Pathogenesis of Extraarticular Manifestations in Rheumatoid Arthritis—A Comprehensive Review

Round 1

Reviewer 1 Report

In this review, the authors provide an existing evidence regarding the pathophysiology of extraarticular manifestations (EAMs) of rheumatoid arthritis (RA). The topic is relevant and interesting. Some comments are as the follows:    

1.     It is well-known that osteoporosis (OP) is recognized as a major source of morbidity in RA, and up to one-third of women with RA experience one episode of osteoporotic fracture during 5-year follow-up period. Besides, OP or bone fragility is the result of a complex interaction of traditional risk factors and systemic inflammation in RA. It would be desirable if the authors could provide the pathophysiology of the occurrence of OP /bone fragility (EAM) in RA in this review article.

2.     It is interesting that another “lipid paradox” could be abnormal high-density lipoprotein (HDL) function for it’s athero-protective role in RA-related atherosclerosis. It would be desirable to have a discussion regarding an association of HDL heterogeneity, such as molecular size or composition, with the athero-protective function in RA-related atherosclerosis. 

3. It would be better to illustrate the pathophysiology of EAMs, particularly in RA-related atherosclerosis and interstitial lung disease, by the figures.

Author Response

In this review, the authors provide an existing evidence regarding the pathophysiology of extraarticular manifestations (EAMs) of rheumatoid arthritis (RA). The topic is relevant and interesting. Some comments are as the follows:   

1. It is well-known that osteoporosis (OP) is recognized as a major source of morbidity in RA, and up to one-third of women with RA experience one episode of osteoporotic fracture during 5-year follow-up period. Besides, OP or bone fragility is the result of a complex interaction of traditional risk factors and systemic inflammation in RA. It would be desirable if the authors could provide the pathophysiology of the occurrence of OP /bone fragility (EAM) in RA in this review article.

Reply. We thank the reviewer for this suggestion. The authors agree that osteoporosis is a significant morbidity factor in the context of RA EAMs and that including its pathophysiology in this review article would be of great relevance. Therefore we have now added the section „Osteoporosis“ to the main text, in which the pathophysiology and risk factors for OP in RA are discussed.

2. It is interesting that another “lipid paradox” could be abnormal high-density lipoprotein (HDL) function for it’s athero-protective role in RA-related atherosclerosis. It would be desirable to have a discussion regarding an association of HDL heterogeneity, such as molecular size or composition, with the athero-protective function in RA-related atherosclerosis.

Reply. We thank the reviewer for this suggestion. HDL structure and function indeed seem to play an important role in RA related atherosclerosis. Therefore we have now complemented the “Atherosclerosis” section with more data about this phenomenon:
“ Under inflammatory conditions, the proteome and lipidome of HDL may change, leading to the development of pro-inflammatory HDL (piHDL). Pro-inflammatory HDL is different in structure than normal HDL, it lacks apolipoprotein A-I (apoA-I) and paraoxonase 1 (PON1), but is enriched with oxidized phospholipids and lysophospholipids, free cholesterol, free fatty acids (FFAs), and triacylglycerols (TAGs). Additionally, piHDL contains pro-inflammatory proteins such as serum amyloid A (SAA) and ceruloplasmin. As for its function, although it possesses the ability to enhance the inflammatory response to infections, piHDL also can promote the oxidation of low-density lipoprotein (LDL), cause endothelial dysfunction, stimulate the activity of monocytes, enhance the secretion of pro-inflammatory molecules and it is less effective in cholesterol efflux activity . Accordingly, levels of piHDL correlated with disease activity in RA patients .”
“Some studies demonstrated that antibodies against HDL and its components were not only present RA onset, but were also detectable prior to the establishment of a clinical diagnosis. These antibodies didn’t corelate with traditional CV risk factors, but were related to biologic processes involved in atherosclerosis”

3. It would be better to illustrate the pathophysiology of EAMs, particularly in RA-related atherosclerosis and interstitial lung disease, by the figures.

Reply. We thank the reviewer for this suggestion and we are in agreement that illustrations provide a valuable means of describing and summarizing different pathophysiological mechanisms. Therefore we have added two illustrations (Figure 1. and 2.) to the manuscript describing the proposed pathophysiological mechanisms underlying RA-related interstitial lung disease and atherosclerosis.

