# HIGH LEVEL SUMMARY --- ## Summary This case report describes a 77-year-old man with severe, refractory multisite mucous membrane pemphigoid (MMP) involving the oral mucosa, ocular surface (with symblepharon), suspected nasopharyngeal/upper-airway mucosa, and extensive cutaneous blistering, complicated by chronic obstructive pulmonary disease (COPD), acute weight loss, and a history of prostate cancer. The authors demonstrate that initiating off-label dupilumab (600 mg loading dose followed by 300 mg biweekly) alongside a scheduled 3-month prednisone taper resulted in rapid control of active mucocutaneous inflammation and pruritus, complete systemic glucocorticoid discontinuation at month 3, and 1 month of steroid-free maintenance remission on dupilumab monotherapy without progression of pre-existing cicatricial damage or serious adverse events. ## Strengths * The manuscript addresses a challenging clinical scenario—managing refractory, high-risk multisite MMP in a frail, elderly patient with cardiopulmonary comorbidities and prior malignancy—where standard-of-care broad immunosuppressants or B-cell-depleting biologics carry substantial risks of life-threatening infection and impaired oncologic surveillance. * While earlier reports of off-label dupilumab in multisite MMP required supplementary systemic glucocorticoids to control persistent oral and ocular lesions at 3 months, this report provides valuable clinical proof-of-concept that scheduled prednisone tapering paired with dupilumab can achieve complete systemic steroid withdrawal and maintain short-term remission across oral, ocular, and cutaneous sites. * The authors establish a rigorous clinicopathological justification for classifying the presentation as multisite MMP with extensive cutaneous involvement rather than classic bullous pemphigoid (BP), appropriately integrating disease chronology, multisite mucosal distribution, and objective cicatricial damage (symblepharon and nasal adhesions) alongside histopathological and direct immunofluorescence findings. * The report maintains a balanced and transparent perspective on the mechanistic rationale and clinical boundaries of IL-4/IL-13 blockade, clearly distinguishing between the arrest of active mucosal inflammation and the inability to reverse established fibrotic tissue damage. ## Weaknesses * The attribution of sustained clinical remission to dupilumab monotherapy is limited by the brief 1-month steroid-free observation window (month 3 to month 4) following 3 months of concomitant systemic prednisone and unspecified topical anti-inflammatory therapy, as well as the lack of serial biomarker reassessment (anti-BP180/BP230 titers, total IgE, and eosinophil counts) beyond month 1; the authors might consider clarifying the exact 1-month monotherapy duration in the Abstract and detailing the specific prednisone tapering and topical regimens. * The clinical evaluation relies on subjective symptom reporting and external photography without standardized objective disease activity scoring—specifically the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI)—or formal subspecialty staging such as slit-lamp ophthalmologic grading (e.g., Foster staging) and endoscopic nasopharyngolaryngoscopy, which is particularly important given that upper-airway MMP remained unverified endoscopically and dupilumab itself can paradoxically induce cicatrizing ocular surface disease (Reference Paper: European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology – Part II, Schmidt et al., 2021; Reference Paper: Dupilumab-associated cicatrizing ocular disease, Reddy et al., 2022). * Although the clinicopathological diagnosis of multisite MMP is well-supported, the immunological workup lacks extended antigen-specific serology (such as anti-laminin 332 ELISA, which is clinically relevant given the patient's upper-airway/ocular scarring and prior prostate cancer, and BP180 midportion/C-terminal epitope mapping), indirect immunofluorescence on salt-split skin, anatomical biopsy site provenance, and commercial ELISA platform/cutoff specifications. * The Discussion section would benefit from condensing the verbatim repetition of 1-month and 4-month laboratory results in favor of a deeper mechanistic analysis of the biomarker kinetics (explaining why rapid clinical resolution preceded substantial clearance of circulating IgG