Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This comprehensive review on Giant Cell Arteritis (GCA) provides a thorough synthesis of current diagnostic challenges, classification criteria, and therapeutic strategies. The manuscript is well-structured and covers important clinical aspects. However, there are several areas requiring significant revision.

 

Comments to Authors

1. The manuscript lacks a clear Methods section describing the literature search strategy, inclusion/exclusion criteria, databases searched, date ranges, and systematic approach to study selection. This is critical for a comprehensive review to establish rigor and reproducibility.
2. Line 100-111: The section on "Cranial Manifestations" states temporal artery abnormalities are present in "only 40-60% of cases" but then describes jaw claudication occurring in "35-50% of patients." This presentation suggests jaw claudication is nearly as common as temporal artery findings, which may mislead readers about the relative diagnostic utility of these findings.
3. Lines 150-152: Internal contradiction exists - the text states ESR elevation occurs in "approximately 84%" of patients while CRP shows "slightly higher sensitivity at 87%," but then immediately states "normal inflammatory markers occur in 5-30% of biopsy-proven cases." These percentages are mathematically inconsistent (if 84-87% have elevated markers, only 13-16% should have normal markers, not 5-30%).
4. Line 232: Reference to "Figure 34" is incorrect - should be "Figure 3" based on figure numbering sequence.
5. Lines 267-268: The figure legend describes features visible in H&E staining but states "Hematoxylin and Eosin (H&E) stain (x25)" for both panels without differentiating magnifications or confirming both are at the same magnification.
6. Table 1 (line 303): Lists sensitivity for 1990 ACR criteria as "53-80%" which is inconsistent with line 278-279 stating "93.5% sensitivity." This major discrepancy needs clarification regarding which comparator groups were used.
7. Lines 385-389: The discussion of upadacitinib approval appears incomplete. The text states it was "FSA-approved" (should be "FDA-approved") but does not provide the approval date or context relative to the knowledge cutoff, creating temporal ambiguity.
8. Lines 406-418: The section on secukinumab and mavrilimumab describes failed Phase III trials but lacks critical dates. The mavrilimumab termination is dated "February 26, 2025" which appears to be after the stated knowledge cutoff of January 2025, creating inconsistency in the temporal framework of the review.
9. Lines 536-974: The reference list is incomplete - most citations lack page numbers, DOI information is incomplete (showing only "https://doi.org/10.3390/xxxxx"), and formatting is inconsistent. Complete bibliographic information must be provided for all 173 references.
10. Line 9: Author affiliation shows an incomplete phone number "(+1-559-" suggesting copy-paste errors or incomplete manuscript preparation.
11. Lines 64-70: Redundant content - the text repeats nearly identical information about familial cases comprising "about 1%" of patients within six lines (lines 64-65 and 67-68).
12. Lines 148-156: The paragraph structure is problematic with an incomplete sentence at line 151-152 ("particularly") followed by a new sentence starting at line 152, suggesting missing text or editing error.
13. The manuscript frequently uses "may" and "might" when describing established relationships (e.g., lines 83-84, 93-97), which undermines the strength of well-documented associations and creates unnecessary hedging throughout.
14. Lines 407-411: The statement about secukinumab Phase III results appears to be based on a press release rather than peer-reviewed publication. Reliance on press releases for negative trial results is problematic for a scientific review and requires either published data or explicit acknowledgment of the preliminary nature of this information.
15. Figure 1 (lines 36-41): The figure legend describes the etiopathogenesis but the actual mechanism described is overly simplified and does not adequately reflect the complexity discussed in the main text (lines 28-33). The disconnect between figure and text diminishes educational value.
16. Lines 319-320: Repetition of information about TAB specificity and sensitivity that was already presented in section 6.1 (lines 228-230), creating unnecessary redundancy.
17. The manuscript inconsistently uses abbreviations - GCA is defined in the title but then re-defined in line 22; similarly, PMR is spelled out multiple times before being abbreviated, and the abbreviation list at lines 534-535 is incomplete.
18. Lines 494-528: The Conclusions section largely repeats content from the Introduction and body without synthesizing novel insights or providing clear future directions beyond listing possibilities already discussed.
19. Statistical reporting lacks consistency - some studies report exact percentages (line 158: "50-70%") while others provide means with standard deviations (line 164: "11.7±1.6 g/dL"), but many other results are presented without measures of variability or confidence intervals.
20. The manuscript does not address limitations of the reviewed literature, publication bias, quality assessment of included studies, or conflicts in the evidence base, which are essential components of a rigorous systematic review.

Author Response

We sincerely thank both reviewers for their thorough evaluation and constructive feedback on our manuscript entitled "Diagnostic Challenges, Evolving Classification Criteria, and Modern Therapeutic Strategies in Giant Cell Arteritis: Addressing Complexity in Clinical Practice." We have carefully addressed each comment and made substantial revisions to improve the quality, clarity, and critical appraisal of our work.

We particularly appreciate Reviewer 1's identification of typographical errors, mathematical inconsistencies, and formatting issues, all of which have been corrected. We also acknowledge Reviewer 2's request for greater critical appraisal and more specific, practical guidance, which we have addressed through substantial expansion of multiple sections and by adding a few new sections.

An important clarification: as noted in our title and confirmed in response to Reviewer 1's first comment, this manuscript was designed as a narrative/comprehensive clinical review rather than a systematic review with formal PRISMA methodology. However, we have added a Material and Methods section to provide transparency about our literature search and study selection approach.

Below, we provide detailed point-by-point responses to each reviewer's concerns, with changed text highlighted for your convenience in the revised manuscript.

Thank you for the opportunity to revise and improve our manuscript.

REVIEWER 1 - RESPONSES TO COMMENTS 1-20

Comment 1

The manuscript lacks a clear Methods section describing the literature search strategy, inclusion/exclusion criteria, databases searched, date ranges, and systematic approach to study selection. This is critical for a comprehensive review to establish rigor and reproducibility.

RESPONSE: We appreciate this important clarification. We respectfully note that our manuscript was designed as a narrative/comprehensive review rather than a systematic review. As stated in our initial title ("Diagnostic Challenges, Evolving Classification Criteria, and Modern Therapeutic Strategies in Giant Cell Arteritis: Addressing Complexity in Clinical Practice"), our goal was to provide a clinically-oriented synthesis of the multifaceted diagnostic and therapeutic landscape of GCA, rather than to conduct a systematic literature review with predefined PRISMA methodology.

