Current and Emerging Treatment Options in Pediatric Onset Multiple Sclerosis

Round 1

Reviewer 1 Report

Here are my comments and suggestions:

Introduction

Overall, the introduction provides a good overview of key background information on pediatric multiple sclerosis (POMS). The writing is clear and concise. Some suggestions for improvement:

1. The introduction could provide more context early on about why understanding and treating POMS specifically is important, rather than focusing only on incidence and epidemiology statistics. Elaborating on the unique considerations, prognosis, and impacts of the disease in children and adolescents compared to adults may help set the stage better.
2. Some statements could benefit from additional supporting citations, such as:

• The statement about higher socioeconomic status correlating with MS diagnosis (lines 44-46)
• The statement about smoking being a risk factor for POMS (lines 57-59)

3. The discussion of genetic factors (lines 52-57) is a bit vague. Consider elaborating on the specific genetic linkage findings rather than just stating genetic studies have been performed.
4. When introducing key terminology like ADEM, EDSS, etc. (lines 67, 90) consider briefly defining the terms before using the acronyms, for clarity.
5. The final statement introducing the purpose of the full review could be strengthened to more precisely foreshadow the content and value of the forthcoming sections.

Treatment of pediatric-onset multiple sclerosis

• The transition from acute attack treatment to disease-modifying therapies (DMTs) is abrupt. Consider adding a sentence or two to connect these ideas and introduce DMTs.
• Define terms the first time they are introduced - for example, define "pulse" and "oral tapering" when first mentioning the steroid regimens
• Provide a bit more background on why most DMTs are used off-label in the pediatric population, since pediatric clinical trials are limited. This context would strengthen the rationale.
• The table on DMTs is comprehensive but quite dense. Consider editing it down to the most salient points or key examples. The length detracts from the flow of the surrounding text.
• Standardize the formatting and terminology in the table for conciseness, for example using the same term for route of administration (IV, oral, subcutaneous etc.)

Discussion

• The discussion of IPMSSG treatment recommendations and recent studies on first-line injectables vs newer DMTs provides important clinical context, but feels slightly out of place organizationally within the Discussion. Consider moving it earlier after the opening summary paragraph to improve flow.
• References are needed to support statements in a few places, for example when stating newer DMTs have higher malignancy risks.
• When discussing adverse effects of medications, include specific examples or rates rather than vague statements about risks. Quantifying it strengthens the discussion.
• The ending is abrupt - the final paragraph does not sufficiently tie together key discussion points to arrive at a conclusion about the future outlook for POMS treatment. Expand on this concept to close the discussion more completely.

Conclusion

• The conclusion is currently very brief and repeats points made earlier in the discussion. Expand on the main takeaways and implications rather than restating the issues.
• Provide more perspective on specific future directions needed - for example elaborate on what kinds of study designs or focus areas would help address these evidence gaps.
• Comment on whether and how the landscape may be evolving - are pediatric trials becoming more feasible now? Is use of real-world data helping? Context about positive future trends would strengthen the conclusion.
• End by driving home the "so what" - why does closing these evidence gaps matter in the big picture? How would it impact outcomes for this vulnerable population? Leaving readers with this perspective gives more purpose.

Overall the conclusion gets at the major lingering problem around lack of pediatric evidence. Expanding on the implications, future directions needed, and why progress matters would elevate this section considerably to match the strength seen throughout most of the rest of the paper.

Author Response

Dear reviewer,

Thank you for the constructive comments.

Here is our reply.

Here are my comments and suggestions:
Introduction
Overall, the introduction provides a good overview of key background information on pediatric multiple sclerosis (POMS). The writing is clear and concise. Some suggestions for improvement:
1. The introduction could provide more context early on about why understanding and treating POMS specifically is important, rather than focusing only on incidence and epidemiology statistics. Elaborating on the unique considerations, prognosis, and impacts of the disease in children and adolescents compared to adults may help set the stage better.
Answer: Thank you for the important comment, we modified the introduction by adding more information regarding the significance of POMS is different from AOMS and the impact it may have on this population

2. Some statements could benefit from additional supporting citations, such as:
The statement about higher socioeconomic status correlating with MS diagnosis (lines 44-46)
Answer: Additional references have been added 

The statement about smoking being a risk factor for POMS (lines 57-59)
Answer: two more articles were cited (a population-based case-control study with
2455 cases and 5336 controls, and a recent review article that also analysed possible pathways involved)

