Abstract
Bullous pemphigoid (BP) is the most common autoimmune blistering disease affecting the skin. It is characterized by a type 2 immune-mediated pathogenesis. BP predominantly affects elderly patients who have multiple comorbidities, and treatment can be particularly challenging in refractory cases or when standard immunosuppressive therapies are limited due to toxicity or contraindications. Here, we present a case series of five patients with confirmed BP who were treated with off-label dupilumab. All five patients achieved sustained clinical improvement with dupilumab treatment, including reductions in disease activity and pruritus. No severe adverse events were reported, except for one case of manageable conjunctivitis. Dupilumab was well tolerated and resulted in marked clinical benefit in all five BP patients included in this case series. These findings support the growing evidence for dupilumab’s potential role as a safe and effective treatment option for BP. Further long-term clinical trials are needed to assess its disease-modifying potential.
1 Introduction
Bullous pemphigoid (BP) is the most prevalent autoimmune blistering disease affecting the skin (1, 2). It is characterized by a type 2 immune-mediated pathogenesis (3). Here, we present a case series of five patients with BP who were either unresponsive to standard therapy, experienced unacceptable adverse effects, or could not receive conventional immunosuppressive treatment due to toxicity or contraindications. All patients were subsequently treated with off-label dupilumab, a monoclonal anti-IL-4-receptor-alpha chain-specific IgG4 antibody blocking the signaling of IL-4 and IL-13 (Table 1).
Table 1
| Pat. no. | Sex (age) | Pre-existing conditions | Previous systemic therapies | Outcome under dupilumab treatment |
|---|---|---|---|---|
| 1 | Male (80s) | Melanoma stage IV Arterial hypertension Atrial fibrillation Chronic venous insufficiency BPH Hypothyroidism |
GCS Dapsone Doxycycline |
Rapid improvement IGA 2 to IGA 0 after 5 months |
| 2 | Male (80s) | History of bladder carcinoma Arterial hypertension BPH |
GCS AZA Doxycycline |
Rapid improvement IGA 3 to IGA 0 after 4 months |
| 3 | Female (90s) | Arterial hypertension Chronic kidney disease Chronic anemia Intraspinal empyema |
GCS Dapsone AZA Doxycycline |
Rapid improvement, rare appearance of blisters IGA 2 to IGA 1 after 2 months |
| 4 | Male (70s) | HIV Arterial hypertension Coronary heart disease Chronic kidney disease DM type II Polyneuropathy BPH |
Dapsone | Rapid improvement IGA 2 to IGA 0 after 6 months |
| 5 | Male (70s) | Gynecomastia | GCS Dapsone AZA Doxycycline |
Rapid improvement IGA 2 to IGA 0 after 13 months 3 months after dupilumab termination still IGA 0 |
Patient profiles and outcomes following treatment with dupilumab.
BPH = benign prostatic hyperplasia, GCS = glucocorticosteroids, AZA = azathioprine, IGA0 = no symptoms, IGA1 = pruritus, no blistering, IGA2 = few blistering, IGA3 = moderate blistering, IGA4 = severe blistering (75% body surface), IGA5 = maximal affected skin.
2 Description of cases
Patient 1 was diagnosed with BP after receiving 12 cycles of pembrolizumab for stage IV malignant melanoma (AJCC classification; diagnosis in 2017; BP onset in 2022). With stable malignant disease, pembrolizumab was paused, and systemic treatment for BP was initiated with dapsone at a dosage of 100 mg daily in addition to topical clobetasol. Due to further progression of BP, oral prednisolone was introduced (initially 40 mg, which was tapered to 5 mg daily) in combination with doxycycline at a dosage of 200 mg daily. After an intermediate clinical response, new blisters appeared. Given the contraindication to immunosuppressants due to the patient’s history of melanoma, an off-label request for dupilumab treatment was submitted to the health insurance provider. In the interim, disease control was maintained with dexamethasone pulse therapy until insurance authorization for dupilumab was granted. Then, dexamethasone pulse therapy was stopped, and dupilumab was subsequently administered following the dosing regimen approved for atopic dermatitis. The patient’s skin condition remained stable, pruritus decreased, and no further blistering was observed within 5 months (IGA score improved from 2 to 0 after 5 months, Table 1).
