016-012-8351-x.

Author Response

Dear Editorial Staff of Multidisciplinary Scientific Journal,

We would like to thank you for taking the time to review our work and for providing us with valuable feedback which helped to greatly increase the quality of information included in our review. Below, please find the comments of each reviewer followed by our responses to their revisions and comments. Our goal is to provide accurate, evidence- based information and to construct a review that is up to the standards of your journal and we thank you for the opportunity to publish our work and for your expertise in reviewing our work and for making sure that the latest, most evidence- based information was included

Reviewer 3:

1.I suggest to include some pictures – although there is a lack of established, specific histologic criteria to diagnose pyoderma gangrenosum and histology is nonspecific, the authors can show some clinical and histological pictures.

2.Cyclosporin, not ciclosporin

3.You should mention the possibility of biological treatment with Infliximab:

Generalized Pyoderma Gangrenosum Associated with Ulcerative Colitis: Successful Treatment with Infliximab and Azathioprine

Chatzinasiou F, Polymeros D, Panagiotou M, Theodoropoulos K, Rigopoulos D. Acta Dermatovenerol Croat.2016 Apr;24(1):83-5

4.Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet's syndrome: a comprehensive review and disease classification criteria. 

Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M.Marzano AV, et al. Clin Rev Allergy Immunol. 2013 Oct;45(2):202-10. doi: 10.1007/s12016-012-8351-x.

Response to Reviewer 3:

1.Thank you very much for your feedback. We greatly appreciate you reviewing our work and giving us your valued input. In regard to your suggestion of including some photos of PG and PG histology, there is not a specific photograph which can explain the lesions of PG completely due to the multiple variants of the disease and the nonspecific histological findings. Therefore, we instead preferred to give detailed descriptions of the histology and physical exam findings of PG in our manuscript rather than to include images. This helps the reader to learn how to describe the lesions or histologic findings of pyoderma gangrenosum when discussing with their colleagues or writing about it themselves and, prevents them from anchoring to one image or histologic finding when thinking about how pyoderma gangrenosum can present clinically, which was one of our goals in writing this review.

2.Please find the spelling of cyclosporine corrected under the section labeled “treatment” in paragraph 2.

3.Please find mention of the use of biological treatment of PG lesions with Infliximab under the section labeled “treatment” in the first sentence of the third paragraph.

4.Please find reference to Dr. Marzano’s work regarding the autoinflammatory nature of PG under the section labeled “pathophysiology” in the third and fourth paragraphs

Thank you for your time and consideration. 

Best,

Maria Skopis, DO

Ayse Bag Ozbek, MD

Round 2

Reviewer 1 Report

I have a few observations

1)PG is a clinical diagnosis and not a diagnosis of exclusion any more as there are 3 different diagnostic frameworks. The work by Haag et was important for validation in dermatological setting. In clinical practice, I favor PARACELSUS. I would like the authors to suggest what they favor in their practices.

2)There was a paper by Dr Ortega's group on gene expression highligthing the innate immune system in the pathogenesis of PG. I think it was published in 2018. This was a short paper but novel as compared lesional vs non-lesional skin in PG.

3)It would be worth it to mention that trials on biologics (Humira--was recently completed in Japan) and JAK kinase (baricitinib) has recently opened and it is available in clinicaltrials.gov

4)Also, of all biologics in PG, Ustekinumab is the one which has been proven effective in all kinds of PG (PMID: 34057010)

5)Any comments on cases of PG and HS--a paragraph would be helpful about therapy. These are challenging cases.

6)Any recommendations on periopeative management of PG--I saw a recent paper in JAAD in 2020. There was anything conclusive but this is not uncommon in clinical practice

Author Response

Dear Editorial staff of Multidisciplinary Scientific Journal,

Thank you for taking the time to review our work and to provide valuable feedback which not only improved the quality of information in this review but, also helped us to learn more about this interesting subject. Below, please find the comments and edits of the reviewers and our responses.

Reviewer 1:

1. I have a few observations:

PG is a clinical diagnosis and not a diagnosis of exclusion anymore as there are 3 different diagnostic frameworks. The work by Haag et al was important for validation in dermatological setting. In clinical practice, I favor PARACELSUS. I would like the authors to suggest what they favor in their practices.

Response to Comment 1:

• In the first paragraph of the diagnosis section, please find that the second sentence has been reworked to no longer name PG as a diagnosis of exclusion but rather, a clinical diagnosis. In the fourth paragraph, last sentence, please find that our preferred criteria when diagnosing PG in the clinical setting is the PARACELSUS score and our reasoning for favoring this criteria.

