The Incidence of IgG4-Related Disease in Slovenia—Single-Centre Experience

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this paper, the authors describe the incidence and clinical characteristics of IgG4-related disease in Slovenia. The study covers a 13-year period, approximately a quarter of the entire Slovenian population, and refers to a small number of cases, as it is a relatively rare, though likely underdiagnosed, condition.

Methods and results are clearly described. The limitations resulting from the study's partial prospective and partial retrospective nature are discussed by the authors. Regarding the discussion, I have some doubts about the authors' idea that the Slovenian data could be extended to the European population (see line 219), given the diverse ethnic composition. Regarding European experiences on the topic, I recommend expanding references, for example with the following works:

Ebbo M, Daniel L, Pavic M, et al. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine (Baltimore). 2012; 91:49–56

Campochiaro C, Ramirez GA, Bozzolo EP, et al. IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients. Scand J Rheumatol. 2016;45(2):135-45.

Author Response

Dear Reviewers!

We sincerely thank reviewers for systematic and constructive review of our manuscript. Their comments and suggestions have enabled us to improve the manuscript and to address several important aspects.

We have addressed each of the comments point by point. To facilitate the review, we have highlighted changes in the manuscript.

 

Reviewer 1

In this paper, the authors describe the incidence and clinical characteristics of IgG4-related disease in Slovenia. The study covers a 13-year period, approximately a quarter of the entire Slovenian population, and refers to a small number of cases, as it is a relatively rare, though likely underdiagnosed, condition.

Methods and results are clearly described. The limitations resulting from the study's partial prospective and partial retrospective nature are discussed by the authors. Regarding the discussion, I have some doubts about the authors' idea that the Slovenian data could be extended to the European population (see line 219), given the diverse ethnic composition. Regarding European experiences on the topic, I recommend expanding references, for example with the following works:

Ebbo M, Daniel L, Pavic M, et al. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine (Baltimore). 2012; 91:49–56

Campochiaro C, Ramirez GA, Bozzolo EP, et al. IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients. Scand J Rheumatol. 2016;45(2):135-45.

 

Response

We agree with the reviewer that it is difficult to extrapolate the results obtained in our study to the whole of European population; therefore, we removed the relevant part of the sentence.

We have also included the suggested references in the Discussion section:

Regarding individual organ involvement, the three most frequently affected organs or body regions in our patients were the retroperitoneum (28%), pancreas (20%) and salivary glands (20%). Our results are consistent with an Italian study in which pancreas (41%), retroperitoneum (19%) and salivary glands (19%) represented the most frequently affected organs. [12] Slightly different findings were reported by Ebbo et al. in a multicentre French study, which identified lymph nodes (76%), pancreas (52%), salivary glands (44%) and kidneys (44%) as the most frequently involved organs. [13]

Reviewer 2 Report

Comments and Suggestions for Authors

This is single centre study on the prevalence of the IgG related disease in Slovenia. This study has many limitations. First of all - authors shouldn't describe their findings as fully reflecting the situation in whole country because the data was collected only from one region (refferal and the biggest but still one). The description of sypmtoms and histological lesions is very basic. Generally, this paper doesn't contain any new knowledge.

Author Response

Dear Reviewers!

We sincerely thank reviewers for systematic and constructive review of our manuscript. Their comments and suggestions have enabled us to improve the manuscript and to address several important aspects.

We have addressed each of the comments point by point. To facilitate the review, we have highlighted changes in the manuscript.

REVIEWER 2

This is single centre study on the prevalence of the IgG related disease in Slovenia. This study has many limitations. First of all - authors shouldn't describe their findings as fully reflecting the situation in whole country because the data was collected only from one region (referral and the biggest but still one). The description of symptoms and histological lesions is very basic. Generally, this paper doesn't contain any new knowledge.

 

Response

We respect the reviewer's perspective but respectfully disagree. Epidemiological data on IgG4-RD remain scarce, and we believe our results contribute to the better understanding and knowledge of the geoepidemiology of this unique disease.

Because of the rarity and complexity of IgG4-RD, patients are usually diagnosed and managed in tertiary centres or centres with expertise in managing this disease. We agree that expanding our study to another tertiary centre in the country could provide even better insight into IgG4-RD.

Due to the partially retrospective nature of patient recruitment and some missing data, in-depth biological analyses were not feasible. Nevertheless, we consider our work to provide a solid foundation for future studies.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors examined the incidences of IgG4-RD in slovenia and concluded an annual incident rate of 5.0 for the region and discussed the associated features of the cases. The work is well-designed with appropriate statistical tests applied and very thorough. The discovery is meaningful and informative regionally and worldwide. However, the manuscript could be further strengthened with minor revision:

• More information should be given for the pathology and pathogenesis of IgG4-RD.
• The rate of patients receiving treatments abroad should be discussed, as that could result in underestimation of the incidence rate.
• The authors implied that the discovery made here could also be extrapolated to Europe as a whole. Given the relatively small size of Slovenian population, and the differences in demographics, more discussion should be provided here.