Similarly, the skin conditions of patients 2 and 3 remained uncontrolled despite multiple therapeutic attempts, all of which had to be discontinued due to either insufficient efficacy or intolerable side effects. Following off-label treatment with dupilumab, both patients experienced sustained clinical improvement: Patient 2 improved from an IGA score of 3 to 0 within 4 months and patient 3 improved from an IGA score of 2 to 1 within 2 months of treatment (Table 1). In patients 4 and 5, due to insufficient response to conventional therapy with dapsone 100 mg or azathioprine 50 mg, an add-on treatment with dupilumab was initiated after receiving off-label authorization. The skin conditions of both patients improved significantly: Patient 4 improved from an IGA score of 2 to 0 after 6 months and patient 5 improved from an IGA score of 2 to 0 after 13 months, at which point azathioprine had been successfully discontinued without any reported exacerbations. All five patients tolerated dupilumab therapy well. Only patient 5 developed recurrent conjunctivitis during treatment with dupilumab. After discontinuing dupilumab, the patient’s ocular symptoms improved, and clinical BP remission was maintained for several months, accompanied by serological conversion to a negative autoantibody status. Table 2 summarizes prior therapies and reasons for changes in the therapy regimen for patients 2–5.
Table 2
| Patient no. | Prior therapies before dupilumab (duration in months) | Reason for therapy regimen changes |
|---|---|---|
| 2 | Azathioprine (N/A) | Insufficient response |
| Doxycycline (N/A) | Insufficient response | |
| Dexamethasone pulse (1) | No persistent improvement | |
| Doxycycline + prednisolone 15 mg – 5 mg (6) | Insufficient response | |
| 3 | Prednisolone (1) | No persistent improvement |
| Dexamethasone pulse (2) | No persistent improvement | |
| Dapsone (1) | Insufficient response | |
| Dexamethasone pulse (1) | No persistent improvement | |
| Dapsone + Azathioprine (1) | Insufficient response | |
| Dexamethasone pulse (2) | No persistent improvement | |
| Doxycycline (1) | Intolerance | |
| 4 | Dapsone (1) | Insufficient response |
| 5 | Dapsone (N/A) | Insufficient response |
| Doxycycline (N/A) | Insufficient response | |
| Prednisolone (N/A) | No persistent improvement | |
| Dapsone (11) | Secondary loss of efficacy | |
| Azathioprine (4) | Insufficient response |
Prior therapies and reasons for therapy regimen changes in patients 2–5.
N/A = Not available.
4 Diagnostic assessment
All five patients met the classical diagnostic criteria for BP, including the clinical appearance of subepidermal blistering, linear deposition of autoantibodies along the basement membrane zone on direct immunofluorescence, and the presence of circulating autoantibodies against BP180 and/or BP230. In addition to cutaneous manifestations, patients 2 and 3 also presented with mucosal lesions, which similarly showed a good clinical response to dupilumab.
Dupilumab was administered following the atopic dermatitis regimen, with an initial dose of 600 mg subcutaneously, followed by 300 mg every 2 weeks.
5 Follow-up and outcomes
All five patients presented in this case series demonstrated sustained improvement in skin lesions and pruritus when treated with dupilumab. No re-hospitalizations were reported. The only notable adverse event was mild recurrent conjunctivitis in one patient, which resolved after discontinuation of dupilumab. Remission was maintained in that patient for several months without treatment.
Table 3 summarizes the concentrations of BP180 and BP230 antibodies at the time of BP diagnosis, before the initiation of dupilumab, and following the onset of treatment. In patients 2 and 5, a clear reduction in antibody concentrations was observed after commencing dupilumab. Patients 1 and 3 demonstrated an increase in antibody concentrations after treatment initiation despite showing good clinical responses. However, in patient 1, a gradual downward trend in antibody concentrations was observed over time. Patient 4 exhibited persistently negative results both at diagnosis and during dupilumab therapy.