However, we acknowledge the reviewer's point about methodological transparency. We have now added a brief Material and Methods section after the Introduction that clarifies:

• Type of review: Narrative/comprehensive review
• Literature sources: PubMed/MEDLINE, Web of Science, Scopus
• Search period: Articles published through 2025
• Search strategy: Combination of MeSH terms and keywords including "giant cell arteritis," "temporal arteritis," "large vessel vasculitis," "diagnosis," "classification criteria," "imaging," "biomarkers," and "treatment"
• Study selection: Focus on peer-reviewed articles, clinical trials, meta-analyses, and authoritative clinical guidelines, with emphasis on recent publications (last 5-10 years) while including seminal earlier works
• We prioritized clinically relevant studies that address diagnostic challenges, classification criteria evolution, imaging advances, and therapeutic developments

This addition provides transparency regarding our methodology while clarifying that this is not a systematic review of formal quality assessment protocols.

Comment 2

Line 100-111: The section on "Cranial Manifestations" states temporal artery abnormalities are present in "only 40-60% of cases" but then describes jaw claudication occurring in "35-50% of patients." This presentation suggests jaw claudication is nearly as common as temporal artery findings, which may mislead readers about the relative diagnostic utility of these findings.

RESPONSE: We appreciate the reviewer highlighting this potential source of confusion. We have revised the text to better contextualize the relative diagnostic utility of these findings. The revised text now reads:

“Temporal artery abnormalities, including tenderness, thickening, or reduced pulsation, provide important physical examination findings and are present in 40-60% of cases, making them one of the more common physical signs in GCA [13,29].

Jaw claudication due to ischemia of masticatory muscles during chewing, demonstrates high specificity for GCA, approximately 90%, and occurs in 35-50% of patients [30-32]. While jaw claudication is less common than temporal artery abnormalities, its high specificity makes it a particularly valuable diagnostic clue when present [13,33,34]. The "chewing gum test," while not superior to clinical history alone, may provide additional diagnostic utility when pain onset occurs within two minutes of chewing [35].”

This revision clarifies that while both findings occur with similar frequency, temporal artery abnormalities are more sensitive physical examination findings, whereas jaw claudication provides higher specificity.

Comment 3

Lines 150-152: Internal contradiction exists - the text states ESR elevation occurs in "approximately 84%" of patients while CRP shows "slightly higher sensitivity at 87%," but then immediately states "normal inflammatory markers occur in 5-30% of biopsy-proven cases." These percentages are mathematically inconsistent (if 84-87% have elevated markers, only 13-16% should have normal markers, not 5-30%).

RESPONSE: We thank the reviewer for identifying this mathematical inconsistency. The confusion arose from citing different studies with varying reference populations. We have clarified this section as follows:

“Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) remain cornerstone laboratory tests in GCA evaluation, though their limitations are well-recognized. ESR elevation (>50 mm/hour using Westergren method) occurs in approximately 76-84% of GCA patients, while CRP demonstrates slightly higher sensitivity at 86-98% depending on the study population [66-70]. However, normal inflammatory markers occur in approximately 4-20% of biopsy-proven cases with most studies reporting 7-10% particularly in patients presenting early in their disease course, those with predominantly large vessel involvement without cranial manifestations, or those taking medications that mask the elevation of the inflammatory markers, such as tocilizumab or steroids [59,71,72].”

 

We have updated the percentages to reflect the most recent meta-analyses and ensured mathematical consistency throughout.

Comment 4

Line 232: Reference to "Figure 34" is incorrect - should be "Figure 3" based on figure numbering sequence.

RESPONSE: We apologize for this typographical error. We eliminated Figure 2. Therefore, the original Figure 3 is now Figure 2 in the revised manuscript. This has been corrected to "Figure 2" throughout the manuscript. We have also carefully reviewed all other figure references to ensure accuracy.

Comment 5

Lines 267-268: The figure legend describes features visible in H&E staining but states "Hematoxylin and Eosin (H&E) stain (x25)" for both panels without differentiating magnifications or confirming both are at the same magnification.

RESPONSE: Thank you for this observation. Both panels are indeed at the same magnification (×25). However, to improve clarity, we have revised the figure legend to explicitly state this for each panel:

"Figure 4. A. Image of a normal temporal artery biopsy without signs of inflammation/vasculitis. Hematoxylin and Eosin (H&E) stain, original magnification ×25. B. This image demonstrates findings consistent with vasculitis in a temporal artery biopsy... Hematoxylin and Eosin (H&E) stain, original magnification ×25 (same magnification as panel A for direct comparison)."

Comment 6

Table 1 (line 303): Lists sensitivity for 1990 ACR criteria as "53-80%" which is inconsistent with line 278-279 stating "93.5% sensitivity." This major discrepancy needs clarification regarding which comparator groups were used.

RESPONSE: We thank the reviewer for identifying this critical discrepancy. This inconsistency arose from citing different validation studies with different comparator groups. We have now clarified this throughout the manuscript:

In the text (Section 8.1): "These criteria demonstrate 93.5% sensitivity and 91.2% specificity when distinguishing GCA from other forms of vasculitis in patients already diagnosed with vasculitis (original ACR validation study [117]), but show significant lower sensitivity (53-80%) when applied in broader clinical settings where the differential diagnosis included non-vasculitic conditions. These criteria show limitations in contemporary practice."

In Table 1: We have revised the sensitivity entry for 1990 ACR criteria to "93.5% (vs. other vasculitides); 53-80% (vs. non-vasculitic conditions)" with a table footnote explaining: "The 1990 ACR criteria were validated against other forms of vasculitis, not against non-inflammatory conditions, which partially explains the performance differences in real-world clinical settings where the differential diagnosis is broader."

This clarification helps readers understand why the criteria may perform differently in clinical practice versus the original validation studies.

Comment 7

Lines 385-389: The discussion of upadacitinib approval appears incomplete. The text states it was "FSA-approved" (should be "FDA-approved") but does not provide the approval date or context relative to the knowledge cutoff, creating temporal ambiguity.

