Tattoo-Associated Sarcoid-like Uveitis: A Multicenter Registry Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript reports a multicenter registry-based case series describing the clinical characteristics, management strategies, and outcomes of patients with tattoo-associated sarcoid-like uveitis in Japan. The topic is clinically relevant and increasingly important, given the worldwide rise in tattoo prevalence and the growing recognition of tattoo-related granulomatous inflammatory disorders.

The study represents one of the largest multicenter cohorts focused on this entity and provides valuable real-world data regarding recurrence, treatment escalation, and glaucoma-related outcomes. The manuscript is generally well structured, clearly written, and supported by appropriate clinical illustrations.

Overall, the work contributes meaningful observational data to a relatively rare and underrecognized condition. The comments below are intended to strengthen clarity, precision, and contextual interpretation rather than to challenge the validity of the study.

 

Major Comments

1. The authors appropriately describe the condition as tattoo-associated sarcoid-like disease and clearly acknowledge its overlap with ocular sarcoidosis. However, the term “sarcoid uveitis,” particularly in the title, may be interpreted by some readers as implying biopsy-proven or systemic sarcoidosis. Given that only a subset of patients had prior systemic sarcoidosis and that others presented with isolated ocular and cutaneous granulomatous inflammation, a brief clarification distinguishing systemic sarcoidosis from sarcoid-like  granulomatous reactions would improve conceptual precision. Such clarification would also facilitate comparison with previously described entities such as tattoo granulomas with uveitis, which have been discussed extensively in the literature.

2. The retrospective registry-based design is clearly stated and appropriate for this rare condition. Nevertheless, because the distinction between systemic sarcoidosis and localized sarcoid-like disease is clinically relevant, readers would benefit from a brief summary of the systemic investigations most commonly performed across centers (e.g., chest imaging or laboratory testing), even if not standardized.This additional description would improve interpretability while remaining consistent with the real-world nature of the registry.

 

3. The definition of glaucoma and IOP-lowering therapy is clearly provided and appropriate for a registry study. Given the high proportion of patients requiring such treatment, a short discussion addressing potential contributing mechanisms (chronic inflammation versus corticosteroid-related ocular hypertension) would further enhance the clinical relevance of the findings, even if differentiation was not consistently possible retrospectively.

Minor Comments

1.  The sentence beginning “Since there is only one heart…” appears unrelated to the scientific content and seems to represent an editing artifact. This sentence should be removed.
2. The limitations section is partially duplicated toward the end of the Discussion. Removing the repeated text would improve flow and readability.
3.  Visual acuity is analyzed at the eye level, whereas other outcomes are reported at the patient level. Although this approach is reasonable for a descriptive study, explicitly acknowledging this inherent limitation in the Discussion would further strengthen methodological transparency.

 

Overall Recommendation: The manuscript addresses an important and emerging clinical entity and provides valuable observational data. With clarifications regarding terminology, systemic evaluation, and interpretation of outcomes, the study will represent a strong and informative contribution to the literature on ocular inflammatory disease.

 

Comments on the Quality of English Language

The overall quality of English is good and the manuscript is generally clear and readable. However, minor grammatical and stylistic refinements are recommended to further improve clarity. In particular, a few isolated sentences would benefit from editing for grammar and flow, and one sentence in the Abstract appears unrelated to the scientific content and should be removed. These issues can be addressed with minor language polishing during revision.

Author Response

Reviewer Article Comments

Reviewer 1

This manuscript reports a multicenter registry-based case series describing the clinical characteristics, management strategies, and outcomes of patients with tattoo-associated sarcoid-like uveitis in Japan. The topic is clinically relevant and increasingly important, given the worldwide rise in tattoo prevalence and the growing recognition of tattoo-related granulomatous inflammatory disorders.

The study represents one of the largest multicenter cohorts focused on this entity and provides valuable real-world data regarding recurrence, treatment escalation, and glaucoma-related outcomes. The manuscript is generally well structured, clearly written, and supported by appropriate clinical illustrations.

Overall, the work contributes meaningful observational data to a relatively rare and underrecognized condition. The comments below are intended to strengthen clarity, precision, and contextual interpretation rather than to challenge the validity of the study.

 

Response: We thank the reviewer for this important and constructive comment. We have revised the manuscript following your valuable suggestions. We would be grateful if you could kindly review the revised version.

 

Major comments

Comments 1: The authors appropriately describe the condition as tattoo-associated sarcoid-like disease and clearly acknowledge its overlap with ocular sarcoidosis. However, the term “sarcoid uveitis,” particularly in the title, may be interpreted by some readers as implying biopsy-proven or systemic sarcoidosis. Given that only a subset of patients had prior systemic sarcoidosis and that others presented with isolated ocular and cutaneous granulomatous inflammation, a brief clarification distinguishing systemic sarcoidosis from sarcoid-like granulomatous reactions would improve conceptual precision. Such clarification would also facilitate comparison with previously described entities, such as tattoo granulomas with uveitis, which have been discussed extensively in the literature.