Table 3
| Patient no. | Antibody concentration at diagnosis | Antibody concentration before the initiation of dupilumab | Antibody concentration after dupilumab treatment (no. of months after dupilumab treatment) |
|---|---|---|---|
| 1 | BP180: 14 U/mL* BP230: 0 U/ml* |
BP180: 50 U/mL* BP230: 0 U/mL* |
BP180: 432 U/mL* (4), 160 U/mL# (7) BP230: 0 U/mL* (4), 0 U/mL* (7) |
| 2 | BP180: 218 U/mL* BP230: 35 U/mL* |
BP180: N/A BP230: N/A |
BP180: 35 U/ml# (15) BP230: 14 U/mL# (15) |
| 3 | BP180: 23 U/mL* BP230: 50 U/mL* |
BP180: 46 U/mL* BP230: 38 U/mL* |
BP180: 102 U/mL# (8), 22 U/mL# (17) BP230: <20 U/ml# (8), <20 U/ml# (17) |
| 4 | BP180: <9 U/ml* BP230: <9 U/ml* Split skin: positive |
BP180: <9 U/mL* BP230: <9 U/mL* |
BP180: <9 U/mL* (12) BP230: <9 U/mL* (12) |
| 5 | BP180: positive immunoblot BP230: negative immunoblot |
BP180: positive immunoblot BP230: negative immunoblot |
BP180: negative immunoblot (1) BP230: negative immunoblot (1) |
BP180 and BP230 antibody serum concentrations at the time of BP diagnosis, before the initiation of dupilumab, and after treatment with dupilumab.
* = Positive ≥ 9 U/mL. # = Positive ≥ 20 U/mL. N/A = Not available.
6 Discussion
This case series of real-world data from the University Hospital Schleswig-Holstein, Campus Kiel, shows both the efficacy and tolerability of dupilumab in five patients with difficult-to-treat BP. BP predominantly affects individuals over the age of 70, an age at which comorbidities commonly manifest and may limit the effectiveness and tolerability of conventional therapies, particularly when higher treatment doses are necessary. This is well recognized for systemic glucocorticoids, particularly with respect to hyperglycemia and/or hypertension, as also observed in our patient group. Furthermore, hematological, organ-specific (most commonly renal), or malignant pre-existing conditions may restrict the use of immunosuppressive agents such as azathioprine, mycophenolate mofetil, or rituximab. Particularly relevant in BP is the intolerance to dapsone, which is often insufficiently effective at low doses (<50 mg/day), while higher doses (>100 mg/day) may lead to reduced physical performance due to anemia and/or increased methemoglobin levels; this was observed in nearly all patients in our case series. In addition, gastrointestinal adverse effects associated with doxycycline, especially in the context of polypharmacy, may result in treatment discontinuation.
Our data support previously published case series and retrospective studies, primarily from the United States and Asia, suggesting the efficacy of dupilumab in the treatment of BP (4–6). We also investigated the evolution of BP180 and BP230 antibody concentrations, which have previously been shown to correlate well with disease severity (7), before and during dupilumab treatment. In some patients, we observed heterogeneous outcomes, which may be explained by differences in epitope specificity and IgG subclasses, as described in pemphigus previously (8). The exact mechanism by which dupilumab affects BP activity is not fully understood. However, recent research has demonstrated that dupilumab exerts effects on both immune cells and skin cells directly (9, 10). In the reported patients, the therapeutic response to dupilumab has remained sustained to date. None of the five patients were readmitted to the hospital. Whether dupilumab exerts a disease-modifying effect must be investigated in long-term, placebo-controlled clinical trials.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics statement
The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individuals for the publication of the data in this article.
Author contributions
YM: Writing – review & editing, Writing – original draft. RA: Writing – review & editing, Data curation. BW: Writing – review & editing, Data curation. CMH: Writing – review & editing, Conceptualization. SG: Conceptualization, Writing – review & editing. GH: Funding acquisition, Writing – review & editing, Formal analysis, Supervision, Conceptualization.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, grant #454193335 – SFB 1526-A02 and -S01 to GH and grant #454193335 – SFB 1526-A05 to CMH).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that Generative AI was not used in the creation of this manuscript.