3. The discussion of genetic factors (lines 52-57) is a bit vague. Consider elaborating on the specific genetic linkage findings rather than just stating genetic studies have been performed.
Answer: We thank the reviewer for the comment. More specific information (including hazard ratio) in pediatric population with MS and the HLA-DR1501 allele was included. 
“More specifically, the presence of one or more HLA-DR1501 allelic variants increases independently the hazard ratio approximately by 2.2, mainly in children with European ancestry”

4. When introducing key terminology like ADEM, EDSS, etc. (lines 67, 90) consider briefly defining the terms before using the acronyms, for clarity.
Answer: Both terms were briefly analysed for better understanding as per the reviewer’s instructions.
“(ADEM) a generally monophasic disease, characterized by a sudden and widespread inflammation and demyelination of the CNS which is mostly triggered by viral infections or vaccinations,” 
“The EDSS is the predominant clinician-administered scale utilized for assessing disability in individuals diagnosed with MS. It serves as an efficacious instrument for quantifying functional disability levels (1). The EDSS employs a scoring metric that ranges from 0 to 10, delineating the severity of the patient's condition. A score of 0 indicates a normal neurological examination, whereas a score of 10 is indicative of mortality attributable to MS. Scores up to 5 signify patients who retain full ambulatory capabilities. Within the scoring framework up to this threshold, functional systems (FS) are the principal determinants of the EDSS score. Beyond a score of 5, the degree of disability is primarily driven by the patient's ambulation status.”

5. The final statement introducing the purpose of the full review could be strengthened to more precisely foreshadow the content and value of the forthcoming sections.
Answer: Thank you for this comment. Modification was made accordingly to emphasize the value of the review. 
Treatment of pediatric-onset multiple sclerosis
The transition from acute attack treatment to disease-modifying therapies (DMTs) is abrupt. Consider adding a sentence or two to connect these ideas and introduce DMTs. 
Answer: It was modified as per your suggestion 

Define terms the first time they are introduced - for example, define "pulse" and "oral tapering" when first mentioning the steroid regimens
 Answer: both terms were briefly defined
  “Intermittent (pulse), intravenous infusion”
 ”Gradually reducing (tapering) oral”

Provide a bit more background on why most DMTs are used off-label in the pediatric population, since pediatric clinical trials are limited. This context would strengthen the rationale.
 Answer: We thank the rewire for the fruitful comment. We explained the off-label use of DMTs in POMS
 Disease Modifying Therapies (DMTs) have been introduced in AOMS for many decades. In the POMS population, treatment remains largely off-label, due to the limited number of randomized controlled clinical trials (RCTs) assessing the safety and efficacy of these medications in children. The higher risk of serious adverse events and potentially unknown long-term side effects associated with these new treatments further complicates their evaluation in children. Ethical considerations, along with practical challenges such as the immunological maturity of the pediatric population, exposure to infections, neurodevelopmental factors, and age-specific toxicities, only add to the problem. Additionally, the relatively small global population of pediatric MS patients limits the feasibility of large-scale studies, affecting the ability to conduct comprehensive research (44). The majority of the data available on those drugs is derived from adult RCTs and pediatric observational studies.

The table on DMTs is comprehensive but quite dense. Consider editing it down to the most salient points or key examples. The length detracts from the flow of the surrounding text.
 Answer: The table has been modified

Standardize the formatting and terminology in the table for conciseness, for example using the same term for route of administration (IV, oral, subcutaneous etc.)
 Answer: They were corrected

Discussion
The discussion of IPMSSG treatment recommendations and recent studies on first-line injectables vs newer DMTs provides important clinical context, but feels slightly out of place organizationally within the Discussion. Consider moving it earlier after the opening summary paragraph to improve flow.
 Answer: it has been modified, as per your suggestion

References are needed to support statements in a few places, for example when stating newer DMTs have higher malignancy risks.
Answer: A WHO Pharmacovigilance Database Analysis reference was added that stated that DF, fingolimod, INFβ, and natalizumab are associated with cancer reporting

When discussing adverse effects of medications, include specific examples or rates rather than vague statements about risks. Quantifying it strengthens the discussion.
  Answer: Thank you for the comment. Adverse events were meticulously analysed in each drug section separately 

The ending is abrupt - the final paragraph does not sufficiently tie together key discussion points to arrive at a conclusion about the future outlook for POMS treatment. Expand on this concept to close the discussion more completely.
 Answer: We took into consideration the reviewer’s comment and expansion/addition was made by addition an extra paragraph has been added. 

