Autoimmune bullous diseases are a group of rare disorders characterized by pathogenic autoantibodies directed against structural proteins of the skin and mucous membranes. Based on blister depth, these diseases are divided into two main groups. Pemphigus diseases cause intraepithelial blisters, while pemphigoid diseases cause subepithelial blisters (1). Among these, bullous pemphigoid (BP) is a distinct subepithelial autoimmune blistering disorder that predominantly affects the elderly. In recent years, the incidence of BP has been rising, correlating with an aging population and an increase in associated comorbidities (2, 3). The primary clinical manifestation of BP is the development of tense blisters across the body, typically arising on normal skin or edematous erythema, accompanied by varying degrees of pruritus. Beyond the debilitating cutaneous symptoms, BP imposes a substantial clinical and economic burden. The disease is inherently associated with a high mortality rate and an elevated risk of severe systemic infections. Traditional treatment plans include the use of systemic and local corticosteroids, as well as immunosuppressive medications. However, the majority of elderly patients cannot tolerate long-term systemic corticosteroids or other immunosuppressants, as they are typically frail and frequently present with multiple underlying comorbidities. Prolonged use frequently leads to severe steroid-related complications, including profound immunosuppression, worsening of metabolic disorders, and increased susceptibility to potentially fatal infections. These profound clinical challenges strongly justify the urgent need for novel, safer, and targeted therapeutic alternatives.

As the pathophysiological mechanisms are further elucidated, increased expression of helper T-cell 2 (Th2) cytokines, including interleukin-4 (IL-4), IL-13, and IL-5, has been detected in the blood, blister fluid, and skin tissues of BP patients (4), indicating a tight relationship between the etiology of BP and the type 2 inflammatory response (5). Recently, targeting the type 2 inflammatory axis has emerged as a promising therapeutic strategy. Dupilumab, a well-known monoclonal antibody targeting the IL-4 receptor alpha subunit (IL-4Rα), which simultaneously inhibits IL-4 and IL-13 signaling pathways, has accumulated growing clinical evidence demonstrating its ability to suppress type 2 inflammation, alleviate severe pruritus, and halt disease progression in BP (6, 7). Although stapokibart, a novel recombinant humanized IL-4Rα inhibitor, shares a comparable mechanism of action, data on its application in BP remain scarce. Specifically, real-world evidence and long-term safety profiles are critically lacking for frail, elderly patients with comorbidities. To bridge this knowledge gap, this study aims to evaluate the real-world clinical efficacy and safety profile of stapokibart in elderly patients with moderate-to-severe BP, thereby exploring its potential as a steroid-sparing alternative.

This study evaluated the clinical efficacy and safety of stapokibart in elderly patients with moderate-to-severe BP. Our findings demonstrate that stapokibart rapidly induced disease control, with 100% of the patients achieving control within 4 weeks (mean time: 10.18 ± 3.06 days). Furthermore, the integration of stapokibart exhibited a substantial steroid-sparing effect, allowing the minimum systemic corticosteroid dosage to be successfully tapered to an average of 6.14 mg/d. These clinical improvements were accompanied by significant reductions in BPDAI, DLQI, and pruritus NRS scores, alongside decreased EOs and anti-BP180 antibody levels. The treatment maintained an acceptable safety profile, with no severe adverse events necessitating drug discontinuation. Regarding long-term outcomes, although mild-to-moderate recurrence was observed in 4 out of 15 patients (26.67%), the majority of the cohort achieved stable remission and maintained clinical responses during the prolonged follow-up period on an extended 8-week dosing interval.

The clinical importance of these findings is particularly pronounced given the demographic most affected by BP. BP is an autoimmune subepidermal dermatosis that predominantly affects older adults (2, 3), a population characterized by distinct clinical vulnerability. Patients with BP are frequently characterized by itchy skin, EO infiltration in the lesions, and high peripheral blood EO counts (11, 12). As observed in our cohort, elderly patients, mean age of 80.42 years, with a high prevalence of underlying conditions such as diabetes mellitus, hypertension, and cardiovascular diseases, are inherently fragile. Glucocorticoids, the cornerstone of BP treatment, can cause severe adverse effects with long-term or high-dose use, particularly in elderly patients with multiple comorbidities, leading to steroid-related complications, such as infections, osteoporosis, metabolic disorders and increased risk of mortality. Consequently, there is an urgent need for safer, long-term therapeutic options that can mitigate these treatment-related risks without compromising disease control.

