Acrodermatitis Chronica Atrophicans in a Patient with Pulmonary Sarcoidosis: Case Report and Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Lines 63 & following, might be worthwhile mentioning that rashes of Lyme disease can adopt a wide range of presentations and that, while the so-called Bull's eye rash is the most readily recognized, that so-called 'classic' presentation occurs in a minority of EM rashes.  If memory serves, the citation of Parenti and colleagues where onset and morphology of Lyme rashes observed in the setting of a Lyme vaccine trial, disclosed a very broad range of presentations that most would not assume were diagnostic of Lyme, but all of which were PCR confirmed on skin biopsy.  The Reviewer does not presently have access to the full text of that ref, but the authors might wish to acquire and review that and see if what the reviewer asserts is cited there.  The point is, that whereas the Bull's eye rash is nearly pathognomonic for Lyme it occurs in the minority of EM rashes.  See Smith et al, below:

Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, Holman MS, Persing DH, Steere AC. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med. 2002 Mar 19;136(6):421-8. doi: 10.7326/0003-4819-136-6-200203190-00005. PMID: 11900494.

Line 104: might wish to include not just 'cognitive impairment' but the more serious neurologic aspects including encephalitis and encephalopathy as has been very well documented, for example, by Oksi and co-workers out of Finland.

Line 126: Perhaps outside of scope of the paper, but perhaps worth mentioning either here or in the discussion, that the 'standard' therapy of doxycycline of 100 mg twice daily is likely inadequate for central nervous system treatment as has been discussed by Dotevall, who showed that 300-400 mg/day was more effective for neuroborreliosis treatment.  Since it has been shown that borreliae can invade the CNS within hours to days of infection, it might be worth commenting that there may be rational for higher doses of doxycycline.  Again, this may fall outside of the scope or objectives of the authors for the purposes of this paper.  On the other hand, such discussion might improve general care for persons with Lyme borreliosis.

Luft BJ, Steinman CR, Neimark HC, Muralidhar B, Rush T, Finkel MF, Kunkel M, Dattwyler RJ. Invasion of the central nervous system by Borrelia burgdorferi in acute disseminated infection. JAMA. 1992 Mar 11;267(10):1364-7. Erratum in: JAMA 1992 Aug 19;268(7):872. PMID: 1740859.

Line 162: eight 'points' - is eight 'bands' on Western blot more correct terminology?

Limitations: Although it seems to the reviewer that the authors have made their point and that their diagnosis seems correct both clinically and with available data they developed with confirmatory response to application of therapy, maximally thorough/academic work-up might have included immunohistochemistry for borreliae in the skin biopsy (e.g. as Eisendle has described) or by tissue PCR and or by borreliae culture.  Again, the authors work-up seems 'sufficient', but at least in the discussion these 'maximally thorough' aspects of a potential work-up might at least be mentioned.  These are not always possible due to availability of local expertise etc. and may not be essential for good clinical care.

Discussion of differential diagnosis of Lyme and sarcoidosis itself might be worth including because both 'entities' can be multi-system in nature including skin, joint, heart and CNS manifestations.

Additionally, there might be room for authors to comment on the desirability of patients with ACA to be followed, even after application of treatment to monitor for relapse of later skin or multi-system complications.  Although many insist there is no such thing as chronic Lyme disease following application of antibiotics courses of limited duration, vast literature contradicts this assertion in the worldwide peer-reviewed published scientific literature.

The manuscript could be published 'as is'.  It is a nice and worthwhile and well-written piece. The Reviewer opines it could be further improved with inclusion of some or all of the considerations raised.

 

Author Response

Comment 1: 

Lines 63 & following, might be worthwhile mentioning that rashes of Lyme disease can adopt a wide range of presentations and that, while the so-called Bull's eye rash is the most readily recognized, that so-called 'classic' presentation occurs in a minority of EM rashes.  If memory serves, the citation of Parenti and colleagues where onset and morphology of Lyme rashes observed in the setting of a Lyme vaccine trial, disclosed a very broad range of presentations that most would not assume were diagnostic of Lyme, but all of which were PCR confirmed on skin biopsy.  The Reviewer does not presently have access to the full text of that ref, but the authors might wish to acquire and review that and see if what the reviewer asserts is cited there.  The point is, that whereas the Bull's eye rash is nearly pathognomonic for Lyme it occurs in the minority of EM rashes.  See Smith et al, below:

Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, Holman MS, Persing DH, Steere AC. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med. 2002 Mar 19;136(6):421-8. doi: 10.7326/0003-4819-136-6-200203190-00005. PMID: 11900494.

