Skin Hypopigmentation in Hematology Disorders

Round 1

Reviewer 1 Report

The manuscript by Mazzetto et al. aims to explore the clinical presentations of hypopigmentation in hematological disorders, focusing on vitiligo, morphea, and syndromic albinism. The paper provides valuable insights into the relationship between dermatological manifestations and underlying hematological conditions, emphasizing the importance of timely diagnosis and management. The paper's strengths lie in its comprehensive review of the topic and the clear discussion of treatment approaches.

 

• The manuscript needs to contain original/ external figures (with permission). Any work on dermatology is insufficient without relevant figures.

 

• Elaborate on the potential implications of elevated serum titers of melanocyte-reactive antibodies in vitiligo on disease prognosis or treatment response.

 

• Expand on the involvement of CD8+ T cells in vitiligo pathogenesis, including their cytotoxic effects on melanocytes and potential therapeutic implications targeting this immune cell subset.

 

• I recommend incorporating a table describing the various mechanisms drugs may cause vitiligo and the incidence of such side effects.

 

• Highlight the advances in understanding the role of Tregs in maintaining immune tolerance in vitiligo and their potential as therapeutic targets.

 

• Provide more details on the clinical presentation of deep morphea and its association with hematological disorders, including specific examples of myeloproliferative disorders or lymphomas linked to this variant.

 

• Compare and contrast the cutaneous modifications seen in generalized morphea vs. systemic sclerosis, emphasizing the key differences in internal organ involvement and vascular manifestation.

 

• Discuss the potential triggers for morpheaform disorders, such as local insults or environmental factors, preferably in a tabular format.

 

• Elaborate on the hematologic conditions associated with syndromic albinism, providing specific examples of blood anomalies and their clinical implications.

 

• Contrast the neutropenia observed in CHS and GS2 to the chronic neutropenia seen in HPS2 and MAPBPIP-deficiency syndrome, preferably in a tabular format.

 

• Provide more detail on the significance of immune dysregulation in drug-induced vitiligo, particularly in the context of immune checkpoint inhibitors.

Author Response

Reviewer 1
Need to add figures.
Need to make the manuscript more comprehensive by discussing hematology-specific literature, adding tables and figures.
The manuscript by Mazzetto et al. aims to explore the clinical presentations of hypopigmentation in hematological disorders, focusing on vitiligo, morphea, and syndromic albinism. The paper provides valuable insights into the relationship between dermatological manifestations and underlying hematological conditions, emphasizing the importance of timely diagnosis and management. The paper's strengths lie in its comprehensive review of the topic and the clear discussion of treatment approaches.

We thank the Reviewer for the valuable feedback on our Manuscript. We have made extensive revisions to address all the comments and suggestions raised. Specifically:

•    The manuscript needs to contain original/ external figures (with permission). Any work on dermatology is insufficient without relevant figures.

We have included original figures of our patients (which provided consent to their use) to enhance the comprehensiveness of the dermatological discussions as suggested. Please see: Figure 1. Vitiligo-like leukoderma. Figure 2. Plaque-type morphea.

•    Elaborate on the potential implications of elevated serum titers of melanocyte-reactive antibodies in vitiligo on disease prognosis or treatment response.

We have discussed the potential implications of elevated serum titers of melanocyte-reactive antibodies in vitiligo concerning disease prognosis and treatment response. Please see in the text: “Elevated serum titers of melanocyte-reactive antibodies against melanocytes are pathogenic in disease models both in vivo and in vitro and are assessed in individuals suffering from vitiligo [1]. Notably, activity of vitiligo is not reflected by autoantibody titers [2]. In addition, vitiligo affects clearly demarcated areas, and does not match with a widespread distribution mediated by autoantibodies: such observations lessen the pathogenic role of antimelanocyte antibodies [3].”

•    Expand on the involvement of CD8+ T cells in vitiligo pathogenesis, including their cytotoxic effects on melanocytes and potential therapeutic implications targeting this immune cell subset.