RESPONSE: We appreciate the reviewer catching this typographical error. We have corrected "FSA" to "FDA" and added the approval date for clarity:

"Upadacitinib was FDA-approved for the treatment of GCA in November 2024 based on the results of the SELECT-GCA clinical trial. The trial demonstrated that 15 mg daily of upadacitinib in combination with a glucocorticoid taper achieved a sustained remission rate of 46% compared to 29% in the placebo group, with a safety profile consistent with other approved indications."

Comment 8

Lines 406-418: The section on secukinumab and mavrilimumab describes failed Phase III trials but lacks critical dates. The mavrilimumab termination is dated "February 26, 2025" which appears to be after the stated knowledge cutoff of January 2025, creating inconsistency in the temporal framework of the review.

RESPONSE: We thank the reviewer for this important observation. We have revised this section to correct the date issue and provide appropriate context:

For mavrilimumab: "In early 2024, Kiniksa terminated its licensing agreement for mavrilimumab and discontinued its development for GCA to pivot to a cardiovascular-focused pipeline, effectively halting the planned Phase III trial [based on corporate communications/regulatory filings]."

For secukinumab: "The Phase III GCaptAIN study (NCT04930094), which evaluated secukinumab in adults with newly diagnosed or relapsing GCA, did not meet its primary endpoint of sustained remission at week 52 according to results announced by Novartis in 2024 [based on company announcement, peer-reviewed publication pending]."

We have also added a statement acknowledging: "As some of these are recently completed trials, we note where information is derived from company announcements pending full peer-reviewed publication."

Comment 9

Lines 536-974: The reference list is incomplete - most citations lack page numbers, DOI information is incomplete (showing only "https://doi.org/10.3390/xxxxx"), and formatting is inconsistent. Complete bibliographic information must be provided for all 173 references.

RESPONSE: We apologize for the incomplete reference formatting in the submitted version. We have now:

• Added complete page numbers for all journal articles as per EndNote
• Updated all DOI links with complete, functional URLs
• Standardized formatting according to journal requirements
• Verified that all references are complete and accurate
• Cross-checked that all in-text citations match the reference list

The updated reference list has been thoroughly reviewed and corrected. We have used EndNote for references and the same format is automatically applied to all the references.

Comment 10

Line 9: Author affiliation shows an incomplete phone number "(+1-559-" suggesting copy-paste errors or incomplete manuscript preparation.

RESPONSE: We apologize for this oversight. The complete contact information has been added. We have also reviewed all other author information fields to ensure completeness.

Comment 11

Lines 64-70: Redundant content - the text repeats nearly identical information about familial cases comprising "about 1%" of patients within six lines (lines 64-65 and 67-68).

RESPONSE: We agree this repetition is unnecessary. We have removed the redundant sentence and consolidated the information into a single, clearer statement:

“While there is a higher incidence of GCA in families with a history of the condition, familial cases are relatively rare, accounting for about 1% of all patients. This complex genetic landscape underscores that while genetics contribute to risk, there are other factors also at play. [14,15].”

Comment 12

Lines 148-156: The paragraph structure is problematic with an incomplete sentence at line 151-152 ("particularly") followed by a new sentence starting at line 152, suggesting missing text or editing error.

RESPONSE: Thank you for identifying this editing error. We have corrected the incomplete sentence. The revised text now reads:

“However, normal inflammatory markers occur in approximately 4-20% of biopsy-proven cases with most studies reporting 7-10% particularly in patients presenting early in their disease course, those with predominantly large vessel involvement without cranial manifestations, or those taking medications that mask the elevation of the inflammatory markers, such as tocilizumab or steroids [59,71,72].

The combination of ESR and CRP provides enhanced diagnostic utility…”

Comment 13

The manuscript frequently uses "may" and "might" when describing established relationships (e.g., lines 83-84, 93-97), which undermines the strength of well-documented associations and creates unnecessary hedging throughout.

RESPONSE: We appreciate this stylistic feedback and agree that overuse of hedging language can weaken the presentation of well-established findings. We have systematically reviewed the manuscript and replaced tentative language with more definitive statements where evidence supports this, while retaining appropriate qualifiers only where genuine uncertainty exists in the literature. Examples of changes made:

• Changed "may reflect hormonal influences" to "likely reflects hormonal influences" (when supported by substantial evidence)
• Changed "may provide" to "provides" (for established diagnostic utilities)
• Changed "might contribute" to "contributes" (for well-documented pathophysiological mechanisms)

We retained cautious language only where appropriate (e.g., for emerging biomarkers not yet validated, for mechanisms that remain incompletely understood).

Comment 14

Lines 407-411: The statement about secukinumab Phase III results appears to be based on a press release rather than peer-reviewed publication. Reliance on press releases for negative trial results is problematic for a scientific review and requires either published data or explicit acknowledgment of the preliminary nature of this information.

RESPONSE: We agree this requires transparency. We have added explicit acknowledgment:

"IL-17 inhibition with secukinumab demonstrated encouraging results in phase II trials, with sustained remission rates of 59.3% compared to 8.0% with placebo. However, the Phase III GCaptAIN study (NCT04930094) did not meet its primary endpoint of sustained remission at week 52 according to company announcement (full peer-reviewed results pending publication). Given the promising phase II results and the clinical need for additional therapeutic options, publication of the complete phase III dataset will be important for understanding the role of IL-17 inhibition in GCA."

This revision acknowledges the source of information while maintaining scientific rigor.

Comment 15

Figure 1 (lines 36-41): The figure legend describes the etiopathogenesis, but the actual mechanism described is overly simplified and does not adequately reflect the complexity discussed in the main text (lines 28-33). The disconnect between figure and text diminishes educational value.

RESPONSE: We have completed change the Figure 1 and its legend to better reflect the mechanistic complexity and we have modified the text accordingly. We have enhanced the figure itself to include more specific cellular and molecular details, and we reference these specific mechanisms more explicitly in both the legend and the text, and within the figure.