Response 1: Thank you for pointing this out. We agree with this comment. Therefore we have added the following information: "Although erythema migrans (EM) is often described as a bull’s eye rash, this so-called ‘classic’ presentation is not the only possible one. Rashes associated with Lyme disease can exhibit a wide range of clinical presentations. Atypical EM lesions reported in the literature include vesicles, erythematous papules, purpura, and lymphangitic streaks, which may lead to diagnostic uncertainty, especially in non-endemic regions." (page 2, paragraph 3, line 65).

Comment 2: Line 104: might wish to include not just 'cognitive impairment' but the more serious neurologic aspects including encephalitis and encephalopathy as has been very well documented, for example, by Oksi and co-workers out of Finland.

Response 2: We also agree with this comment. We have added the following:             In terms of systemic complications, Lyme borreliosis progresses through three stages, resembling syphilis, with intermittent latency. The primary stage presents as erythema migrans at the tick bite site, while the secondary stage involves disseminated skin lesions, meningitis, cranial neuropathies, atrioventricular blocks, and myocarditis. The tertiary stage is marked by acrodermatitis chronica atrophicans (ACA) and neurological deficits such as radiculopathy and cognitive impairment. Additionally, more severe central nervous system involvement may occur, including chronic encephalitis and encephalopathy. These manifestations have been associated with direct invasion of Borrelia burgdorferi into CNS tissue, as evidenced by PCR and culture-based studies. Pathological findings such as perivascular lymphocytic infiltrates, demyelination, vasculitis, and microglial activation have also been documented, suggesting a multifactorial pathogenesis involving both direct infection and immune-mediated mechanisms (page 3, paragraph 2, line 110)

Comment 3: 

Line 126: Perhaps outside of scope of the paper, but perhaps worth mentioning either here or in the discussion, that the 'standard' therapy of doxycycline of 100 mg twice daily is likely inadequate for central nervous system treatment as has been discussed by Dotevall, who showed that 300-400 mg/day was more effective for neuroborreliosis treatment.  Since it has been shown that borreliae can invade the CNS within hours to days of infection, it might be worth commenting that there may be rational for higher doses of doxycycline.  Again, this may fall outside of the scope or objectives of the authors for the purposes of this paper.  On the other hand, such discussion might improve general care for persons with Lyme borreliosis.

Response 3: In order to improve general care for patients with Lyme borreliosis, we included the following information regarding the treatment for neuroborreliosis: In our patient’s case, neurological involvement was ruled out following a neurological evaluation, which found no clinical or paraclinical signs suggestive of neuroborreliosis. However, had there been evidence of central nervous system involvement, treatment options would have needed to be adjusted accordingly. Although the optimal therapy for neuroborreliosis remains undefined, some studies suggest that higher doses of doxycycline—such as 200 mg twice daily (400 mg/day)—may be more effective than the standard 100 mg twice daily regimen. This is due to doxycycline’s superior penetration of the blood-brain barrier and greater efficacy against Borrelia burgdorferi compared to penicillin G. Oral doxycycline also offers the advantage of outpatient treatment, even in more severe cases (page 7, paragraph 3, line 271).

Comment 4: Line 162: eight 'points' - is eight 'bands' on Western blot more correct terminology?

Response 4: We changed the terminology as indicated. Thank you for the suggestion (page 5, paragraph 2, line 172).

Comment 5: Limitations: Although it seems to the reviewer that the authors have made their point and that their diagnosis seems correct both clinically and with available data they developed with confirmatory response to application of therapy, maximally thorough/academic work-up might have included immunohistochemistry for borreliae in the skin biopsy (e.g. as Eisendle has described) or by tissue PCR and or by borreliae culture.  Again, the authors work-up seems 'sufficient', but at least in the discussion these 'maximally thorough' aspects of a potential work-up might at least be mentioned.  These are not always possible due to availability of local expertise etc. and may not be essential for good clinical care.

Response 5: Immunohistochemistry tests were conducted as we mentioned on page 5, paragraph 1, line 171.

Comment 6: Additionally, there might be room for authors to comment on the desirability of patients with ACA to be followed, even after application of treatment to monitor for relapse of later skin or multi-system complications.  Although many insist there is no such thing as chronic Lyme disease following application of antibiotics courses of limited duration, vast literature contradicts this assertion in the worldwide peer-reviewed published scientific literature.

Response 6: Thank you for suggesting this. We have mentioned the following: Overall, the patient’s positive response to treatment and the lack of long-term complications align with recent findings that early, appropriate treatment significantly improves prognosis in ACA cases. Nevertheless, considering the potential for relapse or the emergence of delayed cutaneous or systemic manifestations, the patient remains under ongoing outpatient follow-up, both dermatologically and neurologically (page 7, paragraph 4, line 283).