Reviewer 2 Report

The present article, of review type, presents the pathogenesis of the extra-articular manifestations of rheumatoid arthritis. The subject is an important and current one taking into consideration that quality of life, morbidity and mortality of RA patients is deeply influenced by these manifestations.
The way the article is structured should a be reevaluated. The numbering system in which point 1 is the introduction followed by points 2-10 representing EAM and then 11 with considerations related to DMARDs is a bit strange. Nevertheless some points as #2 and 3 should be discussed together.

Also, there should be consistency in the order of bibliographic references. The first reference in table number 1 is 20, while the last one in the text is 11. Reference 21 appears for the first time much after other larger numbers.

There are several things that require clarification. On introduction you mention that

-          there are several specific antibodies in RA – including rheumatoid factor (RF) – it has to be clarified that RA is characterized by the presence of autoantibodies like rheumatoid factor, ACPAs anti CarP but RF is not “specific”, but highly sensitive

-          “Due to the systemic nature of the disease, RA is associated with an increased acute-phase response followed by long term inflammation which can lead to serious complications, defined as extraarticular manifestations (EAM)” – you should change this definition of EAM because it is too simplistic and has a degree of inaccuracy.

Regarding the discussion related to drugs, perhaps the statements related to the cardiovascular risk of TNF blockers should be revised, including data from PR registries that do not suggest an increase in CV risk associated with such treatments.

Author Response

The way the article is structured should a be reevaluated. The numbering system in which point 1 is the introduction followed by points 2-10 representing EAM and then 11 with considerations related to DMARDs is a bit strange. Nevertheless some points as #2 and 3 should be discussed together.

Reply. The authors thank the reviewer for their comment and suggestions. We agree that the manuscript would benefit from restructuring of certain subsections. Therefore, the  sections „Atherosclerosis“ and „Non-ischemic heart disease“ are now discussed as subsections of the section „Cardiovascular disease“ and the previous section „Pulmonary manifestations in rheumatoid arthritis – interstitial lung disease and bronchiectasis“ has now been restructured into a section called „Pulmonary manifestations“ with separate subsections titled „Interstitial lung disease“ and „Bronchiectasis“. We have also added additional Figures which illustrate the described pathophysiological mechanisms related to RA-related interstitial lung disease and atherosclerosis, which serve to further clarify the described concepts and hopefully make the subsections more easy to follow to the reader. The authors hope that these changes are in agreement with the reviewer's remarks.

Also, there should be consistency in the order of bibliographic references. The first reference in table number 1 is 20, while the last one in the text is 11. Reference 21 appears for the first time much after other larger numbers.

Reply. We thank the reviewer for this suggestion. The table was intended to be at the end of the whole review. Therefore, it is now moved at the end of the text with references adjusted accordingly.

 There are several things that require clarification. On introduction you mention that

-          there are several specific antibodies in RA – including rheumatoid factor (RF) – it has to be clarified that RA is characterized by the presence of autoantibodies like rheumatoid factor, ACPAs anti CarP but RF is not “specific”, but highly sensitive

Reply. We thank the reviewer for this remark, we agree with the suggestion and have now altered the mentioned part of the Introduction section, which now reads: „The presence of certain autoantibodies is a hallmark for the disease, and they include: rheumatoid factor (RF), an antibody recognizing the Fc-tail of immunoglobulin G (highly sensitive but less specific to RA) and specific antibodies against proteins modified by citrullination (antibodies to citrullinated protein antigens-ACPAs) and carbamylation (anti CarP antibodies) .”

-          “Due to the systemic nature of the disease, RA is associated with an increased acute-phase response followed by long term inflammation which can lead to serious complications, defined as extraarticular manifestations (EAM)” – you should change this definition of EAM because it is too simplistic and has a degree of inaccuracy.

Reply. The authors thank the reviewer for this observation and suggestion. We have now altered the mentioned sentence, which now reads: „ Due to the systemic nature of the disease, RA is associated with an increased acute-phase response which can lead to a number of extraarticular manifestations (EAM), which are an important, albeit partially poorly understood aspect of this disease. “

Regarding the discussion related to drugs, perhaps the statements related to the cardiovascular risk of TNF blockers should be revised, including data from PR registries that do not suggest an increase in CV risk associated with such treatments.