We also highlighted the involvement of CD8+ T cells in vitiligo pathogenesis, including their cytotoxic effects on melanocytes and the therapeutic implications. Please see: “Histological analysis of active vitiligo lesions revealed an increase in the lymphocytic infiltrate in their periphery, mainly represented by CD8+ T lymphocytes [6]. Tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2 are the proteins identified by studies on melanoma against which autoreactive CD8+ T lymphocytes are activated [7,8]. Studies performed ex vivo on autologous healthy skin explants demonstrate how CD8+ lym-phocytes are necessary and sufficient for the destruction of melanocytes in vitiligo, unlike CD4+ cells which were unable to do the same [9,10]. Similarly, effective responses fol-lowing anticancer immunotherapy, with anti-PD1 agents that lift the inhibitor T cell immune checkpoint, are associated with activation of CD8+ T cells and their cellular in-filtration into the tumor [11,12].”

•    I recommend incorporating a table describing the various mechanisms drugs may cause vitiligo and the incidence of such side effects.

A detailed table describing the various mechanisms by which drugs may cause vitiligo has been added. Please see: Table 1. Systemic cancer treatments associated with vitiligo-like depigmentation and scleroderma.

•    Highlight the advances in understanding the role of Tregs in maintaining immune tolerance in vitiligo and their potential as therapeutic targets.

Advances in understanding the role of Tregs in maintaining immune tolerance in vitiligo and their potential as therapeutic targets have been also included in the text. Please see: “Additionally, various studies on murine models of vitiligo have demonstrated the correlation between an increased number of Treg cells and a reduced severity of the disease. Moreover, it has been shown that injecting PD-L1-Fc into mice predisposed to vitiligo, increased the concentration of Tregs in the skin and improved depigmentation. These findings suggest that the number of Treg cells is important for controlling the progression of vitiligo. Treg cells naturally reduce the proliferation and activation of autoreactive effector T cells, a phenomenon called anergy; phenotypic analysis of pe-ripheral blood mononuclear cells suggests that melanocyte-reactive CD8+ T cells escape anergy in vitiligo patients [13]. Further studies will be needed to gain in-depth knowledge on Treg cell deficits and their contribution to vitiligo; enhancing Treg cell function might provide novel avenues for drug discovery.”

•    Provide more details on the clinical presentation of deep morphea and its association with hematological disorders, including specific examples of myeloproliferative disorders or lymphomas linked to this variant.

We have provided more details on the clinical presentation of deep morphea and its association with hematological disorders, including specific examples of myeloproliferative disorders and lymphomas linked to this variant citing the relevant literature. Please see: “Deep morphea features involvement beyond the subcutaneous fat and may clinically resemble eosinophilic fasciitis, a distinct fibrosing disorder with rapid clinical progression. The latter has been associated to myeloproliferative disorders and monoclonal gammo-pathy, as well as with aplastic anemia, thrombocytopenia, pancytopenia [36], and lymphoma [37,38]. While there are only anecdotal associations with deep morphea, for example with lymphoma, there is a certain overlap between the two conditions in the literature [39].”

•    Compare and contrast the cutaneous modifications seen in generalized morphea vs. systemic sclerosis, emphasizing the key differences in internal organ involvement and vascular manifestation.

A comparison and contrast of the cutaneous modifications seen in generalized morphea versus systemic sclerosis has been included. Please see: “Generalized morphea may share cutaneous modifications that are similar to diffuse cutaneous systemic sclerosis: the trunk may become entirely affected and shows typical sparing of the periareolar circumference and the disease may extend along the ex-tremities determining a puffy edema of the hands. The absence of internal organ in-volvement and of changes to the digits are sufficient to differentiate between the two disorders. Esophageal dysmotility, small intestine disfunction, interstitial lung disease, pulmonary arterial hypertension at risk for secondary heart failure, fibrotic cardiomy-opathy, hypertension, and renal damage constitute the principal and debilitating internal organ affections related to systemic sclerosis while they are not clinically relevant in generalized morphea. Finally, vascular changes are early events that are shared in the pathogenesis of both systemic sclerosis and morphea: however, digital sclerosis, Raynaud phenomenon, and cutaneous ulcers are features of systemic sclerosis alone [41].   ”

•    Discuss the potential triggers for morpheaform disorders, such as local insults or environmental factors, preferably in a tabular format.