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References
1.
van Beek N Weidinger A Schneider SW Kleinheinz A Glaser R Holtsche MM et al . Incidence of pemphigoid diseases in northern Germany in 2016 – first data from the Schleswig-Holstein registry of autoimmune bullous diseases. J Eur Acad Dermatol Venereol. (2021) 35:1197–202. doi: 10.1111/jdv.17107,
2.
Hammers CM Stanley JR . Mechanisms of disease: pemphigus and bullous pemphigoid. Annu Rev Pathol. (2016) 11:175–97. doi: 10.1146/annurev-pathol-012615-044313,
3.
Zhang L Chen Z Wang L Luo X . Bullous pemphigoid: the role of type 2 inflammation in its pathogenesis and the prospect of targeted therapy. Front Immunol. (2023) 14:1115083. doi: 10.3389/fimmu.2023.1115083,
4.
Murrell DF Joly P Werth VP Ujiie H Worm M Mangold AR et al . Study design of a phase 2/3 randomized controlled trial of dupilumab in adults with bullous pemphigoid: LIBERTY-BP ADEPT. Adv Ther. (2024) 41:2991–3002. doi: 10.1007/s12325-024-02810-3,
5.
Planella-Fontanillas N Bosch-Amate X Jiménez Antón A Moreno-VÃlchez C Guerrero MG Blanes MartÃnez MDM et al . Real-world evaluation of the effectiveness and safety of dupilumab in bullous pemphigoid: an ambispective multicentre case series. Br J Dermatol. (2024) 192:501–9. doi: 10.1093/bjd/ljae403,
6.
Zhang Y Xu Q Chen L Chen J Zhang J Zou Y et al . Efficacy and safety of dupilumab in moderate-to-severe bullous pemphigoid. Front Immunol. (2021) 12:738907. doi: 10.3389/fimmu.2021.738907,
7.
Schmidt E Obe K Bröcker EB Zillikens D . Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid. Arch Dermatol. (2000) 136:174–8. doi: 10.1001/archderm.136.2.174,
8.
Golinski ML Lemieux A Maho-Vaillant M Barray M Drouot L Schapman D et al . The diversity of serum anti-DSG3 IgG subclasses has a major impact on pemphigus activity and is predictive of relapses after treatment with rituximab. Front Immunol. (2022) 13:849790. doi: 10.3389/fimmu.2022.849790,
9.
Werth VP Murrell DF Joly P Heck H Orengo JM Ardeleanu M et al . Pathophysiology of bullous pemphigoid: role of type 2 inflammation and emerging treatment strategies (narrative review). Adv Ther. (2024) 41:4418–32. doi: 10.1007/s12325-024-02992-w,
10.
Toh WH Lee HE Chen CB . Targeting type 2 inflammation in bullous pemphigoid: current and emerging therapeutic approaches. Front Med. (2023) 10:1196946. doi: 10.3389/fmed.2023.1196946,
Summary
Keywords
autoimmune blistering disease, biologic therapy, bullous pemphigoid, dupilumab, elderly patients, pruritus, refractory disease
Citation
Mehrjerdian Y, Atallah R, Wijaya B, Hammers CM, Gerdes S and Heine G (2026) Case Report: Dupilumab in difficult-to-treat bullous pemphigoid at the University Hospital Schleswig-Holstein, Campus Kiel. Front. Med. 12:1697048. doi: 10.3389/fmed.2025.1697048
Received
01 September 2025
Revised
17 December 2025
Accepted
22 December 2025
Published
23 January 2026
Volume
12 - 2025
Edited by
Xuming Mao, University of Pennsylvania, United States
Reviewed by
Li Li, Peking Union Medical College Hospital (CAMS), China
Huijie Yuan, Westlake University, China
Updates
Copyright
© 2026 Mehrjerdian, Atallah, Wijaya, Hammers, Gerdes and Heine.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: G. Heine, gheine@dermatology.uni-kiel.de
†These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.