In the text: “The reason GCA is so difficult to manage is that different "pockets" of inflammation in the artery respond differently to therapy. The clinical manifestations of GCA are the direct result of a spatially organized inflammatory process within the temporal artery wall. Recent research using spatial transcriptomics has demonstrated that macrophages and T cells are not uniformly distributed; rather, they organize into three functionally distinct layers that dictate disease progression and treatment response [7,8]. The adventitia serves as the primary gateway for leukocyte entry and the epicenter of the systemic acute-phase response. Here, cluster of differentiation (CD)64⁺ macrophages and Th17 cells form a potent pro-inflammatory circuit. This layer is characterized by the high production of interleukin (IL)-6, IL-1β, and IL-23. This "adventitial signature" correlates strongly with elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and constitutional symptoms such as fever and weight loss. Importantly, this pathway is highly sensitive to glucocorticoids and IL-6 receptor antagonists, e.g., tocilizumab, often resulting in a rapid normalization of systemic markers. Tissue injury is concentrated in the arterial media, where multinucleated giant cells and CD206⁺ macrophages orchestrate the degradation of the internal elastic lamina. This destructive phenotype is driven by the secretion of matrix metalloproteinase (MMP)-9, YKL-40/chitinase 3-like, and reactive oxygen species (ROS). Recent data highlight granulocyte macrophage colony-stimulating factor (GM-CSF) as the master regulator of this medial destruction, providing a rationale for the use of GM-CSF receptor blockers, e.g., mavrilimumab, to prevent permanent structural damage to the vessel wall. The most clinically catastrophic feature of GCA, luminal occlusion, occurs in the intima. This layer is dominated by CD163⁺ and folate receptor (FR)-β+ macrophages, which drive a "response-to-injury" program. These cells secrete vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), triggering neoangiogenesis and the migration of myofibroblasts. Unlike the adventitial inflammatory markers, this intimal remodeling program is notably resistant to glucocorticoids. This explains the "vascular-systemic dissociation" frequently observed in GCA, where patients may develop ischemic complications, e.g., vision loss, despite having a normal CRP and an apparently suppressed systemic inflammatory response (Figure 1) [7-12].”

In the Figure legend: “Figure 1. Compartmentalized Macrophage and T-Cell Effector Functions in GCA: Layer-Specific Immunopathology and Steroid Resistance Mechanisms. The inflammatory landscape of GCA exhibits a functionally distinct "division of labor" across the arterial wall, with each compartment contributing to specific pathogenic outcomes. (A) Adventitia, systemic signaling hub: CD64⁺ macrophages and CD4⁺ Th17 cells orchestrate systemic inflammation through production of IL-6, IL-1β, and IL-23, which drive hepatic acute-phase protein synthesis, with elevated CRP and serum amyloid A (SAA), and constitutional symptoms like fever and malaise. This axis is highly glucocorticoid-responsive. (B) Media, zone of vascular wall destruction: multinucleated giant cells derived from macrophage fusion and CD206⁺ alternatively activated macrophages localize to the internal elastic lamina (IEL), where they secrete MMP-9, MMP-2, and the chitinase 3-like protein YKL-40. These proteases, combined with reactive oxygen species (ROS) generated by activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mediate degradation of elastin and collagen, resulting in focal wall thinning, medial necrosis, and aneurysmal dilatation. (C) Intima, zone of occlusive remodeling: CD163⁺/FR-β⁺ alternatively activated macrophages and resident myofibroblasts secrete platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), promoting neoangiogenesis, intimal smooth muscle cell hyperplasia, and progressive luminal narrowing leading to tissue ischemia. While the adventitial IL-6/Th17 axis responds dramatically to glucocorticoids, the medial giant cell-driven matrix destruction and CD163⁺-mediated intimal remodeling exhibit relative steroid resistance, perpetuating subclinical inflammation and late-stage ischemic complications even after initial clinical remission. Abbreviations: CD, cluster of differentiation; iNOS, inducible nitric oxide synthase; MMP: matrix metalloproteinases; PDGF, platelet-derived growth factor; IL: interleukin; GM-CSF: granulocyte macrophage colony-stimulating factor; TGF-β1, transforming growth factor-β; IFN, interferon; FR, folate receptor.”

Comment 16

Lines 319-320: Repetition of information about TAB specificity and sensitivity that was already presented in section 6.1 (lines 228-230), creating unnecessary redundancy.

RESPONSE: We agree and have removed the redundant sentence from lines 319-320. When discussing differential diagnosis, we now simply reference: "The temporal artery biopsy, despite its limitations discussed in Section 7, maintains importance as a diagnostic tool, particularly when imaging results are inconclusive..." This eliminates repetition while maintaining appropriate cross-referencing.

Comment 17

The manuscript inconsistently uses abbreviations - GCA is defined in the title but then re-defined in line 22; similarly, PMR is spelled out multiple times before being abbreviated, and the abbreviation list at lines 534-535 is incomplete.

RESPONSE: We have systematically reviewed all abbreviations throughout the manuscript:

• GCA: Now defined only once at first use in the abstract, then consistently used throughout
• PMR: Now defined at first use and consistently abbreviated thereafter
• All other abbreviations have been standardized (defined at first use, then abbreviated consistently)
• The abbreviation list has been expanded to include all abbreviations used in the manuscript, including: AAION, CDUS, CRP, CTA, ESR, FDG-PET, IL-6, LV-GCA, MMP, MRI, SAA, TAB, VEGF, and others

We have also added a note in the abbreviation section that abbreviations are defined at first use in the text.

Comment 18

Lines 494-528: The Conclusions section largely repeats content from the Introduction and body without synthesizing novel insights or providing clear future directions beyond listing possibilities already discussed.

RESPONSE: We have substantially revised the Conclusions section to eliminate repetition and provide synthesis and novel insights. The revised conclusion now emphasizes that GCA management is transitioning from a "one-size-fits-all" steroid approach to a sophisticated model of early imaging and targeted biologics, though further research is needed to refine treatment duration and safety.

This revision provides synthesis rather than repetition and offers concrete future directions with greater specificity than the original version.

Comment 19

Statistical reporting lacks consistency - some studies report exact percentages (line 158: "50-70%") while others provide means with standard deviations (line 164: "11.7±1.6 g/dL"), but many other results are presented without measures of variability or confidence intervals.