Reply. We thank the reviewer for their valuable suggestion. Taking into account suggestions from other reviewers, including the suggestion to omit the section altogether and discuss it in a new separate review, we have decided to exclude the section „Additional considerations - Disease-modifying antirheumatic drugs (DMARDs) and small molecules“ from the final manuscript.
Due to the fact that additional text sections were added in response to reviewer suggestions (i.e. hematological and renal EAM, vasculitis) the authors feel that the aforementioned topic now falls out of the scope of this review, as it would require discussing in more detail, which we plan to do in a future review article.

Reviewer 3 Report

The paper is a narrative review of  the extra articular manifestations of rheumatoid arthritis. Although interesting I think that the paper is poorly organized. 

Major comments:

- It is not clear why sections with adequate subsections have not been created (eg: the authors created three sections about cardiovascular manifestation, I think that a section with subsections should be preferable). Also the sections of the paper are relatively long without a clear break within the text. I strongly suggest to make the sections more readable.

- The authors reported some extra articular manifestations in more than one section (eg: rheumatoid meningitis, serositis. I suggest the authors to rearrange the paper in order to avoid repetitions).

- Every section seems to be written with different structure, I suggest the authors to homogenize the paper. 

- Some extra articular manifestations are lacking (eg: oral, renal, hematological, gastroenterological).

- The "Addional consideration" section is too short and can be misleading. I suggest that the authors include the effect of treatment on extra-articular manifestations in their respective sections of the paper.

Minor comments:

- The references in table 1 do not respect the correct numeration. ù

- Please correct some inconstancies across the paper (eg: EAM/EAMs, CV never defined, RM defined and then not used in the following section). 

- Small molecules are disease-modifying antirheumatic drugs, I suggest to use the current nomenclature csDMARDs, bDMARDs and tsDMARDs.

- For the cardiovascular risk of JAKis I suggest the authors to refer to the ORAL Surveillance trial.

Author Response

Major comments:

- It is not clear why sections with adequate subsections have not been created (eg: the authors created three sections about cardiovascular manifestation, I think that a section with subsections should be preferable). Also the sections of the paper are relatively long without a clear break within the text. I strongly suggest to make the sections more readable.

- Every section seems to be written with different structure, I suggest the authors to homogenize the paper.

Reply. We thank the reviewer for their observations and suggestions. The authors agree that the manuscript would benefit from restructuring of certain subsections and from forming text breaks. We have thus restructured several sections: the previous subheadings „Atherosclerosis“ and „Non-ischemic heart disease“ are now discussed as subsections of the section „Cardiovascular disease“ and the previous section „Pulmonary manifestations in rheumatoid arthritis – interstitial lung disease and bronchiectasis“ has now been restructured into a section called „Pulmonary manifestations“ with separate subsections titled „Interstitial lung disease“ and „Bronchiectasis“. The authors are aware of discrepancies within the text regarding the lenght of the sections. Therefore we have additonally divided the section on athersocleoris into subsections to create text breaks and facilitate reading. Some of the discrepancies are also due to the vast differences in the volume and scope of the literature regarding the discussed topics.
Additionally,in order to homogenize the text, two more Figures were added describing the proposed pathophysiological mechanisms underlying RA-related interstitial lung disease and atherosclerosis to hopefully make the subsections more easy to follow to the reader. The authors hope that these changes are in agreement with the reviewer's remarks.

- The authors reported some extra articular manifestations in more than one section (eg: rheumatoid meningitis, serositis. I suggest the authors to rearrange the paper in order to avoid repetitions).

Reply. We thank the reviewer for this remark. The mentioned manifestations, i.e. rheumatoid meningitis and serositis are only listed as possible manifestations in the respective text sections and are not further discussed. These topics are instead discussed in together in the section „Mebrane involvement“ in order to emphasize their possible shared pathophysiological mechanisms, but we felt  it neccesary to list them in the sections pertaing to their organ systems. We believe none of the EAMs are discussed in detail more than once throughout the text.

- Some extra articular manifestations are lacking (eg: oral, renal, hematological, gastroenterological).