Author Response

Dear Reviewers!

We sincerely thank reviewers for systematic and constructive review of our manuscript. Their comments and suggestions have enabled us to improve the manuscript and to address several important aspects.

We have addressed each of the comments point by point. To facilitate the review, we have highlighted changes in the manuscript.

REVIEWER 3

The authors examined the incidences of IgG4-RD in slovenia and concluded an annual incident rate of 5.0 for the region and discussed the associated features of the cases. The work is well-designed with appropriate statistical tests applied and very thorough. The discovery is meaningful and informative regionally and worldwide. However, the manuscript could be further strengthened with minor revision:

• More information should be given for the pathology and pathogenesis of IgG4-RD.
• The rate of patients receiving treatments abroad should be discussed, as that could result in underestimation of the incidence rate.
• The authors implied that the discovery made here could also be extrapolated to Europe as a whole. Given the relatively small size of Slovenian population, and the differences in demographics, more discussion should be provided here.

Response

We have expanded the Discussion section to include additional information on the pathogenesis of IgG4-RD:

Understanding pathogenetic mechanisms is fundamental for the development of effective treatment of IgG4-RD. At present, the genetic and environmental risk factors for IgG4-RD are still poorly understood, but both influence immune mechanisms that drive inflammation and fibrosis, leading to organ damage and dysfunction. B cells and T cells, in co-operation with fibroblasts and other inflammatory cells, play a key role in the disease process. It has been shown that the concentration of peripheral blood plasmablasts and memory B lymphocytes correlates with disease activity. B cells infiltrate tissues and secrete various inflammatory and profibrotic molecules. Patients with IgG4-RD typically have elevated serum IgG4 concentrations, which probably represent a compensatory response to chronic aberrant immune activation. In addition, B lymphocytes communicate closely with T lymphocytes. Several T cell subsets have been identified in IgG4-RD, for example follicular helper T cells, and CD4+ and CD8+ cytotoxic T lymphocytes. While follicular helper T cells play a role in antibody switching (to IgG4 and IgE) and B cell activation, cytotoxic T lymphocytes contribute to tissue damage and fibrosis by secreting proapoptotic (e.g. perforin, granzyme and granulysin) and profibrotic molecules (such as transforming growth factor β, interleukin-1β and interferon γ). Immunohistochemical studies support the hypothesis of a spatiotemporal progression from the inflammatory to the fibrotic phase of the disease.

[1,14] Alongside this, a classification into two disease phenotypes (predominately proliferative and predominantly fibrotic) has been recently proposed. [2,3] In our cohort, 63% of patients had predominantly proliferative and 37% the predominantly fibrotic phenotype.

 

Regarding treatment abroad, as a rule patients in Slovenia do not seek medical care outside the country. Treatment is fully covered by the Health Insurance Institute of Slovenia (ZZZS), making it highly unlikely that we underestimated cases for this reason.

 

We agree with the reviewer that it is difficult to extrapolate the results obtained in our study to the whole European population; therefore, we removed the relevant part of the sentence.

Reviewer 4 Report

Comments and Suggestions for Authors

The authors are conducting an interesting retrospective study aimed at identifying the incidence of IgG4-RD in the largest city of their country, a European country. The analyzed period is significant, covering almost 13 years. They also reanalyzed the biopsies and selected patients who met the 2019 ACR/EULAR IgG4-RD classification criteria, based on organ involvement. Their results show an incidence of 5 per million adults for their city, which has a population of around 530,000 people.

I found it particularly important that you based the study on pathological examination, one of the most important and reliable criteria for diagnosis in this disease.

Regarding Table 1, it is an interesting presentation of the incidence by years in your city, and it is valuable that you used data approved by the Department of Demographic and Social Statistics.

Regarding Table 2, the stratification by organ involvement is also interesting. It shows that the incidence by organ corresponds to what is most frequently reported in the literature. Geographical incidence is a strong factor to take into consideration.

In patients, organ involvement was observed, often followed by biopsy, which was then interpreted by a pathologist to reach a definitive diagnosis. However, clinical and biological findings are also relevant for the differential diagnosis, since the presence of IgG4 in a biopsy alone does not validate the final diagnosis of IgG4-RD.

In your study, you observed an important finding: 74.3% of the patients fulfilled the 2019 ACR/EULAR IgG4-RD classification criteria.