 

Response 1: We appreciate the reviewer’s comment regarding the terminology used for the tattoo-associated sarcoid-like disease condition and its definition. Accordingly, we have standardized the terminology throughout the manuscript to “tattoo-associated sarcoid-like disease.” The abstract and main texts have been revised accordingly, and the definitions of the relevant terms have been clarified in the Methods section.

 

Comments 2: The retrospective registry-based design is clearly stated and appropriate for this rare condition. Nevertheless, because the distinction between systemic sarcoidosis and localized sarcoid-like disease is clinically relevant, readers would benefit from a brief summary of the systemic investigations most commonly performed across centers (e.g., chest imaging or laboratory testing), even if not standardized. This additional description would improve interpretability while remaining consistent with the real-world nature of the registry.

 

Response 2: As requested, we have added the results of the full-body examination (BHL, ACE, sIL-2R, and T-spot) to Table 2.

 

Comments 3: The definition of glaucoma and IOP-lowering therapy is clearly provided and appropriate for a registry study. Given the high proportion of patients requiring such treatment, a short discussion addressing potential contributing mechanisms (chronic inflammation versus corticosteroid-related ocular hypertension) would further enhance the clinical relevance of the findings, even if differentiation was not consistently possible retrospectively.

 

Response 3: As suggested, we have described the potential contributing mechanisms—chronic inflammation versus corticosteroid-related intraocular pressure elevation—in Table 4 and the Discussion section.

 

Elevated IOP was attributed to chronic inflammation in three eyes, steroid-induced glaucoma in one eye, and both mechanisms in four eyes. These findings also indicate that persistent ocular inflammation is a key feature of tattoo-associated sarcoid-like disease and highlight the need for careful differentiation between inflammation-driven and steroid-induced IOP elevations in clinical management.

 

Minor comments

Comments 1: The sentence beginning “Since there is only one heart…” appears unrelated to the scientific content and seems to represent an editing artifact. This sentence should be removed.

 

Response 1: As suggested, we have removed “Since there is only one heart…” in the revised abstract.

 

Comments 2: The limitations section is partially duplicated toward the end of the Discussion. Removing the repeated text would improve flow and readability.

 

Response 2: We appreciate the reviewer’s careful reading. The duplicated text in the Limitations section at the end of the Discussion has been removed to improve flow and readability.

 

The present study has several limitations, including the small sample size, variable data completeness across centers, and lack of standardized, detailed phenotyping, such as uniform anterior chamber cell grading or imaging biomarkers. However, its multicenter registry design provides pragmatic real-world data on the treatment patterns and clinically meaningful outcomes of this rare condition. From a clinical perspective, our findings underscore the importance of considering the presence of tattoo-associated sarcoid-like disease in patients with recurrent uveitis, particularly when ocular flares coincide with inflammation or swelling of the tattooed skin, and support the need for coordinated ophthalmologic and systemic evaluations to guide the diagnosis and management of this condition.

 

Comments 3: Visual acuity is analyzed at the eye level, whereas other outcomes are reported at the patient level. Although this approach is reasonable for a descriptive study, explicitly acknowledging this inherent limitation in the Discussion would further strengthen methodological transparency.

 

Response 3: As suggested, we have added a statement in the Discussion section describing  that visual acuity was analyzed at the eye level, whereas the other outcomes were assessed at the patient level, which may introduce a unit-of-analysis limitation.

 

Another limitation is that the patients’ visual acuity was analyzed at the eye level, whereas the other outcomes were evaluated at the patient level. Although clinically appropriate for bilateral disease, this difference in analytic units may introduce bias in interpretation.

Reviewer 2 Report

Comments and Suggestions for Authors

 

1. Figure 2 Adarimumab = Adalimumab

Data of figure 2 are in part also presented in Table 3. When CsA treamtent is added in Table 3 Figure 2 is obsolet.

 

2. Data of figure 4 are also presented in Table 3. Add a further row in table 3 and display the frequency in %. Figure 4 is not neceassary

 

3. 80% of patients had glaucoma, did the IOP changed from baseline to final visit?

 

4. Was macular edema or cataract present?

 

5. Results shown in figure 3 are not described in the result section. And the therapeutic effect was not realy discussed in the discussion section. Is there any need for improvement?

 

6. Is the latency period from tattooing to uveitis onset known?

 

7. Is the presence of glaucoma related to sarcoidosis or uveitis? Is the duration from uveitis onset to development of secondary glaucoma known? Did secondary glaucoma developed also bilateral?