autoantibodies) and a broader contextual comparison of dupilumab against established steroid-sparing therapies for high-risk MMP, such as rituximab, intravenous immunoglobulin (IVIG), and omalizumab (Reference Paper: Rituximab therapy for mucous membrane pemphigoid: A retrospective monocentric study with long-term follow-up in 109 patients, Bohelay et al., 2022; Reference Paper: Biologic treatment outcomes in mucous membrane pemphigoid: A systematic review, Lytvyn et al., 2022; Reference Paper: Rapid disease control in first-line therapy-resistant mucous membrane pemphigoid and bullous pemphigoid with omalizumab as add-on therapy: A case series of 13 patients, Alexandre et al., 2022). ## Potential Issues And Suggestions ### [Abstract & Clinical Introduction] (Pages: 1-2) #### Potential Mistakes and Improvements - **Clarification of Follow-Up and Monotherapy Duration in the Abstract:** In the Abstract (Page 1, *Case presentation*), the text states that *"prednisone was discontinued after 3 months, and dupilumab monotherapy maintained remission without serious adverse events."* As detailed later in the *Therapeutic intervention and follow-up* (Page 3) and *Discussion* (Page 4) sections, the latest follow-up occurred at 4 months after treatment initiation, meaning the patient had been maintained on dupilumab monotherapy off systemic glucocorticoids for 1 month at the time of reporting. A potential concern is that readers consulting only the Abstract may infer a longer period of steroid-free maintenance remission. Specifying the total follow-up duration (4 months) and the duration of glucocorticoid-free monotherapy (1 month) directly in the Abstract would improve clinical clarity and align the Abstract with the study limitations discussed on Page 4. **Verification Summary:** * **Internal Consistency:** Aside from the follow-up duration detail noted above, the patient demographics (77-year-old man), clinical presentation (recurrent painful oral erosions, ocular symptoms, suspected nasopharyngeal/upper-airway involvement, and widespread cutaneous blisters), medical history (COPD, prior prostate cancer, and 7.5-kg acute weight loss), immunopathological findings (subepidermal blister, linear C3 and IgG along the basement membrane zone, and elevated BP180 and BP230 antibodies), and therapeutic timeline summarized in the Title, Abstract, and Introduction accurately match the detailed clinical data reported in the subsequent sections. * **Domain Accuracy & Scope:** The characterization of mucous membrane pemphigoid (MMP), its target autoantigens (BP180/collagen XVII, BP230, laminin 332, $\alpha6\beta4$ integrin, and type VII collagen), and standard-of-care systemic therapies aligns with current European (EADV S3) clinical practice guidelines. The manuscript appropriately distinguishes between the approved indication of dupilumab for adult bullous pemphigoid and its off-label application in scar-forming MMP, and clearly states the scope and limitations of the clinical findings regarding established cicatricial damage. #### Minor Corrections and Typos - **Page 1, Abstract (*Case presentation*, lines 13–15):** There is a comma splice in the sentence *"Pruritus and new blister formation rapidly decreased, erosions re-epithelialized, and oral symptoms, ocular dryness, and tearing improved, prednisone was discontinued after 3 months, and dupilumab monotherapy maintained remission without serious adverse events."* Consider replacing the comma before *"prednisone"* with a semicolon or splitting the clause into two sentences. ### [Case Presentation, Diagnostic Assessment, Therapeutic Course, and Clinical/Histological Figures] (Pages: 2-4) #### Potential Mistakes and Improvements * **Verification Summary:** The internal clinical timeline (a 2-year history of oral erosions and nasopharyngeal surgery with subsequent nasal adhesions, a 1-year history of ocular symptoms, and a 1-month generalized cutaneous flare), medication schedules (prednisone escalation from approximately $0.5\text{ mg/kg/day}$ to $1\text{ mg/kg/day}$ followed by a 3-month taper to discontinuation; 8 administrations of dupilumab over the 4-month follow-up via a $600\text{-mg}$ loading dose at week 0 followed by seven $300\text{-mg}$ biweekly maintenance doses at weeks 2, 4, 6, 8, 10, 12, and 14, while remaining off systemic glucocorticoids for 1 month after month-3 