Effective response to high-frequency and prolonged dupilumab therapy in severe refractory bullous pemphigoid: A case study

ABSTRACT

Bullous pemphigoid (BP) is an autoimmune blistering disorder primarily affecting elderly individuals, with its incidence increasing with age. Standard treatments, such as glucocorticoids and immunosuppressive agents, are generally effective but often associated with notable side effects. More importantly, during the tapering phase of corticosteroid treatment, recurrence of erythema and blisters is common. There is growing demand for alternative or adjunctive therapies with fewer adverse effects and a low recurrence rate. Dupilumab, a humanized monoclonal IgG4 antibody targeting interleukin-4 (IL)-4 and IL-13 signaling, has shown efficacy in atopic dermatitis and asthma and has more recently been explored for its potential in bullous diseases. We present a case of a 65-year-old woman with BP who had an inadequate response to the conventional therapies. After the initiation of dupilumab, her skin lesions significantly improved, allowing corticosteroid use to be reduced. This case highlights both the short-term efficacy and long-term stability of dupilumab in managing severe refractory BP. As an adjunctive therapy, dupilumab may offer promising benefits in the treatment of refractory BP cases.

Introduction

Bullous pemphigoid (BP) is an autoimmune blistering disease that predominantly affects elderly individuals, with its incidence rising sharply with age. In patients with BP, autoantibodies target two hemidesmosomal proteins: transmembrane collagen XVII (BP180) and the plakin family protein BP230. The 16th non-collagenous domain (NC16A) of BP180 serves as the immunodominant region, containing the primary epitopes recognized by these autoantibodies.^1,2 Moreover, research has shown that type 2 cytokines, such as interleukin (IL)-4 and IL-13, are involved in the pathogenesis of BP.^3,4 As indicated in previous research, significantly higher levels of IL-4- and IL-13-producing cells were found in the peripheral blood of patients with BP compared to healthy controls, with the majority of these type 2 cells positive for cutaneous lymphocyte-associated antigen (CLA). Furthermore, corticosteroid treatment reduced the frequency of IL-13-producing cells in these patients.⁵ Recent advancements in immunology have introduced new therapeutic targets, offering the potential for more effective and safer treatment options for BP. Dupilumab, a fully humanized monoclonal antibody, targets the IL-4 receptor alpha (IL-4 Rα), a receptor subunit shared by the type 2 cytokines IL-4 and IL-13, which play critical roles in the pathogenesis of atopic dermatitis (AD).⁶ In addition to its proven efficacy in treating moderate-to-severe AD, recent studies have reported dupilumab to be effective in managing BP, suggesting it could be a beneficial treatment option for patients with BP. Here, we present a case demonstrating successful treatment of severe, refractory BP with dupilumab.

Case report

A 65-year-old woman presented with a 10-day history of relapsing widespread erythema, blisters, and intense pruritus. She was not taking any medications suspected of causing the rash. Prior treatments, including high-potency topical corticosteroids (TCS), antihistamines, and sodium thiosulfate, had failed to control her symptoms. She had a history of eczema that had resolved two years ago. On examination, she displayed generalized scaly erythroderma with blisters (Figure 1a). A skin biopsy revealed spongiosis with focal epidermal vesicle formation and a superficial dermal perivascular infiltrate composed of eosinophils and lymphocytes (Figure 1d). Direct immunofluorescence showed linear IgG and C3 deposition at the dermal-epidermal junction (Figure 1e), consistent with a diagnosis of bullous pemphigoid. The enzyme-linked immunosorbent assay (ELISA) for BP180 was positive (176 RU/mL; normal range <20 RU/mL). Blood tests showed a slight increase in eosinophil count (0.7 × 10⁹/L; normal range 0.02–0.52 × 10⁹/L) and a markedly elevated serum IgE level (743 kU/L; normal range <165 kU/L). The diagnosis of bullous pemphigoid (BP) was confirmed.

Figure 1.

Clinical and histopathological findings for the patient. (a) Clinical photograph at the time of hospital admission. (b) Clinical photograph taken during the treatment course, before dupilumab was give. (c) Clinical photograph taken at the 3-week follow-up. (d) Histopathological image showing spongiosis with focal epidermal vesicle formation. (e) Direct immunofluorescence microscopy showing linear C3 deposition at the dermal-epidermal junction.