As the pathophysiological mechanisms of BP are thoroughly investigated, an increasing number of studies have discovered that type 2 inflammatory pathways are crucial to the pathophysiology of BP. Th2 cells and Th2 cytokines, including IL-4 and IL-13, were reported to be markedly elevated in the skin lesions and serum of BP patients in investigations (13). Significant itching is common in BP sufferers as well. Chronic pruritus can occur as a result of IL-4 and IL-13 binding to IL-4R, which can directly stimulate human sensory neurons (14). Furthermore, the type 2 inflammatory response is characterized by higher peripheral blood EO counts and serum levels of total IgE in BP patients (15). Accordingly, when administered to BP patients, the IL-4Rα-targeting biologic dupilumab can considerably alleviate their symptoms (16). Similarly, stapokibart is a humanized monoclonal antibody against IL-4Rα that has been approved for the treatment of type 2 inflammatory diseases, including atopic dermatitis (17–19), severe eosinophilic chronic rhinosinusitis with nasal polyps (20), seasonal allergic rhinitis (21), and others. By binding to IL-4Rα, it can block IL-4 and IL-13 signaling. Additionally, stapokibart binds to IL-4Rα closer to the ligand-binding site than dupilumab, has distinct binding epitopes, and varies in cross-reactivity between species. Stapokibart demonstrates an equal or higher capacity to block IL-4Rα-mediated signaling in vitro than dupilumab (22). Translating these findings to routine practice, the primary clinical advantage of stapokibart is its steroid-sparing effect (21). By enabling early and rapid tapering of systemic corticosteroids, it helps clinicians balance disease control with the critical need to limit iatrogenic toxicity. It is well established that high-dose systemic steroids are a major driver of opportunistic infections and mortality in elderly BP cohorts (23, 24). Consequently, minimizing steroid exposure directly translates to fewer fatal complications and a better-preserved quality of life. For frail older patients or those with multiple comorbidities who are poor candidates for conventional immunosuppression, biologics like stapokibart provide a practical and safer strategy for long-term maintenance (25).

The IL-4Rα inhibitor stapokibart is a new potential treatment option for BP, according to the Chinese Expert Consensus on the Diagnosis and Treatment of Herpetiform Pemphigoid Sclerosis (2025). However, there aren’t many extensive clinical trials on the safety and effectiveness of Stapokibart for BP in China. Given the foregoing context, we investigated the use of Stapokibart in the management of moderate-to-severe BP in the elderly.

Within two weeks of starting stapokibart monotherapy, the severity of the condition in our study’s BP patients improved considerably, and by week 4, it had further diminished. As early as one week, patients with BP receiving stapokibart monotherapy showed a significant improvement in new blisters, pruritus, and EO levels without experiencing any notable side effects. Elderly people made up the study population, and most of them had severe conditions with several comorbidities. Infections and hypoproteinemia are frequently linked to severe BP in the elderly, which can significantly affect their psychological health and quality of life. The combination of stapokibart with conventional therapy offers a favorable safety profile, a quick onset of action, and significant long-term efficacy in improving BP. Therefore, we think that stapokibart can assist in inducing and maintaining remission and long-term control when administered as an adjuvant to glucocorticoid tapering or other basal treatments. Enhancing the quality of survival and compliance is beneficial and is anticipated to increase the longevity of older people. Regarding long-term disease control, clinical recurrence were observed in 26.67% (4/15) of our cohort. This recurrence rate is consistent with existing real-world observations for dupilumab in BP (26, 27). Several factors may contribute to these recurrences. Clinically, rapid tapering of systemic steroids can easily expose ongoing, low-level disease activity (27). Pharmacologically, extending the stapokibart dosing interval might cause drug levels to drop below the therapeutic threshold in certain patients. Furthermore, while IL-4Rα blockade safely suppresses inflammation, it does not directly clear long-lived plasma cells or tissue-bound anti-BP180 antibodies, allowing a temporary window for new blisters to form (28, 29). These findings suggest that standard tapering protocols may not suit everyone. Patients with high baseline autoantibodies may require slower steroid tapering and customized biologic dosing intervals (30). Therefore, long-term follow-up is essential to manage late-onset recurrence and determine the most effective maintenance strategy for each individual.

In conclusion, stapokibart may serve as an effective and well-tolerated adjunctive option for alleviating skin lesions and pruritus in elderly patients with moderate-to-severe BP. However, the stability of the results and the level of evidence may be impacted by this single-center, small-sample, uncontrolled study and the dosage of stapokibart in this study was based on its experience in treating atopic dermatitis. Future larger, prospective randomized controlled trials are required to definitively confirm its long-term efficacy and safety in elderly BP patients who do not respond well to systemic therapy or who are intolerant of or contraindicated for systemic therapy.