 

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a detailed description of a rare late-stage Lyme disease skin manifestation—chronic atrophic acrodermatitis (ACA)—and its association with the patient's history of pulmonary nodules. Such case reports are scarce in the medical literature and offer significant clinical reference value. ignificant Treatment Effect: After receiving doxycycline treatment, the patient’s skin lesions completely resolved, with no adverse reactions. The remarkable efficacy and safety of this treatment provide strong evidence to support its use in clinical practice.Additionally, there are diagnostic challenges and risks of misdiagnosis: Through detailed case analysis, the manuscript reveals the diagnostic challenges and misdiagnosis risks of ACA, particularly when symptoms are atypical or when the patient lacks a clear history of tick bites. This helps raise clinicians' awareness of the disease, preventing misdiagnosis and missed diagnoses. But this manuscript have many of shortcomings.
1.The manuscript reports only a single case, and the sample size is too small, which may not fully reflect the presentation and treatment outcomes of ACA in different patients. A study with multiple cases could be more convincing.
2.The manuscript lacks data on long-term follow-up of the patient, making it impossible to assess the long-term effects of treatment and the risk of recurrence. Long-term follow-up data are crucial for evaluating the durability and safety of the treatment.
3.It is suggested to add more reports of similar cases to enhance the representativeness and persuasiveness of the study.
4.Use diagrams to illustrate and improve the quality of the diagram.
5.There are errors in the citation format of the references such as 104, cite the references according to the format of the journal.
6.Add some new and relevant references and write them in the format of this journal.
7.Refine the sulk full text.
8.Rewrite refining conclusion.

Comments on the Quality of English Language

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Author Response

Comment 1: The manuscript reports only a single case, and the sample size is too small, which may not fully reflect the presentation and treatment outcomes of ACA in different patients. A study with multiple cases could be more convincing.

Response 1: We appreciate the reviewer’s observation regarding the limitations inherent to a single case report. However, we would like to emphasize that the primary objective of this manuscript is to contribute to the literature by documenting a rare cutaneous manifestation, acrodermatitis chronica atrophicans (ACA), which remains underreported, particularly in certain geographical areas. Given the scarcity of such cases and the limited number of detailed clinical descriptions available, we believe that this report adds meaningful value by increasing awareness and enhancing recognition of this condition among clinicians. While we acknowledge that larger studies are important for understanding broader patterns of disease, individual case reports continue to play a crucial role in highlighting rare presentations, especially those that may otherwise go unrecognized in routine clinical practice.

Comment 2: The manuscript lacks data on long-term follow-up of the patient, making it impossible to assess the long-term effects of treatment and the risk of recurrence. Long-term follow-up data are crucial for evaluating the durability and safety of the treatment.

Response 2: Thank you for your valuable suggestion. We fully agree that long-term follow-up is important in assessing treatment efficacy and the potential risk of recurrence. The case we presented is a recent one, and at the time of submission, we reported all the clinical details available. Nevertheless, following the reviewers’ recommendations, we have updated the manuscript to mention that the patient remains under outpatient dermatological and neurological follow-up and is currently asymptomatic. We have added the following: "Overall, the patient’s positive response to treatment and the lack of long-term complications align with recent findings that early, appropriate treatment significantly improves prognosis in ACA cases. Nevertheless, considering the potential for relapse or the emergence of delayed cutaneous or systemic manifestations, the patient remains under ongoing outpatient follow-up, both dermatologically and neurologically" (page 7, paragraph 4, line 282).  We appreciate your input, which helped us improve the clarity and completeness of the report.

Comment 3: It is suggested to add more reports of similar cases to enhance the representativeness and persuasiveness of the study.

Response 3: We appreciate the suggestion. However, given the rarity of the condition, especially in presentations similar to the one described in our report, the number of published cases in the literature remains limited. Precisely due to this scarcity, we believe that documenting and sharing individual cases such as ours contributes meaningfully to the existing body of knowledge and may aid clinicians in recognizing and managing similar cases in the future.

Comment 4: Use diagrams to illustrate and improve the quality of the diagram.

Response 4: We appreciate the recommendation. However, as our manuscript presents a single case report rather than a statistical or comparative analysis, the inclusion of diagrams or graphical data representations is not directly applicable in this context. The aim of the article is to highlight the clinical features and management of a rare dermatological manifestation, for which narrative description remains the most appropriate format. That said, if the reviewer has a specific suggestion regarding a diagram that could enhance the clarity or value of the case presentation, we would be happy to consider and include it.

Comment 5: There are errors in the citation format of the references such as 104, cite the references according to the format of the journal.

Response 5: We have made the necessary changes in order to have the references in line with the journal's requirements. Thank you for pointing this out. 

Comment 6: Add some new and relevant references and write them in the format of this journal.