Reply. We thank the reviewer for pointing this out. The authors agree that the manuscript would benefit from discussing certain EAM, which is why have added new sections to the text – „Renal manifestations“ and „Hematological manifestations“, as well as a section discussing RA-related vasculitis („Vasculitis“). To the best of our knowledge, the literature regarding oral and gastrointestinal manifestations in RA is inconclusive, and these are frequently not described as classical EAM of RA, but rather as iatrogenic. This, in addition to the relative rarity of their occurence led us to conlcude that these manifestations might be outside of the scope of this manuscript.

- The "Addional consideration" section is too short and can be misleading. I suggest that the authors include the effect of treatment on extra-articular manifestations in their respective sections of the paper.

Reply. We thank the reviewer for their valuable suggestion. Taking into account suggestions from other reviewers, including the suggestion to omit the section altogether and discuss it in a new separate review, we have decided to exclude the section „Additional considerations - Disease-modifying antirheumatic drugs (DMARDs) and small molecules“ from the final manuscript. Due to the fact that additional text sections were added in response to reviewer suggestions (i.e. hematological and renal EAM, vasculitis) the authors feel that the aforementioned topic now falls out of the scope of this review, as it would require discussing in more detail, which we plan to do in a future review article.

Minor comments:

- The references in table 1 do not respect the correct numeration.

Reply. We thank the reviewer for making us aware of this mistake, which was due to an error in citing, as the table was intended to be placed at the end of the manuscript. This has now been corrected.

- Please correct some inconstancies across the paper (eg: EAM/EAMs, CV never defined, RM defined and then not used in the following section).

Reply. The authors agree with the reviewers and thank them for pointing out these errors, which have now been corrected throughout the text.

- Small molecules are disease-modifying antirheumatic drugs, I suggest to use the current nomenclature csDMARDs, bDMARDs and tsDMARDs.

- For the cardiovascular risk of JAKis I suggest the authors to refer to the ORAL Surveillance trial.

Reply. We thank the reviewer for pointing out this ommision and for their suggestion. We will certainly heed these suggestions while describing this topic in a future review article, as explained above.

Reviewer 4 Report

Dear Authors,

In your review you try to explain manifestations, complications and co-morbidities of rheumatoid arthritis by cellular, humoral, combined mechanisms. They invoke close to 170 epidemiological data, animal experimental and in vitro studies.

Arteriosclerosis, non-ischemic heart failure, pulmonary disease, serositides, neurological manifestations, ocular involvement, Felty syndrome, and rheumatoid nodules as extraarticular manifestations are focused on.

Table 1 provides an overview of possible risks in the context of rheumatoid arthritis. Thereby, the criteria for the selection of those mentioned here are not obvious from the comprehensive text.

The text blocks are a listing of the main statements of the cited publications. No weighting is given with regard to methodological relevance and quality of the cited papers, and in particular their limitations. A recognizable basic structure is missing, which embeds the cited studies in an overall concept that allows the reader to build up an understanding of possible pathogenesis steps. A better categorization would be into (local) cellular mechanisms, (systemic) humoral mechanisms, other influences (such as exogenous substances or drugs). 

Here, the illustration can be used as a basis. The benefit for the reader is then also improved by weighting the cited studies (arth of the study, population size, inclusion criteria, target variables). This could be done in tabular form for the individual statements, for example, but the text should then be significantly shortened.

The paper makes the reader assume that RA is a disease. There are special manifestations, such as nodulosis or serositis, which are strictly linked to the rheumatoid factor. 

This could be used to differentiate between extra-articular manifestations with association to rheumatoid factor and those without.

Almost all studies consider RA as an independent risk factor for atherosclerosis. Nevertheless, most authors see atherosclerosis, especially CHD, as a co-morbidity rather than a manifestation, because patient age, lipids, diabetes, hypertension, obesity, exercise ... play at least as important a role. 

Regarding ocular manifestations, although several manifestations are named, only keratitis is discussed in the text, especially (epi-)scleritis fezhlt as a typical manifestation.

Vasculitides are typical manifestations of seropositive RA. They may manifest as livedo, purpura or extensive necrosis. Except for a discussion in Rheumatoid Nodules and Axonal Neuropathy, vasculitides do not find their way into this publication. This is not plausible considering much rarer manifestations such as meningeal.