discontinuation), and quantitative laboratory biomarkers (baseline and 1-month follow-up values for anti-BP180, anti-BP230, anti-desmoglein 1 and 3, total serum IgE, and absolute eosinophil counts) are mathematically and internally consistent across the text and figures. Furthermore, the clinical photographs in `Figure 1` (including visible lower-fornix conjunctival adhesion/symblepharon in `Figures 1B` and `1F`) and the histopathological and direct immunofluorescence images in `Figure 2` align with their textual descriptions. However, several substantive areas regarding data provenance, assay parameters, diagnostic completeness, and therapeutic documentation warrant clarification. 1. **Missing Assay Specifications, Target Epitopes, and Positive Cutoff Thresholds for Serological Biomarkers (`Diagnostic assessment` and `Therapeutic intervention and follow-up`, Pages 2–3):** - **Potential Concern:** In the *Diagnostic assessment* and *Therapeutic intervention and follow-up* sections, serum autoantibody concentrations are reported in relative units per milliliter ($\text{RU/mL}$)—specifically baseline and 1-month follow-up levels for anti-BP180 ($35.83 \rightarrow 30.62\text{ RU/mL}$), anti-BP230 ($44.53 \rightarrow 42.17\text{ RU/mL}$), anti-desmoglein 1 ($47.77 \rightarrow 38.96\text{ RU/mL}$), and anti-desmoglein 3 ($26.64 \rightarrow 25.59\text{ RU/mL}$)—alongside total serum IgE ($125.62 \rightarrow 87.53\text{ IU/mL}$) and absolute eosinophil counts ($0.1 \times 10^9\text{/L}$). However, the text does not specify the commercial enzyme-linked immunosorbent assay (ELISA) manufacturer/platform, the targeted BP180 epitope domain (e.g., whether the assay detects only the immunodominant NC16A domain or includes midportion/C-terminal epitopes frequently targeted in mucous membrane pemphigoid [MMP]), the positive diagnostic cutoff thresholds (such as $\ge 20\text{ RU/mL}$ in standard commercial Euroimmun platforms), or the institutional reference intervals for total IgE and eosinophils. Because different commercial platforms use different positivity cutoffs, omitting these reference parameters makes it difficult for readers to independently gauge the magnitude of the elevations—particularly given that the baseline anti-desmoglein 1 titer ($47.77\text{ RU/mL}$) is numerically higher than both anti-BP180 ($35.83\text{ RU/mL}$) and anti-BP230 ($44.53\text{ RU/mL}$), yet is characterized as "mildly elevated" while anti-BP180 and anti-BP230 are described as "elevated." While the absence of acantholysis on histopathology and intercellular IgG deposition on direct immunofluorescence (`Figure 2`) validly excludes concomitant pemphigus, specifying the assay platform, target domains, and positive cutoff thresholds would improve data provenance and clarify that the 1-month titers (all $> 25\text{ RU/mL}$) likely represent persistent seropositivity (consistent with downstream Type 2 inflammatory blockade preceding autoantibody clearance) rather than seroreversion. - **Suggested Improvement:** Specify the commercial ELISA manufacturer/platform, target antigen domains, and institutional positivity cutoffs or reference ranges for all reported serological and hematological parameters. 2. **Unspecified Anatomical Biopsy Site and Omission of Indirect Immunofluorescence on Salt-Split Skin (`Diagnostic assessment`, Page 2; `Figure 2`, Page 4):** - **Potential Concern:** In the *Diagnostic assessment* section and `Figure 2`, the authors document a "subepidermal blister with inflammatory-cell infiltration" on hematoxylin and eosin (H&E) staining (`Figure 2A`) and linear C3 and IgG deposition along the basement membrane zone on direct immunofluorescence (DIF, `Figures 2B–C`). However, neither the text nor the `Figure 2` caption specifies the exact anatomical site(s) from which the lesional histopathological biopsy and perilesional DIF specimen were obtained (e.g., trunk skin versus oral mucosa, although the keratinized stratified squamous epithelium in `Figure 2A` indicates a cutaneous biopsy), nor whether IgA (or IgE) conjugate staining was included in the DIF panel (as linear IgA deposition is frequent in multisite MMP). Because mucosal and cutaneous biopsies differ in histological appearance and DIF sensitivity, explicitly documenting the biopsy location is important for tissue provenance. Additionally, while the authors transparently