BP treatment can be very challenging as BP is a chronic disease requiring long-term management. Glucocorticoids are the cornerstone of BP treatment. High-dose systemic corticosteroids are used to induce remission, followed by gradual tapering (Table 1) [6]. However, BP is a chronic disease and therefore frequently requires long-term use of systemic corticosteroids, which may cause a variety of adverse effects, such as hypertension, bone fracture, cataract, gastrointestinal discomfort and metabolic conditions (e.g. weight gain, hyperglycemia) [24].

Table 1 Synopsis of the current treatment options in bullous pemphigoid

Consequently, one of the key principles in the management of BP is to reduce the patient’s exposure to systemic glucocorticoids. Using high potency topical corticosteroids, such as clobetasol propionate, as a topical regimen may have similar efficacy but is often difficult to realize in the home-setting of elderly patients [25]. Corticosteroid-sparing adjuvant agents are prescribed when monotherapy with glucocorticoids is inadequate to achieve disease control or when there is a relapse during corticosteroid tapering [25, 26]. Moreover, these drugs are considered if there are contraindications to oral corticosteroids or existing comorbidities, such as hypertension, diabetes mellitus, osteoporosis and psychosis [27]. The choice of adjuvant agents depends on the availability, price, practical experience of the treating clinician, and the presence of specific contraindications [27]. For BP, the adjuvant agents may include (Table 1):

azathioprine – depending on thiopurine methyltransferase activity [28];

doxycycline – alone or in combination with daily oral nicotinamide [29];

mycophenolate mofetil or mycophenolic acid [28];

methotrexate – which may eventually be used as a monotherapy also [30, 31];

dapsone [32];

cyclosporin [33];

rituximab.

However, certain patients remain irresponsive to conventional therapies, highlighting a pressing demand for treatments with reduced adverse effects and enhanced efficacy.

The aim of this review was to summarize and discuss the novel targeted BP treatment options that have been developed and tested in clinical trials in recent years, based on the complex pathophysiology of BP.

2.1 Rituximab

B lymphocytes play an important role in the pathogenesis of autoimmune bullous diseases. They participate in several cellular functions, including the secretion of autoantibodies, activation of T cells, and production of proinflammatory cytokines [6]. Therefore, they are considered an important therapeutic target.

Rituximab, a chimeric IgG1 monoclonal antibody, targets the CD20 transmembrane receptor expressed on the surface of B lymphocytes and in the pre-plasma cell lineage. It induces a B lymphocyte depletion and prevents the differentiation of B lymphocytes into antibody-secreting plasma cells (Fig. 2) [6]. Moreover, rituximab inhibits CD4+ T lymphocytes and increases the number of FOXP3+ regulatory cells [6]. Rituximab therapy usually results in a major reduction in circulating BP180-specific B lymphocytes, as well as a dramatic reduction of anti-BP180 antibodies, and decreases expression of proinflammatory IL-15 and IL-6, leading to an improvement of BP skin manifestations [6, 34, 35].

Fig. 2

Th2 pathways are considered the primary triggers for antibody production in BP. Rituximab targets the CD20 transmembrane receptor expressed on the surface of B-lymphocytes. It induces a B-lymphocyte depletion and prevents the differentiation of B-lymphocytes into antibody-secreting plasma cells. Th2 cytokines IL-4 and IL-13 play an important role in eosinophil chemoattraction. Autoreactive Th2 cells stimulate B-cell autoantibody production and participate in the recruitment and activation of eosinophils. Eosinophils also contribute to the maintenance of Th2-type inflammatory responses by further producing IL-4, IL-5 and IL-13. IL-13 can directly stimulate peripheral nerve fibers and indirectly recruit IL-31-secreting eosinophils to the site of skin lesions, and is therefore involved in BP-associated itch. Dupilumab can inhibit IL-4 and IL-13 signaling. It downregulates eosinophil chemotaxins and inhibits Th2-associated chemokine activity, B-cell proliferation and autoantibody production. Dupilumab may further improve pruritus in BP by directly reducing IL-13 and by indirectly downregulating IL-31 production by eosinophils. Nemolizumab is an anti-IL-31 receptor A antibody that can contribute to a great reduction of pruritus. BP bullous pemphigoid, IL interleukin, CD20 cluster of differentiation 20, Th2 type 2 helper