2. There was a paper by Dr. Ortega’s group on gene expression highlighting the innate immune system in the pathogenesis of PG. I think it was published in 2018. This was a short paper but novel as compared to lesional vs non-lesional skin PG.

Response to Comment 2:

• Under the Pathophysiology section in paragraphs 4 and 5, please find the study mentioned by Ortega et al as it applies to the overexpression of genes implicated in the innate and adaptive immune systems

3. It would be worth it to mention that trials on biologics (Humira-was recently completed in Japan) and JAK kinase (baricitinib) has recently opened and it is available in clinical trials.gov

Response to Comment 3:

• Under the treatment section in paragraph 3 sentence 3, please find mention of the clinical trials you recommended and the reference to clinical trials.gov.

4. Also, of all biologics in PG, Ustekinumab is the one which has been proven effective in all kinds of PG (PMID: 34057010).

Response to Comment 4:

• Under the treatment section in paragraph 3 sentence 5, please find the study outlining the efficacy of ustekinumab in treating all forms of PG as recommended.

5. Any comments on cases of PG and HS – a paragraph would be helpful about therapy. These are challenging cases.

Response to Comment 5:

• Under the treatment section in paragraph 5, please find added information and literature review outlining the treatment of HS and PG overlap syndrome.

6. Any recommendations on perioperative management of PG – I saw a recent paper in JAAD in 2020. There was anything conclusive but this is not uncommon in clinical practice.

Response to Comment 6:

• Under the treatment section in paragraph 5, please find added information on the perioperative treatment of PG.

Thank you, and we look forward to hearing from you.

Sincerely,

Maria Skopis, DO

Ayse Bag Ozbek, MD

Round 3

Reviewer 1 Report

Some observations

Introduction Line 44: There is only one paper suggesting autoreactive T cells for PG pathogenesis—Please switch “Some of these theories…” to one of these theories. Please add the most widely accepted theory is the autoinflammatory one with several publications.

Diagnosis line 248—please be consistent when naming the diagnostic criteria. Dr Su was at Mayo clinic, Dr Maverakis published the diagnostic criteria as a Delphi consensus and Dr Dissemond led the PARACELSUS criteria group. A suggestion would be Mayo diagnostic criteria, International Delphi Criteria and PARACELSUS diagnostic tool or you can use SU et al, Maverakis et al and Dissemond et al.

Diagnosis line 278—delete word exclusion and replace with “remains exclusively a clinical diagnosis”

I do not recall reading papers by Dr. Ortega, I think the author cited in the manuscript is Ortega-Loayza

Author Response

Dear Editorial Staff of Multidisciplinary Scientific Journal,

Thank you for your continued feedback regarding our manuscript. Below, please find the comments and edits of the reviewers and our responses.

Reviewer 1:

1. Introduction Line 44: There is only one paper suggesting autoreactive T cells for PG pathogenesis-Please switch “some of these theories…” to one of these theories. Please add the most widely accepted theory is the autoinflammatory one with several publications.

Response to Comment 1:

• In the introduction paragraph, Line 44, please find the recommended edits to the sentence to include that the most widely accepted theory of the pathogenesis of PG is that it is autoinflammatory in nature.

2. Diagnosis line 248 – please be consistent when naming the diagnostic criteria. Dr. Su was at Mayo Clinic, Dr. Maverakis published the diagnostic criteria as a Delphi consensus and Dr. Dissemond led the PARACELSUS criteria group. A suggestion would be Mayo diagnostic criteria, International Delphi Criteria, and PARACELSUS diagnostic tool or you can use Su et al, Maverakis et al and Dissemond et al.

Response to Comment 2:

• Thank you for the clarification. In the diagnosis section, line 248, please find that the naming of the diagnostic criteria has been adjusted to reflect consistency.

3. Diagnosis line 278- delete the word exclusion and replace with “remains exclusively a clinical diagnosis”.

Response to Comment 3:

• In the Diagnosis section line 278 please find the suggested edits to this sentence.

4. I do not recall reading papers by Dr. Ortega, I think the author cited in the manuscript is Ortega-Loayza

Response to Comment 4:

• The author’s name has been corrected to reflect “Ortega-Loayza” throughout the manuscript where cited.

Thank you,

Maria Skopis, DO

Ayse Bag Ozbek, MD