acknowledge that antigen-specific ELISAs for laminin 332, $\alpha6\beta4$ integrin, and type VII collagen were unavailable at their institution, the text does not state whether indirect immunofluorescence (IIF) on $1\text{ M}$ NaCl human salt-split skin was performed. Under the cited European S3 guidelines for MMP (References 3 and 8), IIF on salt-split skin is a primary diagnostic step when specialized target antigen assays are unavailable because it distinguishes epidermal-side (roof) autoantibody binding (typical of BP180, BP230, and $\alpha6\beta4$ integrin) from dermal-side (floor) binding (typical of laminin 332 and type VII collagen). Given the patient's remote history of prostate cancer and upper-airway/ocular scarring—clinical features associated with anti-laminin 332 MMP—clarifying whether salt-split skin IIF was performed or was similarly unavailable would strengthen the differential diagnostic workup. - **Suggested Improvement:** State the exact anatomical site(s) from which the H&E and DIF biopsies in `Figure 2` were obtained, clarify whether IgA staining was performed on DIF, and indicate whether IIF on salt-split skin was performed or unavailable. 3. **Incomplete Dosing Details for Prednisone Tapering, Baseline Body Weight, and Concomitant Topical Anti-Inflammatory Regimens (`Case presentation` and `Therapeutic intervention and follow-up`, Page 2):** - **Potential Concern:** A central clinical finding of this report is that dupilumab enabled complete glucocorticoid withdrawal by month 3 in a patient whose disease previously relapsed on oral prednisone at "approximately $0.5\text{ mg/kg/day}$" and progressed despite escalation to "approximately $1\text{ mg/kg/day}$." However, the manuscript reports prednisone dosing only as weight-based approximations without stating the patient's baseline body weight (noting only a $7.5\text{-kg}$ acute weight loss prior to admission and subsequent weight recovery by month 4) or the actual starting daily milligram dose and step-down tapering intervals over the 3-month period. Moreover, *Therapeutic intervention and follow-up* notes that supportive management included "topical anti-inflammatory therapy," without specifying the pharmacological identity, potency, frequency, duration, or anatomical application sites (cutaneous, oral, or ophthalmic) of these agents. Because high-potency topical corticosteroids or topical calcineurin inhibitors can independently induce rapid local re-epithelialization and symptom relief in pemphigoid-spectrum disorders, omitting the specific topical regimen (including whether topical immunomodulators were continued during the month 3–4 "dupilumab monotherapy" phase) and absolute systemic steroid doses introduces a potential confounder when evaluating the 1-month clinical improvement (`Figures 1E–H`) and the independent steroid-sparing contribution of dupilumab. - **Suggested Improvement:** Provide the patient's baseline body weight (or absolute daily prednisone dose in $\text{mg/day}$), outline the 3-month prednisone tapering schedule, and specify the exact agents, potencies, duration, and target sites used for concomitant topical anti-inflammatory therapy. --- #### Minor Corrections and Typos * **Page 2, Right Column, last line (`Therapeutic intervention and follow-up`):** Missing space between `"were"` and `"30.62"` in `"anti-desmoglein 3 antibody levels were30.62, 42.17,"` $\rightarrow$ change to `"anti-desmoglein 3 antibody levels were 30.62, 42.17,"`. * **Page 2, Right Column, line 18 (`Diagnostic assessment`):** Inconsistent typography for integrin subunit notation: `"alpha6beta4 integrin"` is spelled out in Latin characters here, whereas Greek letters (`"α6β4 integrin"`) are used earlier on Page 2 (Left Column, line 14). Standardizing to `"α6β4 integrin"` is recommended. * **Page 2, Right Column, line 15 (`Diagnostic assessment`) and Page 3, Left Column, line 6 (`Therapeutic intervention and follow-up`):** The exponential notation for the absolute eosinophil count uses a plain-text caret (`"0.1 × 10^9/L"`) instead of superscript formatting (`"0.1 × 10⁹/L"`). * **Page 4, `Figure 2`:** The photomicrographs in panels **A**, **B**, and **C** lack internal scale bars or original objective magnification values (e.g., $\times 100$, $\times 200$) in the figure caption. ### [Clinical Discussion, Mechanistic Rationale, and Study Limitations] (Pages: 