The potential triggers for morpheaform disorders are now discussed in a tabular format. Please see: Table 2. Scleroderma-like disorders and hypothesized etiological factors or triggers.

•    Elaborate on the hematologic conditions associated with syndromic albinism, providing specific examples of blood anomalies and their clinical implications.

A table contrasting the neutropenia and hematologic condition observed in each syndromic form of albinism has been created. Please see: Table 3. Hematologic alterations and the related clinical implications in syndromic forms of albinism.

•    Contrast the neutropenia observed in CHS and GS2 to the chronic neutropenia seen in HPS2 and MAPBPIP-deficiency syndrome, preferably in a tabular format.

The comparison between the types of neutropenia associated to these syndromes has been included in Table 3. Hematologic alterations and the related clinical implications in syndromic forms of albinism.

•    Provide more detail on the significance of immune dysregulation in drug-induced vitiligo, particularly in the context of immune checkpoint inhibitors.

The significance of immune dysregulation in drug-induced vitiligo, particularly in the context of immune checkpoint inhibitors, has been highlighted. Please see in the text: “Similarly, effective responses fol-lowing anticancer immunotherapy, with anti-PD1 agents that lift the inhibitor T cell immune checkpoint, are associated with activation of CD8+ T cells and their cellular in-filtration into the tumor [11,12].”

Reviewer 2 Report

The paper entitled Skin Hypopigmentarion in Hematology Disorders is an interesting narrative review aiming to evaluate cutaneous changes occuring in several blood diseases and/or the administration of treatment. 

Which is the incidence of skin changes in hematological disorders? Did treatment with monoclonal antibodies, tyrosine kinase inhibitors or other novel drugs increase their frequency?

Does the onset of these symptoms influence the quality of life of patients with blood afflictions?

Does the treatment of these skin alterations influence in any way the specific treatment of the hematological disorder? Did it influence prognosis or treatment outcome if the therapy was changed due to side effects?

The paper could be improved by adding some images of skin lesions.

The paper entitled Skin Hypopigmentarion in Hematology Disorders is an interesting narrative review aiming to evaluate cutaneous changes occuring in several blood diseases and/or the administration of treatment. 

Which is the incidence of skin changes in hematological disorders? Did treatment with monoclonal antibodies, tyrosine kinase inhibitors or other novel drugs increase their frequency?

Does the onset of these symptoms influence the quality of life of patients with blood afflictions?

Does the treatment of these skin alterations influence in any way the specific treatment of the hematological disorder? Did it influence prognosis or treatment outcome if the therapy was changed due to side effects?

The paper could be improved by adding some images of skin lesions.

Author Response

Reviewer 2
The paper entitled Skin Hypopigmentarion in Hematology Disorders is an interesting narrative review aiming to evaluate cutaneous changes occuring in several blood diseases and/or the administration of treatment. 

Dear Reviewer 2,
Thank you for your careful review of our manuscript and for the constructive comments.
We have carefully considered each issue raised, please find our responses provided point by point below:

Which is the incidence of skin changes in hematological disorders? Did treatment with monoclonal antibodies, tyrosine kinase inhibitors or other novel drugs increase their frequency?

Please see “Table 1. Systemic cancer treatments associated with vitiligo-like depigmentation and scleroderma” where the incidence of vitiligo related to novel therapeutic agents is detailed and “Table 2. Scleroderma-like disorders and hypothesized etiological factors or triggers” in which manifestations related to drugs are discussed.

Does the onset of these symptoms influence the quality of life of patients with blood afflictions? 