The effects of the therapy are briefly named, but very superficial and the therapy with the most common use and great evidence, steroids, are not mentioned at all. it is better to mention this area as an aspect and evaluate it in a separate review.

A very important aspect of systemic manifestations is the time from the initial symptom of RA to therapy/remission. This important aspect should at least be discussed.

The abstract should address the clear limitations of the cited papers, small groups, models or in vitro experiments, selected questions and an overall very heterogeneous disease.

Author Response

In your review you try to explain manifestations, complications and co-morbidities of rheumatoid arthritis by cellular, humoral, combined mechanisms. They invoke close to 170 epidemiological data, animal experimental and in vitro studies.

Arteriosclerosis, non-ischemic heart failure, pulmonary disease, serositides, neurological manifestations, ocular involvement, Felty syndrome, and rheumatoid nodules as extraarticular manifestations are focused on.

Table 1 provides an overview of possible risks in the context of rheumatoid arthritis. Thereby, the criteria for the selection of those mentioned here are not obvious from the comprehensive text.

Reply. We thank the reviewer for their comments and observations. Table 1 contains a summary only of the pathophysiological mechanisms of EAMs discussed in the main text. Taking into account suggestions from other reviewers, as well as this reviewer's suggestion to discuss RA-related  vasculitis, additional text sections (discussing renal and hematological manifestations as well as RA-related vasculitis) have now been added to the manuscript. The authors hope that this version of the manuscript offers an even more comprehensive discussion of the various RA-related EAMs, which are the most common and/or contribute significantly to morbidity and mortality. To make this more clear in the manuscript, we added the following sentence to the introduction section: „The pathophysiology of several more common EAMs affecting different organ systems with significant morbidity and mortality are discussed in this review “. We have also added additional clarifications in some of the sections, such as: “Reports on the respective prevalence of different pulmonary manifestations are varying. However, ILD and rheumatoid nodules are reported to be the most common parenchymal pulmonary manifestations, while bronchiectasis may be the most common lower airway manifestation.The pathogenesis of these more common pulmonary manifestations of RA will be discussed below.” and “Regarding their influence on mortality and morbidity in RA patients, but also growing evidence of pathogenic relation to RA, atherosclerosis and non-ischemic heart disease will be discussed in this section.”

The text blocks are a listing of the main statements of the cited publications. No weighting is given with regard to methodological relevance and quality of the cited papers, and in particular their limitations. A recognizable basic structure is missing, which embeds the cited studies in an overall concept that allows the reader to build up an understanding of possible pathogenesis steps. A better categorization would be into (local) cellular mechanisms, (systemic) humoral mechanisms, other influences (such as exogenous substances or drugs).

Here, the illustration can be used as a basis. The benefit for the reader is then also improved by weighting the cited studies (arth of the study, population size, inclusion criteria, target variables). This could be done in tabular form for the individual statements, for example, but the text should then be significantly shortened.

Reply. We thank their reviewer for their well-placed suggestions and remarks which prompted the authors to make several additions and changes to the manuscript, which we think have brought additional value to it. Firstly, we have restructured some of the sections in order to create a more systemic and readable approach to the topics, where applicable. The previous sections „Atherosclerosis“ and „Non-ischemic heart disease“ are now discussed as subsections of the section „Cardiovascular disease“ and the previous section „Pulmonary manifestations in rheumatoid arthritis – interstitial lung disease and bronchiectasis“ has now been restructured into a section called „Pulmonary manifestations“ with separate subsections titled „Interstitial lung disease“ and „Bronchiectasis“. We have also divided the text on atheroscleoris into subsections to create a more recognizeable structure. The discrepancies in the discussion of different topics, i.e. subsections are mainly due to the vast differences in the volume and scope of the literature regarding the discussed topics. Secondly, we have also added two additional Figures which serve to describe the proposed pathophysiological mechanisms underlying RA-related interstitial lung disease and atherosclerosis and hopefully make the subsections more easy to follow to the reader. Finally, heeding your suggestion, we have created a comprehensive table (Table 2.), which describes the studies used in the main text by citing the type of study, studied mechanisms, study groups and main points of interest.

The paper makes the reader assume that RA is a disease. There are special manifestations, such as nodulosis or serositis, which are strictly linked to the rheumatoid factor.