RESPONSE: We have improved the consistency and rigor of statistical reporting throughout the manuscript:

1. Where the original studies provided confidence intervals or measures of variability, we now include them
2. For prevalence data and percentages, we specify whether these represent pooled estimates from meta-analyses or ranges from individual studies
3. For diagnostic test characteristics (sensitivity, specificity), we now consistently provide ranges or confidence intervals where available
4. We have added clarifying language such as "pooled estimate," "reported range," or "95% CI" where appropriate

Examples of revisions:

• "Thrombocytosis (>400×10³/μL) occurs in 50-70% of GCA patients (range from multiple studies) and demonstrates specificity of 80-90% (95% CI: 75-92%) for positive temporal artery biopsy"
• "Normochromic normocytic anemia affects approximately 60-80% of patients, with mean hemoglobin levels of 11.7±1.6 g/dL reported in cohort studies"

While we acknowledge that not all cited studies provided complete statistical information, we have maximized transparency by clarifying the type of estimate being presented.

Comment 20

The manuscript does not address limitations of the reviewed literature, publication bias, quality assessment of included studies, or conflicts in the evidence base, which are essential components of a rigorous systematic review.

RESPONSE: As noted in our response to Comment 1, we respectfully clarify that this is a narrative/comprehensive clinical review rather than a systematic review. However, we acknowledge the value of discussing evidence limitations and conflicts. We have now added:

1. A brief statement in the Methods section clarifying: "As a narrative review, we did not conduct formal quality assessment or systematic bias evaluation of individual studies. However, we prioritized high-quality evidence including randomized controlled trials, systematic reviews and meta-analyses, large cohort studies, and evidence-based guidelines."
2. Throughout the manuscript, we now explicitly note areas of conflicting evidence or methodological limitations, including:
• The variability in temporal artery biopsy sensitivity based on specimen handling and interpretation
• Conflicting results from methotrexate trials and possible explanations
• Limitations of imaging modalities (operator-dependence of ultrasound, limited sensitivity of FDG-PET for cranial vessels)
• The challenge that most emerging biomarker studies are single-center with limited sample sizes
• Recognition that many diagnostic test accuracy studies used the 1990 ACR criteria as reference standard, which has limitations
3. A new paragraph in the Conclusions acknowledging: "Important limitations remain in the GCA literature, including heterogeneity in diagnostic criteria across studies, limited head-to-head comparisons of imaging modalities, predominantly Caucasian study populations limiting generalizability, and paucity of data on optimal treatment duration and predictors of safe treatment discontinuation."

This addition provides appropriate critical appraisal while maintaining the narrative review format.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript addresses a clinically relevant topic and highlights the diagnostic complexity of GCA. However, parts of the text remain somewhat generic and predominantly descriptive, with frequent use of broad phrasing. As a result, the level of critical appraisal of the available evidence could be strengthened. I suggest to include articulation of the authors’ interpretative or conceptual contribution, and to emphasize why this review is specific. With refinement, the manuscript has the potential to move beyond a descriptive overview and offer more original insight, beyond a summary of existing literature.

Specific comments:

Title: consider simplifying and shortening

Methodology: Even for a narrative review, greater methodological transparency is expected. Please specify the type of review, databases searched, search strategy, time frame, and the study selection process.

Figures: Figure 1 is informative but too general, and would benefit from the inclusion of more detailed, GCA-specific pathogenic mechanisms, such as key immune cell populations, cytokine pathways, and vessel wall–specific processes. Figure 2 is not particularly informative. Figure 4 could be improved in terms of image quality. Please clarify the origin of the figure (e.g., personal collection, published source). Would it be possible to provide an alternative version with greater magnification? Figure 5: add abbreviations in the caption. Also the figure 5 captions should focus more on explaining the figure itself rather than general therapeutic comment.

Risk factors and epidemiological considerations: I would recommend revising this section to improve conciseness, as it includes several general statements and some repetition.  The concept of pathophysiological risk factors requires further elaboration. Please expand on underlying biological and mechanistic processes that are being referred to.

Clinical Presentations and Diagnostic Complexity: Consider expanding the discussion on extracranial involvement, as this aspect of GCA is often under-recognized and has important diagnostic and therapeutic implications.

Laboratory Findings and Biomarkers: The section on biomarkers could be expanded. I suggest discussing more recent studies on emerging biomarkers, emphasizing what they add to current understanding. Are there any biomarkers that could realistically be implemented in clinical practice in the near future? This could enhance the translational relevance of the manuscript.

Imaging Advances and Diagnostic Modalities: The statement regarding the limited availability of CDUS is not only applicable to the USA. Consider including discussion of fast-track clinics and their impact on patient prognosis. Overall, this section is insufficiently developed and would benefit from incorporating commentary on the recommendations for the use of imaging in large vessel vasculitis in clinical practice, 2023.

Classification criteria evolution: Add more critical appraisal, including discussion of limitations of the new criteria (reliance on imaging availability, challenges in applying weighted scoring in routine clinical practice).

Differential Diagnostic Challenges: The distinction between differential diagnoses and true mimickers needs to be clarified. Currently, the section is too general and would benefit from a more specific, practical viewpoint highlighting how these conditions can be distinguished in clinical practice.

Treatment Implications and Monitoring: The therapeutic section should be expanded and strengthened. It would benefit from:

• More discussion on optimized use of glucocorticoid regimens.
• Expanded coverage of methotrexate, including dosing strategies and evidence for its role.
• Critical appraisal of studies evaluating tocilizumab and upadacitinib, highlighting strengths, limitations, and gaps.
• Inclusion of emerging therapeutic targets currently under investigation.
• An expanded section on predictors of relapse, supported by up-to-date evidence.

Prognosis and long term outcomes: expand to include strategies for the prevention of complications associated with GCA and its treatment (guidance on minimizing glucocorticoid-related adverse effects, monitoring for vascular complications such as vision loss or aortic aneurysm, and implementing risk mitigation strategies informed by current evidence.

Future Directions and Emerging Technologies: The section on a personalized medicine approach should be emphasized and made more specific, rather than remaining a general discussion.

Conclusion: The section is too generic and includes several repeated statements. It also mixes therapeutic and diagnostic statements. The section should be more concise focusing on the key take-home messages and emphasizing the manuscript’s original contributions.

 

Author Response

We sincerely thank both reviewers for their thorough evaluation and constructive feedback on our manuscript entitled "Diagnostic Challenges, Evolving Classification Criteria, and Modern Therapeutic Strategies in Giant Cell Arteritis: Addressing Complexity in Clinical Practice." We have carefully addressed each comment and made substantial revisions to improve the quality, clarity, and critical appraisal of our work.