The patient’s Bullous Pemphigoid Disease Area Index (BPDAI) activity score was assessed using the BPDAI skin erosions/blisters subscale (range: 0–120). The baseline BPDAI score was 35 on day 0 (Figure 1a), which increased to 77 after 3 days of treatment with intravenous methylprednisolone (80 mg daily, 1.5 mg/kg/day) (day 3, Figure 1b). Despite initial treatment, the patient continued to experience intense pruritus and pain, leading to significant sleep disturbances. On day 6, we started intravenous immunoglobulin (IVIG) therapy at 20 g/day for 5 days. Unfortunately, the combined regimen of methylprednisolone and IVIG failed to prevent disease relapse. To achieve faster control of the rapidly progressing blister formation and severe pruritus, we additionally administered cyclophosphamide (400 mg every other day for two doses). Nevertheless, the patient’s condition remained refractory, with new blister development exceeding 100 lesions daily, persistent pruritus, and ongoing sleep deprivation that profoundly impacted her quality of life.

Given the severity of her disease and lack of response to multiple treatment regimens, the immunomodulatory agent dupilumab was introduced. An initial loading dose of 600 mg was administered subcutaneously on day 14. By the second day after dupilumab initiation, no new blisters emerged, and her pruritus score on the Visual Analog Scale (VAS) improved from 9 to 2 out of 10 (Figure 2b). However, after a brief period of improvement, new blisters recurred when methylprednisolone was reduced to 60 mg daily. A maintenance dose of dupilumab (300 mg) was administered weekly thereafter, stabilizing the BPDAI score below 10 (Figure 2b). To achieve complete disease control, IVIG (20 g/day for 5 days) was reintroduced on day 26 as adjunctive therapy. Methylprednisolone was tapered weekly (e.g., 60 mg to 40 mg) without disease rebound. The timeline of medication modification is summarized in Figure 2a, along with clinical photographs documenting treatment progression.

Figure 2.

Medication regimen and trends in clinical and laboratory parameters. (a) Timeline of medication use, including methylprednisolone, IVIG, CTX, and dupilumab, accompanied by clinical photographs. (b) Changes in BPDAI score, VAS score, IgE levels, and eosinophil counts throughout the treatment period.

Upon discharge from the hospital, the patient’s methylprednisolone dose was reduced to 40 mg per day orally. Outpatient treatment continued with weekly subcutaneous dupilumab (300 mg) and a gradual reduction of methylprednisolone by 4 mg per week. After three weeks of combined treatment with dupilumab and corticosteroids, the patient achieved clinical remission (Figure 1c). BP180 ELISA levels significantly decreased to 57.0 RU/mL, with a notable reduction in serum IgE levels and blood eosinophil counts (Figure 2b). During the final phase of glucocorticoid therapy, methylprednisolone was tapered to 4 mg per day and maintained with weekly dupilumab injections for three months. With no recurrence of erythema or blisters, methylprednisolone was discontinued, and the intervals of dupilumab administration were progressively extended: every two weeks for ten months, every four weeks for two months, and finally every eight weeks for six months. All treatments were ultimately discontinued. Over a two-year follow-up, the patient remained symptom-free without relapse or treatment-related adverse effects.

Discussion

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by tense bullae and intense pruritus, which impacts patients’ quality of life. Almost all patients with BP experience severe pruritus, often leading to sleep disturbances and psychological distress. The pathogenesis of BP remains unclear; however, BP180 and BP230 are two key antigens involved in blister formation.^7–9 Recent studies have identified elevated levels of Th2-associated cytokines, particularly IL-4 and IL-13, in blister fluid and skin biopsies from patients with BP.¹⁰

The treatment of BP can be challenging. First-line therapies, such as systemic glucocorticoids and broad-spectrum immunosuppressants, achieve disease control in most patients; however, long-term high-dose glucocorticoid regimens carry a high risk of adverse effects, including osteoporosis, diabetes, and infections – particularly in older adults with preexisting comorbidities. Furthermore, refractory BP exhibits resistance to both glucocorticoids and conventional immunosuppressants, with relapse rates reported between 27.9% and 53%, predominantly within 6 months of treatment withdrawal.¹¹ This underscores the urgent need for targeted therapies with improved safety profiles and sustained efficacy.