I found it a very good idea to also study the prevalence of this pathology in your country and to analyze the prevalence of organ involvement. This type of simple study should be carried out in all European countries in order to provide a clear panorama of the incidence of this pathology, which is still not frequently recognized or well known by many colleagues worldwide.

I am not sure, however, if a precise prevalence strictly related to Europe can be determined. Why? Because in the last one to three decades, the demographic structure of Europe has changed significantly, with strong migration of many ethnicities, particularly from Africa and Asia. For this reason, a well-done family origin anamnesis is important in every patient.

I also noticed that you mentioned the American and Chinese studies, which reported a higher incidence of pancreato-hepato-biliary disease. Your observations in a European country, with a predominantly Slavic population are therefore very interesting.

Finally, I appreciate that you also mentioned the treatment received by these patients.

I have nothing to add to your study idea. It is a simple and clear retrospective study.

 

Author Response

Dear Reviewers!

We sincerely thank reviewers for systematic and constructive review of our manuscript. Their comments and suggestions have enabled us to improve the manuscript and to address several important aspects.

We have addressed each of the comments point by point. To facilitate the review, we have highlighted changes in the manuscript.  

REVIEWER 4

The authors are conducting an interesting retrospective study aimed at identifying the incidence of IgG4-RD in the largest city of their country, a European country. The analyzed period is significant, covering almost 13 years. They also reanalyzed the biopsies and selected patients who met the 2019 ACR/EULAR IgG4-RD classification criteria, based on organ involvement. Their results show an incidence of 5 per million adults for their city, which has a population of around 530,000 people.

I found it particularly important that you based the study on pathological examination, one of the most important and reliable criteria for diagnosis in this disease.

Regarding Table 1, it is an interesting presentation of the incidence by years in your city, and it is valuable that you used data approved by the Department of Demographic and Social Statistics.

Regarding Table 2, the stratification by organ involvement is also interesting. It shows that the incidence by organ corresponds to what is most frequently reported in the literature. Geographical incidence is a strong factor to take into consideration.

In patients, organ involvement was observed, often followed by biopsy, which was then interpreted by a pathologist to reach a definitive diagnosis. However, clinical and biological findings are also relevant for the differential diagnosis, since the presence of IgG4 in a biopsy alone does not validate the final diagnosis of IgG4-RD.

In your study, you observed an important finding: 74.3% of the patients fulfilled the 2019 ACR/EULAR IgG4-RD classification criteria.

I found it a very good idea to also study the prevalence of this pathology in your country and to analyze the prevalence of organ involvement. This type of simple study should be carried out in all European countries in order to provide a clear panorama of the incidence of this pathology, which is still not frequently recognized or well known by many colleagues worldwide.

I am not sure, however, if a precise prevalence strictly related to Europe can be determined. Why? Because in the last one to three decades, the demographic structure of Europe has changed significantly, with strong migration of many ethnicities, particularly from Africa and Asia. For this reason, a well-done family origin anamnesis is important in every patient.

I also noticed that you mentioned the American and Chinese studies, which reported a higher incidence of pancreato-hepato-biliary disease. Your observations in a European country, with a predominantly Slavic population are therefore very interesting.

Finally, I appreciate that you also mentioned the treatment received by these patients.

I have nothing to add to your study idea. It is a simple and clear retrospective study.

 

Response

We thank the reviewer for their valued opinion. We agree that it is difficult to extrapolate the results obtained in our study to the whole European population due to the heterogeneity of populations and migration flows.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors tried to improve their work, however, there are still weak point. There are no photos proving the giagnosis (at least one h&e picture as well as IgG snd IgG4 staining. I still do not agree with authots explanation- all rare diseases in most counrtries are diagnosed and than treated in refferal hospitals, nonetheless, some cases are probably lost. Thus I suggest to chamge the titlr and adf phrade ”single- centre experience”

Comments on the Quality of English Language

English is ok

Author Response

We thank the reviewer for their careful assessment and helpful suggestions.

As recommended, we have added representative histological and immunostaining images (H&E, IgG and IgG4) to the manuscript to further support the diagnosis.

We agree that it cannot be assumed with certainty that all patients with IgG4-RD in Slovenia are managed exclusively in tertiary centres. This limitation is inherent in studies of both rare and more common diseases, where some cases may not be captured. Nevertheless, we hope that our cohort may serve as a useful contribution to understanding IgG4-RD in Slovenia, while acknowledging the limitations the reviewer has highlighted.

In line with the reviewer’s advice, we have revised the manuscript title to: “The Incidence of IgG4-Related Disease in Slovenia – Single-Centre Experience.”

All changes in the text are highlighted in green.