4-5) #### Potential Mistakes and Improvements 1. **Unverified Upper-Airway Response and Absence of Objective Subspecialty Staging Frameworks (`Case presentation` and `Diagnostic assessment`, Page 2; `Therapeutic intervention and follow-up` and `Discussion`, Pages 2–5):** - **Potential Concern:** Suspected scar-forming nasopharyngeal/upper-airway involvement (nasal adhesions following prior surgery, breathing discomfort, and hoarseness) and cicatricial ocular involvement (symblepharon) are cited as key clinical criteria favoring multisite MMP over bullous pemphigoid, and in the third paragraph of the `Discussion` (page 4, right column), the authors state that *"oral, ocular, suspected upper-airway, and extensive cutaneous disease improved during combined prednisone and dupilumab therapy."* However, neither the `Case presentation`, `Diagnostic assessment`, `Therapeutic intervention and follow-up`, nor the `Discussion` reports the histopathology or specific nature of the prior nasopharyngeal surgery, any baseline or follow-up otolaryngologic/endoscopic evaluation (e.g., flexible nasopharyngolaryngoscopy to evaluate for active laryngeal/nasopharyngeal erosions or stenosis), or specific post-treatment respiratory/phonatory outcomes (specifically whether the baseline breathing discomfort, hoarseness, or nasal adhesions improved or merely remained stable in a patient with comorbid chronic obstructive pulmonary disease). Because laryngeal and nasopharyngeal mucous membrane pemphigoid (MMP) falls into the high-risk category under the cited European S3 guidelines (References 3 and 4) due to the risk of occult, progressive airway stenosis even when subjective symptoms improve, claiming therapeutic improvement in upper-airway disease without objective verification is a potential concern. Similarly, while the `Discussion` concludes that *"no further progression [of symblepharon] was observed during the 4-month follow-up"* and highlights the need for ocular monitoring due to both ocular MMP and dupilumab-associated ocular surface disease (References 11 and 19), ocular assessment across the report is limited to qualitative symptom reporting (dryness, tearing) and external photography (`Figures 1B, 1F`) without noting whether formal ophthalmologic slit-lamp staging (e.g., visual acuity, measurement of inferior fornix foreshortening, or Foster/Mondino staging) was performed during the "multidisciplinary monitoring." Finally, while the authors note *"the short follow-up"* and *"the absence of standardized MMP disease activity scoring"* as limitations, the patient had been off systemic glucocorticoids for only 1 month (within a 4-month total observation period); because MMP flares frequently recur several months after steroid withdrawal, a 1-month steroid-free interval demonstrates initial feasibility of glucocorticoid discontinuation rather than durable monotherapy remission. - **Suggested Improvement:** Explicitly report the post-treatment clinical evolution of the patient's upper-airway symptoms (hoarseness and breathing discomfort) in `Therapeutic intervention and follow-up` and clarify in the `Discussion` what specific clinical observations support the statement that suspected upper-airway disease improved (or temper the claim if upper-airway symptoms and nasal adhesions were not formally re-evaluated). Furthermore, clarify whether endoscopic otolaryngological evaluation and formal ophthalmological slit-lamp staging were performed at baseline and follow-up, and when discussing *"the absence of standardized MMP disease activity scoring"* and short follow-up as limitations (page 4, right column), explicitly reference the international consensus **Mucous Membrane Pemphigoid Disease Area Index (`MMPDAI`)**—which separately quantifies active mucosal/cutaneous inflammation versus chronic post-inflammatory scarring across individual anatomical sites—and note the absence of serial nasopharyngolaryngoscopy, quantitative ophthalmologic staging, and post-withdrawal observation beyond 1 month of dupilumab monotherapy as specific limitations of the clinical follow-up. 2. **Verbatim Repetition of Follow-Up Data Instead of Mechanistic Interpretation of Biomarker Kinetics (Page 4, Paragraph 4):** - **Potential Concern:** In the fourth paragraph of the `Discussion` (page 4, right column), a 160-word passage—spanning from *"At the 1-month follow-up, pruritus and new blister formation had markedly decreased..."