In recent years, biologic agents have emerged as safer and more effective treatments for refractory BP.¹² Dupilumab, an IgG4 human monoclonal antibody, targets IL-4 Rα, inhibiting the signaling of both IL-4 and IL-13, thus downregulating Th2-driven inflammation. Dupilumab has revolutionized the treatment of Th2-mediated conditions such as atopic dermatitis (AD) and asthma and potentially other allergic conditions.¹³ Several large multicenter case series and retrospective studies have confirmed the efficacy and safety of dupilumab in moderate-to-severe BP cases, particularly in combination with other therapies.^14,15 IL-31 is another Th2 cytokine that induces severe pruritus and inflammation, with high levels observed in BP blister fluid. However, nemolizumab, a humanized monoclonal antibody against the IL-31 receptor A, did not suppress BP symptoms, as reported in a case study.¹⁶ It may be due to that IL-31, as the downstream of the pathogenesis, the inhibition of whose receptor may lead to a compensatory increase in Th2 cell-produced cytokines (IL-4/13, IL-5, etc.). In this case, dupilumab finally prevented the relapse of BP symptoms. This highlights IL-4/13‘s central role in BP pathogenesis.

To assess disease severity, the Bullous Pemphigoid Disease Area Index (BPDAI) is used internationally. The BPDAI score evaluates skin involvement (erosions and blisters) as mild (<20), moderate (20–34), or severe (>34), while pruritus severity is assessed using the Visual Analog Scale (VAS) ranging from 0 to 10 over the last 24 hours.¹⁷ In our case, despite two weeks of combination therapy with systemic steroids, IVIG, and cyclophosphamide (CTX), the patient continued to develop new lesions daily, with persistent pruritic symptoms, indicating insufficient disease control. However, this case highlights the potential of dupilumab as a novel therapy for severe treatment-resistant BP. The single BPDAI (blister-specific) score reached 0 by day 3 post-dupilumab, indicating resolution of active blisters, though residual hyperpigmentation persisted. It thus allows for a reduction in corticosteroid dosage.

Pruritus in BP is complex, but recent studies, including one by Chao et al.¹⁸ suggest that inhibiting IL-13 and IL-4 activity can provide a promising treatment strategy, particularly when pruritus is uncontrolled. Based on this, we recommend a higher dosing frequency of dupilumab for severe BP than that used in AD. Following the initiation of a more frequent dupilumab regimen, our patient showed a significant decrease in eosinophil counts, IgE levels, and ELISA-BP180 values, consistent with previous findings.¹⁸ Remarkably, the patient remained relapse-free for over two years, underscoring the critical role of type 2 inflammation in BP pathogenesis. Early and frequent administration of dupilumab may effectively block IL-4 and IL-13, thereby preventing skin inflammation and leading to favorable outcomes.

Biography

Hao Cheng graduated from Nanjing Medical University with a bachelor’s degree in medicine in July 1984. She then pursued her master’s degree at Zhejiang Medical University and her Ph.D. at Zhejiang University School of Medicine. She studied at Hautklinik of the Medical University of Lübeck, Germany as a visiting scholar and was a postdoctoral fellow and guest scientist at the German Cancer Research Center. She is engaged in clinical, scientific and teaching work related to dermatology and venereology. She specializes in the diagnosis and treatment of skin diseases, especially atopic eczema, sexually transmitted disease, Autoimmune diseases, skin tumors, as well as dermatopathological diagnosis and cosmetic laser treatment. Dr. Cheng has been responsible for 5 projects of the National Natural Science Foundation of China (NSFC) and several provincial and international cooperative research projects as well. She has published over 100 papers in her field.

Funding Statement

This work was supported by grants from the Medical Science and Technology Project of Zhejiang Province [2020KY601].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

XY Jiang wrote the manuscript and generated figures. LX Chen wrote the manuscript. YJ Zhu, N Jin and H Cheng revised the manuscript. All authors contributed to the article and approved the final submitted version.

Data availability statement

The raw data of this article will be available from the authors, without undue reservation.

Ethics statement

Ethical approval was obtained from the Sir Run-Run Shaw Hospital Ethical Committee. The patient provided the written informed consent for the publication of any potentially identifiable clinical data and images included in this article.