Reply. We thank the reviewer. The authors agree relation to rheumatoid factor is important when discussing EAMs of RA. Therefore to emphasize this relation to certain EAMs, additional text was added to respective sections, such as: “Furthermore, pleural, pericardial effusion, as well as rheumatoid meningitis are linked to high titers of RF, implicating its role in their pathogenesis.”

This could be used to differentiate between extra-articular manifestations with association to rheumatoid factor and those without.

Reply. We thank the reviewer for this suggestion. The authors agree that this is a concept worth pointing out, which is why we have added the following text to the introduction section: „The presence of RF in RA patients may predispose them to more erosive joint disease and make them more likely to develop extraarticular manifestations (EAMs), especially rheumatoid nodulosis, vasculitis, Felty syndrome (FS) and serositis.”

Almost all studies consider RA as an independent risk factor for atherosclerosis. Nevertheless, most authors see atherosclerosis, especially CHD, as a co-morbidity rather than a manifestation, because patient age, lipids, diabetes, hypertension, obesity, exercise ... play at least as important a role.

Reply. We thank the reviewer for this observation. The authors agree that traditional risk factors play a very important role in atherosclerosis development in RA patients and that this should be considered when discussing atherosclerosis as a co-morbidity or extra-articular manifestation. Therefore, we changed the text in the section Cardiovascular disease as follows:
“Although traditional risk factors have a major contribution to CVD risk, this increased risk cannot be completely explained by them. Therefore, CVD could be discussed not only as comorbidity, but also as EAM of RA.”

Regarding ocular manifestations, although several manifestations are named, only keratitis is discussed in the text, especially (epi-)scleritis fezhlt as a typical manifestation.

Reply. We thank the reviewer for this suggestion. The authors agree that scleritis and episcleritis are also important manifestations observed in RA patients. Therefore, we added additional text about scleritis and episcleritis pathogenesis in the section “Ocular involvement”:

„Episcleritis is hypothesized to be a result of non-granulomatous inflammation of superficial blood vessels of episcleral resulting in their dilatation and perivascular infiltration.“ … „While episcleritis refers to inflammation of a thin layer of of tissue between the conjunctiva and sclera, scleritis is more serious condition affecting whole sclera. Nishio et al. in their study on arthritis mice models showed macrophages, plasma cells, deposition of immune complexes, and growth of blood and lymphatic vessels could play a role in RA scleritis pathogenesis. In addition, treatment targeted to macrophages, such as IL-6 and TNF-α inhibition, and to B-lymphocytes and not to T-lymphocytes showed better efficacy in murine models and joined case report of RA patient with scleritis. „

Vasculitides are typical manifestations of seropositive RA. They may manifest as livedo, purpura or extensive necrosis. Except for a discussion in Rheumatoid Nodules and Axonal Neuropathy, vasculitides do not find their way into this publication. This is not plausible considering much rarer manifestations such as meningeal.

Reply. We thank the reviewer for this suggestion. The authors agree that vasculitis, although not prevalent as before the advent of newer treatment modalities, still remains an important manifestation of seropositive RA. Accordingly, the new section “Vasculitis” was added to the text. Additonally, the text about neuropathy was adjusted in order to avoid repetitions.

The effects of the therapy are briefly named, but very superficial and the therapy with the most common use and great evidence, steroids, are not mentioned at all. it is better to mention this area as an aspect and evaluate it in a separate review.

Reply. We thank the reviewer for their remark. The authors agree that the effects of therapy, which were briefly discussed, ideally require a separate review in order to comprehensively discuss this topic in detail and to discuss other treatment modalities, such as steroids. Therefore we have decided to exclude the section „Additional considerations - Disease-modifying antirheumatic drugs (DMARDs) and small molecules“ from the final manuscript and the other plan to make this the topic of a future review, as the reviewer suggested.

A very important aspect of systemic manifestations is the time from the initial symptom of RA to therapy/remission. This important aspect should at least be discussed.

Reply. We thank the reviewer for this suggestons. We have now made several additions in the text, in order to emphasize the different timeframes in which EAMs can appear in the disease course, such as the following in the introduction section: „Several EAMs also present with different timeframes of occurrences in the disease – e.g. interstitial lung disease may even appear before onset of classical RA symptoms, or in longstanding disease, while vasculitis, FS or meningitis often occur later in the disease course.”