Thank you, these are very important considerations from the dermatologist’s perspective. To further highlight this aspect, the following statements were added to our Conclusions: “Pigmentary alterations constitute a potential cause of severe cosmetic concern in patients living with hematologic conditions; therefore, the treating dermatologist is a key figure in improving the overall quality of life and in promoting adherence to therapy. While novel targeted therapeutics, that may be tolerable even in patients receiving systemic cancer treatments, are highly anticipated, current management must also consider cosmetic camouflage as a strategy that may be employed by patients in their daily life to address cosmetic impairment.”

Does the treatment of these skin alterations influence in any way the specific treatment of the hematological disorder? Did it influence prognosis or treatment outcome if the therapy was changed due to side effects?

We have accordingly added a statement to the Conclusions: “Finally, although the onset of skin manifestations does not influence the natural history of the underlying hematologic conditions, timely skin directed treatment, as well as the option of replacing the responsible drug when feasible, have the potential to alter the progression of cutaneous involvement.”

The paper could be improved by adding some images of skin lesions.

We have included original figures of our patients (which provided consent to their use) to enhance the comprehensiveness of the dermatological discussions as suggested. Please see: 
-    Figure 1. Vitiligo-like leukoderma.
-    Figure 2. Plaque-type morphea.

Reviewer 3 Report

Dear Editor,

The review entitled: "Skin Hypopigmenatation in Hematology Disorders" by Mazzetto et al is a comprenhensive and well written review of dermatological manifestations of hematological diseases. My main comments is related to the structure and aim of the manuscript. Authors review 3 distinct dermatological diseases (vitiligo, morphea and albinism) and correlate this to the use of treatment for the hematological diseases (checkpoint inhibitors, TKIs, ecc) but they also report data about diseases that have hematological findings that have also dermatological manifestations. To my the aim of the review is not clear. I mean they should focus only on the use of newer agents and the development of dermatological manifestations that should be of interest for the reader of a hematology journal.

1. Authors should add a table about the newer agents used in hematology (TKIs, small molecules, ecc) and the related dermatological manifestations. 

2. No mechanism about leukoderma and use of monoclonal antibodies have been reported or at least hypothysed.

3. Treatment options for each disease should be reported in the paragraph that described the disease and its pathogenesis.

Author Response

Reviewer 3
Dear Editor,

The review entitled: "Skin Hypopigmenatation in Hematology Disorders" by Mazzetto et al is a comprenhensive and well written review of dermatological manifestations of hematological diseases. My main comments is related to the structure and aim of the manuscript. Authors review 3 distinct dermatological diseases (vitiligo, morphea and albinism) and correlate this to the use of treatment for the hematological diseases (checkpoint inhibitors, TKIs, ecc) but they also report data about diseases that have hematological findings that have also dermatological manifestations. To my the aim of the review is not clear. I mean they should focus only on the use of newer agents and the development of dermatological manifestations that should be of interest for the reader of a hematology journal.

Dear Reviewer 3,
Thank you for your careful revision of our manuscript and for your constructive comments. We have considered each issue raised and made changes to the manuscript accordingly; our responses are provided point by point below.

1.    Authors should add a table about the newer agents used in hematology (TKIs, small molecules, ecc) and the related dermatological manifestations. 

We are aware that treatment considerations are a main interest for the clinically oriented readership of the journal, therefore we have added a description of the newer agents used in hematology with related cutaneous manifestations.  
Please see: Table 1. Systemic cancer treatments associated with vitiligo-like depigmentation and scleroderma.

2.    No mechanism about leukoderma and use of monoclonal antibodies have been reported or at least hypothysed.

We have added additional details on leukoderma and the use of monoclonal antibodies as suggested. Please see in the text: “Similarly, effective responses fol-lowing anticancer immunotherapy, with anti-PD1 agents that lift the inhibitor T cell immune checkpoint, are associated with activation of CD8+ T cells and their cellular in-filtration into the tumor [11,12].”

3.    Treatment options for each disease should be reported in the paragraph that described the disease and its pathogenesis.