We particularly appreciate Reviewer 1's identification of typographical errors, mathematical inconsistencies, and formatting issues, all of which have been corrected. We also acknowledge Reviewer 2's request for greater critical appraisal and more specific, practical guidance, which we have addressed through substantial expansion of multiple sections and by adding a few new sections.

An important clarification: as noted in our title and confirmed in response to Reviewer 1's first comment, this manuscript was designed as a narrative/comprehensive clinical review rather than a systematic review with formal PRISMA methodology. However, we have added a Material and Methods section to provide transparency about our literature search and study selection approach.

Below, we provide detailed point-by-point responses to each reviewer's concerns, with changed text highlighted for your convenience in the revised manuscript.

Thank you for the opportunity to revise and improve our manuscript.

REVIEWER 2 - RESPONSES TO COMMENTS

General Comment

The manuscript addresses a clinically relevant topic and highlights the diagnostic complexity of GCA. However, parts of the text remain somewhat generic and predominantly descriptive, with frequent use of broad phrasing. The level of critical appraisal of the available evidence could be strengthened.

GENERAL RESPONSE: We sincerely appreciate the reviewer's constructive feedback. We have undertaken substantial revisions to strengthen the critical appraisal throughout the manuscript, reduce generic/descriptive content, and emphasize our interpretative and conceptual contributions. Specific changes are detailed in our responses below.

Comment: Title

Consider simplifying and shortening.

RESPONSE: We have revised the title to be more concise while retaining the key focus areas: It now reads: “Diagnostic Challenges and Modern Therapeutic Strategies in Giant Cell Arteritis”

Comment: Methodology

Even for a narrative review, greater methodological transparency is expected. Please specify the type of review, databases searched, search strategy, time frame, and the study selection process.

RESPONSE: We have added a new "Material and Methods" section after the Introduction (Section 1.1) that provides methodological transparency. [See full Methods section in response to Reviewer 1, Comment 1]

Comment: Figures

Multiple concerns about figures 1-5

RESPONSE: We have addressed each figure concern comprehensively:

Figure 1: Completely changed and enhanced with specific GCA mechanisms including dendritic cell activation, CD4+ T cell differentiation (Th1/Th17), specific cytokines (IFN-γ, IL-6, etc.), macrophage activation, and giant cell formation.

Figure 2: We acknowledge this may be redundant. We prefer to remove Figure 2 and incorporate its key concepts into the text to streamline the manuscript.

Figure 4: Now it is Figure 3 because Figure 2 has been removed. Legend now states: "Temporal artery biopsy specimens from the personal collection of Dr. Rodriguez-Pla. Original magnification ×25 for both panels.” Unfortunately, higher magnification views are not available, and it has not been possible to increase the resolution of these figures because they were obtained during the realization of my PhD thesis over 20 years ago.

Figure 5: Now Figure 4. Revised caption to focus on explaining the figure with all abbreviations defined.

Comment: Risk Factors Section

Revise to improve conciseness; includes general statements and repetition. The concept of pathophysiological risk factors requires further elaboration.

RESPONSE: We have substantially revised Section 2, reducing it by approximately 25% while adding mechanistic depth:

• Added mechanistic insight on HLA-DRB1 molecules and antigen presentation
• Expanded immunosenescence discussion with specific mechanisms (CD28-null T cells, decreased thymic output, ‘inflammaging’)
• Added vascular aging mechanistic details (vasa vasorum loss, oxidative damage, advanced glycation end products)

Comment: Clinical Presentations

Consider expanding the discussion on extracranial involvement, as this aspect is often under-recognized.

RESPONSE: We have substantially expanded Section 3.4 (Extracranial Large Vessel Disease) by approximately 40%, including:

• Clinical presentation details (limb claudication, blood pressure discrepancies, bruits)
• Imaging patterns ("macaroni sign," vessel distribution)
• Diagnostic implications (recognition challenges, 2022 criteria improvements)
• Therapeutic implications (longer treatment duration, higher relapse rates)

Comment: Laboratory Findings and Biomarkers

Expand section on emerging biomarkers, emphasizing translational relevance. Are there any biomarkers that could realistically be implemented in clinical practice in the near future?

RESPONSE: We have substantially revised and expanded Section 5.3 to address:

• Critical appraisal of single-center studies and validation gaps
• Near-term clinical potential of specific biomarkers:
• Serum amyloid A (SAA): Most near-term potential (already available in many labs)
• Interleukin-6: Validated pathogenic role but needs standardized cutoffs
• MMPs: Research tools rather than clinical biomarkers
• Composite biomarker panels with machine learning as most promising future approach

Comment: Imaging Section

CDUS availability statement not only applicable to USA. Include discussion of fast-track clinics. Incorporate 2023 EULAR recommendations.

RESPONSE: We have made several substantive revisions:

• Revised CDUS availability to note global variations
• Added new subsection 6.5: Fast-Track Diagnostic Pathways describing:
• Implementation and structure
• Evidence of improved outcomes (reduced time to diagnosis, decreased vision loss)
• Critical elements and implementation challenges
• Incorporated 2023 EULAR imaging recommendations with specific guidance on multimodal approaches

Comment: Classification Criteria

Add more critical appraisal, including discussion of limitations of the new criteria.

RESPONSE: We have added substantial critical appraisal including:

• Dependency on imaging, availability and expertise
• Challenges of weighted point-based system in clinical practice
• Age ≥50 requirement excludes rare younger cases
• Classification vs. diagnosis distinction
• Equal weighting of halo sign and TAB despite different performance characteristics

Comment: Differential Diagnosis

The distinction between differential diagnoses and true mimickers needs clarification. Currently too general.

RESPONSE: We have substantially revised Section 9.1:

• Added clarifying statements of that differential diagnosis includes all kind of mimickers
• Created new Table 2 with specific distinguishing features for major mimickers (infectious endocarditis, ANCA-associated vasculitis, CNS vasculitis, metastatic cancer, atherosclerotic disease)
• Added practical clinical approach paragraph with systematic workup strategy

Comment: Treatment Section

Expand and strengthen with more discussion on optimized glucocorticoid regimens, methotrexate dosing, critical appraisal of biologics, emerging targets, and predictors of relapse.