* through *"...immediate hypersensitivity reaction, or other serious adverse event had occurred"*—repeats almost verbatim the clinical narrative, dosing counts, and exact laboratory values already reported in the `Therapeutic intervention and follow-up` section (pages 2–4). Beyond textual redundancy, restating the raw baseline and 1-month autoantibody titers (`35.83`, `44.53`, `47.77`, and `26.64 RU/mL` vs. `30.62`, `42.17`, `38.96`, and `25.59 RU/mL`), total serum IgE (`125.62` to `87.53 IU/mL`), and absolute eosinophil count (`0.1 × 10^9/L`) in full misses an opportunity to critically analyze two notable patterns in the reported biomarker profile: 1. Rapid clinical resolution at month 1 (markedly reduced blistering, pruritus cessation, and re-epithelialization of erosions) occurred alongside only minimal reductions in circulating IgG autoantibody titers (anti-BP180 declining by ~14.5% and anti-BP230 by ~5.3%). 2. Although the `Discussion` cites eosinophilic inflammation and linear tissue-bound IgE as key biological rationales for IL-4/IL-13 blockade, the patient's baseline peripheral absolute eosinophil count was normal (`0.1 × 10^9/L`), baseline total serum IgE was only mildly elevated (`125.62 IU/mL`), and IgE was not assessed on direct immunofluorescence. - **Suggested Improvement:** Condense the verbatim recitation of the 1-month and 4-month numerical results in the `Discussion` and replace it with a focused mechanistic interpretation of these biomarker kinetics. Specifically, discuss how early clinical improvement under combined IL-4R$\alpha$ blockade and systemic prednisone can precede substantial clearance of circulating IgG autoantibodies due to rapid downstream suppression of local tissue type 2 cytokine signaling, neuroimmune pruritus pathways, and effector-cell/fibroblast recruitment rather than immediate depletion of autoreactive plasma cells, and note that baseline peripheral eosinophil counts were likely suppressed by chronic pre-admission systemic glucocorticoid exposure (`0.5–1 mg/kg/day`). *Verification Summary:* The justification for classifying the presentation as multisite MMP with extensive cutaneous involvement rather than bullous pemphigoid (based on European S3 consensus criteria, disease chronology, multisite mucosal distribution, and objective nasal/ocular scarring), the transparent acknowledgment of unavailable anti-laminin 332 serology in the context of prior prostate cancer, the caveat regarding confounding from concomitant systemic prednisone during the first 3 months, and the synthesis of prior literature on dupilumab in MMP and Brunsting-Perry pemphigoid are clinically balanced and well-supported. #### Minor Corrections and Typos None. ### [Declarations, Ethics Statement, and References] (Pages: 5-6) #### Potential Mistakes and Improvements No significant issues found. The declarations—including the Ethics statement documenting institutional review board approval and written informed consent for both study participation and the publication of potentially identifiable facial/ocular clinical photographs—as well as the data availability, author contributions, funding, conflict of interest, generative AI disclosures, and references on pages 5–6 are complete and consistent with the main text. #### Minor Corrections and Typos * **Page 5, References (References 3, 4, and 7):** *"European academy of dermatology and venereology"* should be capitalized as *"European Academy of Dermatology and Venereology"* for consistency with proper noun formatting in academic citations. * **Page 5, Reference 11:** As an electronic regulatory prescribing document, the citation for the U.S. Food and Drug Administration prescribing information (`DUPIXENT (Dupilumab) Injection, for Subcutaneous Use: Prescribing Information`, 2025) includes an access date ("Accessed June 16, 2026") but omits a direct URL or DailyMed/FDA document identifier. Adding the URL or regulatory application number (BLA 761055) would improve bibliographic completeness. * **Page 6, Reference 16:** The fourth author's surname is spelled "Wirthmuller" without the umlaut ("Wirthmüller" in the original publication). * **Page 6, Reference 17:** The first author's initials are listed as "Saw VPJ," whereas the standard citation format for this article is "Saw VP."