Conclusion
The conclusion is currently very brief and repeats points made earlier in the discussion. Expand on the main takeaways and implications rather than restating the issues.
Provide more perspective on specific future directions needed - for example elaborate on what kinds of study designs or focus areas would help address these evidence gaps.
Comment on whether and how the landscape may be evolving - are pediatric trials becoming more feasible now? Is use of real-world data helping? Context about positive future trends would strengthen the conclusion.
End by driving home the "so what" - why does closing these evidence gaps matter in the big picture? How would it impact outcomes for this vulnerable population? Leaving readers with this perspective gives more purpose.
Overall the conclusion gets at the major lingering problem around lack of pediatric evidence. Expanding on the implications, future directions needed, and why progress matters would elevate this section considerably to match the strength seen throughout most of the rest of the paper
 Answer: Thank you for the comments, The entire conclusion paragraph has been t changed
 

Reviewer 2 Report

The paper reviews the 'current' and emerging treatment options in POMS. The paper is well-designed and represents a comprehensive presentation, helpful to the reader. This reviewer has the following observations:

1. The section discussing Teriflunomide mentions the treatment was approved for children ages 10-17 by EMA in 2021, however, the FDA (US)  rejected the application due to insufficient clinical effectiveness.  To prevent erroneous perception the product is globally licensed for POMS, this should be clarified. In the other hand, Fingolimod was approved for children by both, EMA and the FDA in 2018.  

2. Daclizumab constitutes just an historical reference, but the molecule has been totally discarded (as current and future option of therapy) due to its reported serious adverse effects. While I probably would mention it in the discussion, I would not dedicate a special segment to review it.  

3. The last lines of the 'Conclusion' discuss a proposal for future evaluations of MS therapies in POMS. Are the authors referring to the design of Pragmatic Clinical Trials? or simply "well-designed long-term observational studies? 

Author Response

Dear reviewer,

Thank you for your comments and fruitful thoughts on the manuscript.

Here is our reply.

The paper reviews the 'current' and emerging treatment options in POMS. The paper is well-designed and represents a comprehensive presentation, helpful to the reader. This reviewer has the following observations:

1. The section discussing Teriflunomide mentions the treatment was approved for children ages 10-17 by EMA in 2021, however, the FDA (US) rejected the application due to insufficient clinical effectiveness.  To prevent erroneous perception the product is globally licensed for POMS, this should be clarified. In the other hand, Fingolimod was approved for children by both, EMA and the FDA in 2018.  
   Answer: It has been clarified.
                           Fingolimod: Fingolimod was approved as the first oral DMT for relapsing forms of  AOMS by the US Food and Drug Administration (FDA) in 2010, and subsequently by the European Medi-cines Agency (EMA) in 2011 and based on the PARADIGMS trial was subsequently ap-proved for pediatric population in 2018 by both organizations 
                           Teriflunomide: In 2021 EMA approved teriflunomide for treatment of POMS patients aged 10–17 years old, while the FDA rejected its application in pediatric patients due to insufficient data .
2. Daclizumab constitutes just an historical reference, but the molecule has been totally discarded (as current and future option of therapy) due to its reported serious adverse effects. While I probably would mention it in the discussion, I would not dedicate a special segment to review it. 

We thank the reviewer regarding this insightful comment. The paragraph has been rigorously reduced to match the rest of the manuscript regarding its non-use.

3. The last lines of the 'Conclusion' discuss a proposal for future evaluations of MS therapies in POMS. Are the authors referring to the design of Pragmatic Clinical Trials? or simply "well-designed long-term observational studies? 
   Answer: In the discussion section a new paragraph addresses this issue: “Real-world evidence could also provide insights into the effectiveness and safety of DMTs outside the strict clinical trial settings, offering a better understanding on different treatment approaches in diverse patient populations and over longer period. A recent opinion paper called for regulatory agencies to reassess the evaluation and approval process of new medications based on pediatric-onset multiple sclerosis. Given the essentially similar immunopathophysiologic mechanisms observed in pediatric and adult MS, and the accumulating evidence over recent years indicating a comparable safety profile of DMTs in children and adolescents with MS to that in adults, studies should predominantly prioritize pharmacokinetic/pharmacodynamic (PK/PD) evaluations.”

Round 2

Reviewer 1 Report

The authors responded to my comments very well. Thank you.

Reviewer 2 Report

None. Do not expect further replies.