RESPONSE: We have substantially expanded Section 10:

1. Glucocorticoid optimization: Added discussion of optimal initial dosing (30-60 mg), tapering strategies, and alternative delivery strategies
2. Methotrexate: Expanded with conflicting trial results, meta-analysis data, practical dosing considerations (15-20 mg weekly), and appropriate patient selection
3. Critical appraisal of biologics by added subsection 10.2.1. Critical Appraisal of Biologic Evidence:

• Tocilizumab: Analyzed limitations (50% relapse after discontinuation, exclusion of recent visual loss, cost, residual glucocorticoid exposure)
• Upadacitinib: Analyzed modest absolute benefit (17 percentage points), shorter follow-up, JAK-inhibitor class warnings
• Noted lack of head-to-head trials

4. Predictors of Disease Relapse: New subsection (10.5) detailing:

• Clinical factors (large vessel involvement HR 1.5-2.5, younger age, female sex, prior relapse HR 3.0-5.0)
• Laboratory/imaging markers
• Treatment-related factors
• Machine learning algorithms (71-76% accuracy)

Comment: Prognosis Section

Expand to include prevention strategies for complications associated with GCA and its treatment.

RESPONSE: We have added comprehensive new subsection 11.3. Prevention and Mitigation of GCA-Related and Treatment-Related Complications, covering:

Glucocorticoid adverse effect prevention:

• Bone health (DEXA, calcium/vitamin D, bisphosphonates)
• Metabolic complications (glucose and blood pressure monitoring)
• Infection prevention (vaccinations, PJP prophylaxis)
• Ophthalmologic surveillance
• GI protection

Vascular complication surveillance:

• Aortic aneurysm screening protocols (baseline and periodic imaging, high-risk monitoring)
• Visual complication prevention (emergency protocols, patient education, aspirin)

Quality of life optimization:

• Symptom assessment, physical therapy, early steroid-sparing agents, psychological support

Comment: Future Directions

The section on personalized medicine approach should be emphasized and made more specific.

RESPONSE: We have substantially revised and expanded Section 12.3 with specific, concrete examples:

Phenotype-based treatment stratification:

• Cranial-predominant GCA (shorter treatment, 18-24 months)
• Large vessel-predominant GCA (longer treatment, >2-3 years, imaging surveillance)
• PMR-overlap phenotype (management uncertainty)

Biomarker-guided therapeutic selection:

• IL-6 levels predicting tocilizumab response
• Imaging-detected persistent inflammation identifying relapse risk
• Glucocorticoid receptor polymorphisms

Pharmacogenomic applications:

• Glucocorticoid pharmacogenomics (NR3C1, HSD11B1, ABCB1)
• Biologic therapy pharmacogenomics
• Osteoporosis risk prediction

Composite risk stratification tools:

• Diagnostic risk scores
• Relapse risk scores
• Complication risk scores

Implementation pathway: Specific steps needed for translation to clinical practice

Comment: Conclusion

Too generic, includes repeated statements, mixes therapeutic and diagnostic content. Should be more concise and emphasize original contributions.

RESPONSE: We have completely rewritten the Conclusions section to:

• Lead with synthesis of three key paradigm shifts (our conceptual contribution)
• Provide specific, prioritized future directions
• Eliminate repetition of introduction material
• Focus on manuscript's interpretive contribution
• Conclude with forward-looking perspective

The revised conclusion emphasizes:

1. Diagnostic paradigm shift (biopsy-centric to multimodal)
2. Therapeutic advances (biologics but with remaining questions)
3. Evolution toward personalized medicine (potential but requiring validation)

We believe these revisions have substantially strengthened the manuscript and addressed all reviewer concerns. We thank both reviewers for their thoughtful feedback that has improved the quality and utility of our work.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

1. The manuscript states a knowledge cutoff of "end of January 2025" (line in Methods), yet cites events from "early 2024" (mavrilimumab termination) and "2024" (secukinumab trial results, upadacitinib FDA approval in November 2024) as if they are historical. However, the current date referenced in the document is January 20, 2026. The authors must clarify the actual knowledge cutoff date and ensure all temporal references are internally consistent.

 

2. While the authors added a "Critical Appraisal of Biologic Evidence" section in response to reviewer comments, this section reveals significant problems:

1. 1. Secukinumab: The authors cite phase II results showing 59.3% vs 8.0% sustained remission but then state the phase III trial failed to meet its primary endpoint. They dismiss this with "full peer-reviewed results pending publication" but continue to suggest IL-17 inhibition has promise. This is scientifically inappropriate—a failed phase III trial directly contradicts positive phase II results and suggests the phase II may have been a false positive.
   2. Upadacitinib: The absolute benefit is modest (46% vs 29% = 17 percentage points), yet the authors do not adequately contextualize this against tocilizumab's performance (56% vs 14% = 42 percentage points). The comparative effectiveness discussion is superficial.
   3. Mavrilimumab: The drug development was terminated by the sponsor, yet it remains prominently featured in Figure 4 as a therapeutic target without adequate discussion of why development was discontinued. 

The authors must provide rigorous critical analysis of why phase III trials failed, what this means for the therapeutic targets, and how these failures inform our understanding of GCA pathophysiology. The discussion of terminated/failed agents should be substantially reduced or moved to a separate section on "lessons learned from failed trials."

3. Response to Comment 3 is inadequate. The authors state ESR sensitivity is 76-84% and CRP is 86-98%, yet maintain that normal markers occur in "4-20% of cases with most studies reporting 7-10%." Similarly, in Table 1, the 1990 ACR criteria show "93.5% (vs. other vasculitides); 53-80% (vs. non-vasculitic conditions)" but the original ACR validation study did NOT test against non-vasculitic conditions, so where does the 53-80% figure originate?

4. The added Methods section, while an improvement, remains inadequate for a "comprehensive review" making strong clinical recommendations. "We prioritized peer-reviewed original research articles, systematic reviews and meta-analyses..." but no explanation of how "prioritization" was operationalized. Were lower-quality studies excluded? On what basis? Lines 108-113 state "we critically evaluated the strength and consistency of evidence" but provide no framework for how this was done (quality scoring? level of evidence grading?). Please conduct and report a systematic methodology with explicit inclusion/exclusion criteria, quality assessment, and PRISMA flow chart.

5. Figure 4 (lines 639-653) shows therapeutic targets but does not indicate which therapies are approved (tocilizumab, upadacitinib), which failed trials (secukinumab, mavrilimumab), or which are investigational. This is misleading for readers.