Treatment options for each disease are now reported in the corresponding paragraphs that describe the disease and its pathogenesis even though effective dermatological therapies are often lacking. These additions provided a more comprehensive understanding of the topics and enhanced the clarity of our manuscript.

Reviewer 4 Report

The manuscript is written on ten pages, three of which contain references. It includes no figures and no tables. It fullfils the standard criteria of the review and it is written in the standard English language.

 

Content suggestions:

1.         Could the Authors add the theory about the involvement of these described skin disorders in the bleeding disorders / coagulopathy associated with morphea or albinism ?

2.         What are the recommendations of the Authors in the practice ?

The manuscript is written on ten pages, three of which contain references. It includes no figures and no tables. It fullfils the standard criteria of the review and it is written in the standard English language.

 

Content suggestions:

1.         Could the Authors add the theory about the involvement of these described skin disorders in the bleeding disorders / coagulopathy associated with morphea or albinism ?

2.         What are the recommendations of the Authors in the practice ?

Author Response

Reviewer 4
The manuscript does not contain any figures.
The manuscript is written on ten pages, three of which contain references. It includes no figures and no tables. It fullfils the standard criteria of the review and it is written in the standard English language.

Dear Reviewer 4,
Thank you for your constructive comments.
Two figures and three tables were added to the manuscript.
We have made the following updates to our manuscript: 

Content suggestions:
1.    Could the Authors add the theory about the involvement of these described skin disorders in the bleeding disorders / coagulopathy associated with morphea or albinism ?

We have added a comprehensive discussion on the theory regarding the involvement of the described skin disorders in bleeding disorders and coagulopathy associated with deep morphea and albinism: please see paragraph 2.1, which was extensively rewritten, and the revised paragraphs 3.1 and 4.

2.    What are the recommendations of the Authors in the practice ?

We have specified our recommendations for clinical practice, emphasizing the importance of monitoring hypopigmentations in hematology. Please see in the Conclusions: “Hypopigmentation skin disorders could thus represent not only potential side effects of systemic therapies but also important indicators for further investigation within the hematological spectrum. These aspects emphasize the necessity of continuous dialogue between hematologists and dermatologists in patient management. … Pigmentary alterations constitute a potential cause of severe cosmetic concern in patients living with hematologic conditions; therefore, the treating dermatologist is a key figure in improving the overall quality of life and in promoting adherence to therapy. While novel targeted therapeutics, that may be tolerable even in patients receiving systemic cancer treatments, are highly anticipated, current management must also consider cosmetic camouflage as a strategy that may be employed by patients in their daily life to address cosmetic impairment. Finally, although the onset of skin manifestations does not in-fluence the natural history of the underlying hematologic conditions, timely skin directed treatment, as well as the option of replacing the responsible drug when feasible, have the potential to alter the progression of cutaneous involvement.”

Reviewer 5 Report

This article is a comprehensive and informative review of hypopigmentation in hematologic disorders. The article's thorough examination of the topic using current literature makes it a valuable resource for hematologists and medical students

They may consider adding figures and tables illustrating different types of hypopigmentation.

Author Response

Reviewer 5
This article is a comprehensive and informative review of hypopigmentation in hematologic disorders. The article's thorough examination of the topic using current literature makes it a valuable resource for hematologists and medical students.

They may consider adding figures and tables illustrating different types of hypopigmentation.

Dear Reviewer 5,
Thank you for reviewing our manuscript and for your encouraging comments.
The following figures and tables were added to the manuscript:
-    Figure 1. Vitiligo-like leukoderma.
-    Figure 2. Plaque-type morphea.
-    Table 1. Systemic cancer treatments associated with vitiligo-like depigmentation and scleroderma.
-    Table 2. Scleroderma-like disorders and hypothesized etiological factors or triggers.
-    Table 3. Hematologic alterations and the related clinical implications in syndromic forms of albinism.

Round 2

Reviewer 3 Report

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