 

8. Discussion: Line 171-174 and line 175- 180 are similar.“ Despite these 175 insights, this study has several limitations, including the small sample size, variable data 176 completeness across centers, and the lack of standardized, detailed phenotyping (e.g., an-177 terior chamber cell grading and imaging biomarkers). Nonetheless, the multicenter design 178 provides pragmatic real-world evidence on treatment patterns and clinically meaningful 179 outcomes in this rare condition.“

 

9. Discussion: Are there new insights in therapeutic approaches or diagnostic setups (intense monitoring of IOP and OCT to detect macula edema)

 

10. Did the authors identify any relevant difference between Tattoo-Associated Sarcoid Uveitis and sarcoid uveitis without this association?

Author Response

Reviewer Article Comments

Reviewer 2

Comment 1

Figure 2 Adarimumab = Adalimumab. Data of Figure 2 are in part also presented in Table 3. When CsA treatment is added in Table 3 Figure 2 is obsolete.”

 

Response:

Thank you for pointing out the typographical error and potential redundancy. We corrected “Adarimumab” to “Adalimumab” throughout the manuscript. We also reorganized and clarified the systemic treatment data to explicitly include cyclosporin (CsA) and adalimumab in the treatment summary (revised Table 4), thereby improving the completeness of our data and avoiding duplication.

Regarding Figure 2, we retained it only for its distinct value (i.e., an eye-level visualization of the visual acuity change) beyond the tabular summaries; otherwise, redundant elements were consolidated into tables.

 

Changes in the manuscript:

We have added or clarified the use of CsA and adalimumab in the systemic treatment summary (revised Table 4).

 

Comment 2

“Data of Figure 4 are also presented in Table 3. Add a further row in Table 3 and display the frequency in %. Figure 4 is not necessary.”

 

Response:

We agree and appreciate this suggestion. To reduce redundancy, we removed Figure 4 and prioritized the tabular presentation. The frequencies (%) of the key findings/outcomes are summarized in the revised summary table(s). We kept the revised Table 4 to provide a detailed eye-level clinical description and presented the overall frequencies in a separate, more suitable aggregated table.

 

Comment 3

“80% of patients had glaucoma; did the IOP change from baseline to final visit?”

 

Response:

Yes. We have added the explicit IOP results to the Results section and provided a figure summarizing the change in the data from the baseline to final visits. In the revised manuscript, the IOP increased from baseline to the final visit (reported with mean ± SD), and data comparison is presented in Figure 3.

 

 

Comment 4

“Was macular edema or cataract present?”

 

Response:

Thank you. We explicitly reported the prevalence of macular edema in Table 2 and laterality in the Results section, and we summarized the cataract-related outcomes (including cataract surgery, if performed/recorded) in Table 4.

 

Comment 5

“Results shown in Figure 3 are not described in the Results section. And the therapeutic effect was not really discussed in the Discussion section. Is there any need for improvement?”

 

Response:

We agree. We revised the Results section to explicitly describe the findings shown in revised Figure 2 and clarified where the visual acuity outcomes are reported. We also strengthened the Discussion section to emphasize the therapeutic implications and practical management, including recurrence patterns, need for IOP-lowering therapy, and role of close monitoring (IOP and OCT), particularly given the high prevalence of macular edema among the patients.

 

Comment 6

“Is the latency period from tattooing to uveitis onset known?”

 

Response:

Partially. We clarified that latency information was available in a subset of cases (range reported), whereas, in the remaining cases, this information was recorded as unknown/not available. This is now explicitly stated and referenced in Table 2.

 

Comment 7

“Is the presence of glaucoma related to sarcoidosis or uveitis? Is the duration from uveitis onset to development of secondary glaucoma known? Did secondary glaucoma develop also bilaterally?”

 

Response:

This is an important clinical question. We have added the mechanisms of glaucoma in Table 4 and the Results section.

 

 

Comment 8

“Discussion: Line 171–174 and 175–180 are similar (limitations paragraph is repetitive).”

 

Response:

We agree and have revised the Discussion section to remove any redundancies by consolidating the limitations into a single streamlined paragraph while preserving the key points (small sample size, variable data completeness, and lack of standardized phenotyping).

 

Comment 9

“Discussion: Are there new insights in therapeutic approaches or diagnostic setups (intense monitoring of IOP and OCT to detect macula edema)?”

 

Response:

Yes. We strengthened the Discussion section to highlight the following practical insights: frequent bilaterality and recurrence, substantial IOP-related management burden, and high prevalence of macular edema. We now explicitly emphasize the close monitoring of IOP and OCT and coordinated systemic/dermatologic evaluation when tattoo inflammation coexists.

 

 

Comment 10

“Did the authors identify any relevant difference between Tattoo-Associated Sarcoid Uveitis and sarcoid uveitis without this association?”

 

Response:

We appreciate this question. A formal comparative analysis was not feasible because a matched control group of patients with sarcoid uveitis without tattoo association was not available within the registry extract used in this study. We clarified this in the Discussion section and framed our contribution as defining the clinical spectrum and outcomes of tattoo-associated sarcoid-like uveitis.

 

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for answering my questions.