Author Response

We thank the reviewer for these constructive comments that have substantially improved the manuscript's scientific rigor and clarity.

Response to Reviewer 1 - Round 2

Comment 1: Knowledge Cutoff Date Clarification

Reviewer's Concern: The manuscript states a knowledge cutoff of "end of January 2025" (line in Methods) yet cites events from "early 2024" (mavrilimumab termination) and "2024" (secukinumab trial results, upadacitinib FDA approval in November 2024) as if they are historical. However, the current date referenced in the document is January 20, 2026. The authors must clarify the actual knowledge cutoff date and ensure all temporal references are internally consistent.

Response: 

We apologize for the confusion, but we cannot understand this question very well. In Methods, we mention that “The literature search was conducted through 2025”, but I cannot find January 2025 anywhere in the paper. To make the dates clearer, we have specified December 2025 in the Methods. We have corrected this in the Methods section to accurately reflect that our search encompassed publications "through December 2025," which is why 2024 events (mavrilimumab termination, secukinumab Phase III results, upadacitinib FDA approval in November 2024) are appropriately referenced as historical. All temporal references have been reviewed for internal consistency.

Comment 2: Critical Appraisal of Biologic Evidence Section

Reviewer's Concern: Three issues raised: (a) Secukinumab Phase III failure contradicts Phase II results, but authors still suggest IL-17 has promise; (b) Upadacitinib absolute benefit not adequately contextualized against tocilizumab; (c) Mavrilimumab development terminated but still prominently featured in Figure 4.

Response: We have substantially revised this section:

Secukinumab: We agree that Phase III failure contradicts Phase II results. We have revised the text to explicitly state that IL-17 inhibition does not appear to be an effective therapeutic target based on current evidence. The language suggesting ongoing 'promise' for IL-17 inhibition has been removed.

Upadacitinib: We have added direct comparative context showing tocilizumab's superior absolute benefit (42 percentage points) versus upadacitinib's more modest benefit (17 percentage points), which better contextualizes the relative effectiveness of these agents.

 

Mavrilimumab: We have added explanation of why mavrilimumab development was discontinued and have moved the detailed discussion of failed agents to a reorganized section with updated Figure 4 that clearly distinguishes FDA-approved from terminated agents (see Comment 5).

We have considered that adding a new subsection called “Lessons Learned from Failed Trials” is not necessary as we have added succinct comments and minimal edits.

Comment 3: ESR/CRP Sensitivity Data Inconsistency

Reviewer's Concern: ESR sensitivity of 76-84% and CRP sensitivity of 86-98% don't align with claim that normal markers occur in "4-20% with most studies reporting 7-10%." Also, Table 1 ACR 1990 criteria show "53-80% vs. non-vasculitic conditions" but original ACR validation did not test against non-vasculitic conditions.

Response:

ESR/CRP: The reviewer correctly identified this inconsistency. The 4-20% figure represents normal markers in biopsy-proven GCA (from references 71-72), which inherently represents a selected population enriched for atypical presentations. The 76-84% and 86-98% sensitivity figures are from general GCA populations. We have clarified that the 4-20% figure with normal inflammatory markers represents biopsy-proven GCA cases, which are enriched for atypical presentations. The higher sensitivities (76-84% for ESR, 86-98% for CRP) apply to general GCA populations. This distinction resolves the apparent inconsistency.

Table 1 ACR 1990: The reviewer is correct that the original Hunder et al. 1990 ACR validation study tested GCA against controls with other vasculitides only. The 53-80% specificity against non-vasculitic conditions comes from subsequent validation studies (references 118, 120). We have revised Table 1 to clarify: "93.5% (vs. other vasculitides, original validation); 53-80% (vs. non-vasculitic conditions, subsequent validation studies)." We also added a footnote to Table 1 clarifying the validation populations: the original ACR 1990 study tested against other vasculitides only, while the 53-80% figure against non-vasculitic conditions comes from subsequent validation studies (Wiberg et al. 2021; Marvisi et al. 2025)."

Comment 4: Methods Section Inadequacy

Reviewer's Concern: Methods section lacks explanation of how "prioritization" was operationalized, quality assessment framework, inclusion/exclusion criteria, and PRISMA flow chart.

Response: We respectfully emphasize that this is explicitly a narrative review, not a systematic review, as stated in the Methods section: "We emphasize that this is narrative and not a systematic review. Therefore, we did not conduct formal systematic quality assessments or meta-analysis..."

Narrative reviews, by design, do not employ the structured methodology, PRISMA compliance, or formal quality scoring required of systematic reviews. Instead, they synthesize current evidence using expert judgment to provide clinical perspective. Our "prioritization" refers to preferentially citing high-quality sources (randomized trials, systematic reviews, large cohorts, evidence-based guidelines) over lower-quality evidence when both are available, which is standard practice for narrative reviews.

However, to clarify our approach, we have added: ”'prioritization' means preferentially citing higher-quality evidence sources (RCTs, meta-analyses, systematic reviews) over lower-quality sources, which is standard for narrative reviews. We emphasized that narrative reviews do not employ the structured methodology, PRISMA compliance, or formal quality scoring required of systematic reviews."

Comment 5: Figure 4 Does Not Indicate Regulatory/Development Status

Reviewer's Concern: Figure 4 shows therapeutic targets but doesn't indicate which therapies are FDA-approved, which failed trials, or which are investigational.

Response: We have revised Figure 4 to include clear annotations for regulatory and development status:

• FDA-approved agents: Tocilizumab and upadacitinib are now marked with a green checkmark symbol and labeled "FDA-approved"
• Failed/terminated development: Secukinumab and mavrilimumab are now marked with a red X symbol and labeled "Phase III failed/development terminated"
• Investigational agents: Abatacept, ustekinumab, anakinra, and endothelin receptor antagonists are marked with a blue triangle and labeled "Investigational"

The figure legend has been updated accordingly to explain these symbols.

We thank the reviewer for these constructive comments that have substantially improved the manuscript's scientific rigor and clarity.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have successfully addressed all comments and suggestions raised during the previous review round. The manuscript has been substantially improved in terms of clarity, methodological transparency, and overall coherence. In its current form, the work represents a significant and meaningful contribution to the field. I have no further major comments and support its acceptance.

Author Response

Thanks very much for your thoughtful review.

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

The concerns have been adequately resolved.