Response 6: We appreciate the reviewer’s suggestion. However, given that the manuscript focuses on a rare dermatological manifestation of Lyme borreliosis, we conducted a thorough review of the available literature and included all relevant and accessible references that we could identify. Due to the scarcity of similar reported cases, the number of pertinent publications is limited. Nonetheless, if the reviewer has specific references in mind that would enhance the manuscript, we would be grateful to review and include them accordingly.

Comments 7 and 8: Refine the sulk full text, Rewrite refining conclusion. Responses 7 and 8: We have made revisions to improve the clarity of the text and conclusion for better readability and focus on key points, and we hope it meets your expectations.    

 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a detailed description of a rare late-stage Lyme disease skin manifestation—chronic atrophic acrodermatitis (ACA)—and its association with the patient's history of pulmonary nodules. Such case reports are scarce in the medical literature and offer significant clinical reference value. ignificant Treatment Effect: After receiving doxycycline treatment, the patient’s skin lesions completely resolved, with no adverse reactions. The remarkable efficacy and safety of this treatment provide strong evidence to support its use in clinical practice.Additionally, there are diagnostic challenges and risks of misdiagnosis: Through detailed case analysis, the manuscript reveals the diagnostic challenges and misdiagnosis risks of ACA, particularly when symptoms are atypical or when the patient lacks a clear history of tick bites. This helps raise clinicians' awareness of the disease, preventing misdiagnosis and missed diagnoses. The authors have made great improvement to the question, but there are some problems.

1.Borrelia serology via Western blot was 172 positive for both IgG (31 bands) and IgM (8 bands), confirming the diagnosis of ACA in 173 its inflammatory phase. The diagnostic basis of this manuscript is based on the above data, but it should be discussed in the discussion that the serological diagnosis and those pathogens cross-react to cause false positives, and the author should discuss in the discussion and suggest adding this part of the data.

2. Cite and write references according to the format of this journal, and check the citation serial number and format.

Comments on the Quality of English Language

/

Author Response

Comment 1: Borrelia serology via Western blot was 172 positive for both IgG (31 bands) and IgM (8 bands), confirming the diagnosis of ACA in 173 its inflammatory phase. The diagnostic basis of this manuscript is based on the above data, but it should be discussed in the discussion that the serological diagnosis and those pathogens cross-react to cause false positives, and the author should discuss in the discussion and suggest adding this part of the data.

Response 1: We thank the reviewer for this insightful comment and valuable suggestion. In response, we have expanded the Discussion section to address the potential limitations of Western blot serology, including issues related to cross-reactivity and false positives. Specifically, we have added the following:

"Although the serological diagnosis using Western blot provided strong evidence supporting the diagnosis of ACA in its inflammatory phase (positive IgG with 31 bands and IgM with 8 bands), it is crucial to acknowledge and address the limitations inherent to these methods. Western blot, despite its high specificity compared to ELISA, is not devoid of challenges, particularly those related to cross-reactivity and interpretative subjectivity.
Several infectious agents and conditions can cause cross-reactions with Borrelia burgdorferi antigens, potentially leading to false-positive results. Notably, antibodies elicited by Treponema pallidum, Anaplasma phagocytophilum, Yersinia spp., Epstein–Barr virus (EBV), Cytomegalovirus (CMV), Parvovirus B19, and even autoimmune markers such as rheumatoid factor (RF), have shown reactivity with common Borrelia antigens like OspC, FlaB, BmpA, and VlsE. These interactions are particularly problematic in the IgM class, where non-specific responses are more common due to the immature nature of early immune responses [24].
Moreover, endemic prevalence of B. burgdorferi s.l. antibodies, especially in high-risk European populations, further complicates interpretation, as positive serology does not necessarily indicate active infection. It is also notable that patients may retain specific IgG (and in some cases IgM) antibodies for years post-infection, which can mislead clinicians when diagnosing late manifestations such as ACA [24].
In this context, it is important that positive serologic findings are interpreted in conjunction with clinical presentation and epidemiologic exposure. A thorough differential diagnosis is necessary, especially in patients with nonspecific symptoms or atypical manifestations." (page 7, paragraph 2, line 255).

We hope this addition adequately addresses the reviewer’s concern.

Comment 2: Cite and write references according to the format of this journal, and check the citation serial number and format.

Response 2: We thank the reviewer for pointing out the issue regarding citation format and reference numbering. In response, we have carefully revised and updated all references to comply with the journal's formatting guidelines. We ensured that the in-text citation numbers are correctly matched to the reference list and that the formatting aligns with the journal’s required style. We appreciate your attention to this detail and hope the revised version meets the editorial standards.

 

Author Response File: Author Response.docx

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

it is ok