The abstract should address the clear limitations of the cited papers, small groups, models or in vitro experiments, selected questions and an overall very heterogeneous disease.

Reply. The authors agree that these limitations should be addresed in the review. In order to keep the abstract brief and concise we have decided to add the following to the conclusion section: „The pathophysiological mechanisms of several more frequent EAMs are discussed in this review, in order to provide an overview and aid further advancements in research. The heterogenicity of the disease, as well as the fact that some of the cited studies used small groups, models or in vitro experiments present clear limitations of this comprehensive review.”

Round 2

Reviewer 1 Report

The authors have addressed all of my queries. I do not have any further comment.     

Author Response

Reviewer 1

The authors have addressed all of my queries. I do not have any further comment.    

Reply. The authors thank the reviewer for their suggestions and comments which have aided in elevating the content and quality of this manuscript, and are glad the reviewer found all their queries have been addressed.

Reviewer 3 Report

I have no further comments.

Author Response

Reviewer 3

I have no further comments.

Reply. The authors thank the reviewer for their suggestions and comments which have aided in elevating the content and quality of this manuscript.

Reviewer 4 Report

Dear authors

thank you for the revised version of your paper which is now better structured.

The heading 2.1.3 "Immune cells" should be clarified to "Role of immune cells" ... in arteriosclerosis.

You write "Atherosclerosis, a complication of RA, is an extracellular manifestation". but you want to say "Atherosclerosis, usually mentioned a complication of RA, could be handled as an extracellular manifestation"

You name "pneumoconiosis (Caplan syndrome)" an old but potentially relevant EAM for understanding the disease. Later you do not follow that item. Perhaps at least 1 or 2 sentences should be added.

In the overview on point 3 pulmonal manifestations you name nodules as well as pleural effusions but discuss them later. Perhaps you should advise, that they are reported later in the text.

In table 2 there is enough place to write arteriosclerosis instead of ATH, ....

Author Response

Reviewer 4

The heading 2.1.3 "Immune cells" should be clarified to "Role of immune cells" ... in arteriosclerosis.

You write "Atherosclerosis, a complication of RA, is an extracellular manifestation". but you want to say "Atherosclerosis, usually mentioned a complication of RA, could be handled as an extracellular manifestation"

Reply. We thank the reviewer for their suggestions, we have now edited the respective text sections as suggested.

You name "pneumoconiosis (Caplan syndrome)" an old but potentially relevant EAM for understanding the disease. Later you do not follow that item. Perhaps at least 1 or 2 sentences should be added.

Reply. The authors thank the reviewer for this suggestion. We have now added the following text to the introductory part of the “Pulmonary manifestations” section: “Nodules of the lung parenchyma may appear in the form of rheumatoid nodules (discussed below in a separate section) or due to pneumoconiosis, an inflammatory lung condition which occurs due to extensive occupational exposure to silica, asbestos and coal [13]. Pneumoconiosis associated with RA, also known as Caplan syndrome, is a rare clinical condition characterised by the development of multiple nodules, mainly in the lung periphery of affected patients [13,86].”

In the overview on point 3 pulmonal manifestations you name nodules as well as pleural effusions but discuss them later. Perhaps you should advise, that they are reported later in the text.

Reply. We thank the reviewer for their remark, according to which we have edited the introductory section of the “Pulmonary manifestations” section, which now reads:  “Pulmonary manifestations can manifest in different forms, affecting different lung compartments: in the form of interstitial lung disease (ILD), pulmonary nodules and pneumoconiosis – affecting lung parenchyma, as well as pleural effusions – affecting the pleura (discussed later in the section “Membrane involvement”), or obliterative/constrictive bronchiolitis and bronchiectasis - affecting the lower airways [13].” …
“Nodules of the lung parenchyma may appear in the form of rheumatoid nodules (discussed below in a separate section) or due to pneumoconiosis, which occurs due to extensive occupational exposure to silica, asbestos and coal [13]. “

In table 2 there is enough place to write arteriosclerosis instead of ATH, ....

Reply. The table has been edited as suggested, the row has been changed to read “Atherosclerosis” instead of “ATH”.

The authors would like to thank the reviewer for all their suggestions and corrections, which helped elevate the quality, structure and content of this comprehensive review.