Rituximab has the ability to significantly reduce the concentration of serum autoantibodies without substantially affecting the overall antibody titers [36]. That is because rituximab primarily acts on plasma cells producing pathogenic autoantibodies and not on CD20 plasma cells that produce antimicrobial antibodies [36]. These autoreactive plasma cells differ fundamentally from the protective antimicrobial plasma cells in terms of their differentiation, migration, and survival characteristics [36]. Rituximab specifically targets short-lived autoreactive plasmablasts expressing CD20, which represent an early stage of differentiation into plasma cells [36]. These plasmablasts have a shorter lifespan and higher turnover rate compared with normal, long-lived plasma cells [36].

The current body of evidence supporting the use of rituximab in refractory BP stands at a C grade level. This evidence is primarily derived from various study types, including prospective and retrospective cohort studies, case-control studies, and case series [37]. Notably, the field lacks robust, well-designed, randomized controlled clinical trials in this context [37]. Consequently, rituximab has gained approval exclusively for pemphigus treatment. However, it is frequently employed off-label for managing severe refractory pemphigoid disease or for BP patients with contraindications or poor tolerance to conventional immunosuppressive agents [37].

Furthermore, it appears that rituximab is less efficacious in treating BP compared with pemphigus. BP patients tend to exhibit a lower frequency of complete response, a higher rate of relapse, and reduced tolerance to rituximab treatment compared with pemphigus patients [38,39,40,41]. This variance might stem from the persistence of IgE autoantibodies or CD20-positive plasma cells in BP, which can endure even after rituximab intervention [42]. These lingering elements have been associated with early relapse of blistering skin lesions, posing a challenge to sustained therapeutic outcomes [42]. Additionally, the role of complement in activating innate immunity may further exacerbate the immune response in BP [43,44,45]. This heightened response suggests that even low levels of anti-BP180 autoantibodies can exert a profound impact, making it challenging to achieve a response after rituximab treatment or to taper patients off low doses of prednisolone.

The initial documentation of rituximab's application in BP dates back to 2007 and was based on the lymphoma protocol, involving a dosage of 375 mg/m2 administered weekly for 4 weeks [46]. The rheumatoid arthritis protocol, which consists of two infusions of 1000 mg spaced 2 weeks apart, has also been utilized. Presently, the optimal dosing regimen for BP remains ambiguous. However, an escalating number of studies are exploring the effectiveness of lower doses (such as two infusions of 500 mg 2 weeks apart or four weekly infusions of 500 mg), or even ultra-low doses (100 mg administered weekly for 4 weeks) of rituximab in the context of BP [39, 47,48,49].

2.2 Dupilumab

Type 2 inflammation is an immune response against parasites, allergens, certain viral or bacterial infections and endogenous molecules [50]. It is predominately mediated by group 2 innate lymphoid cells, type 2 helper (Th2) cells, eosinophils and cytokines, such as IL-4, IL-5 and IL-13 [51, 52].

Th2 pathways are considered the primary triggers for antibody production in BP [53]. BP patients show higher concentrations of IL-4 and IL-13 producing CD4+ and CD8+ T cells in their blister fluids and sera than healthy controls [54], as well as elevated serum levels of IgE and eosinophilia [55]. Th2 cytokines IL-4, IL-13 and IL-31 play an important role in eosinophil chemoattraction, maturation and activity and therefore in the induction of pruritus [56, 57]. They have been found elevated in peripheral blood and skin lesions of BP patients [56,57,58] and they upregulate Th2 immunological responses that are responsible for the loss of tolerance towards BP180 (Fig. 2) [59]. Autoreactive Th2 cells stimulate B-cell autoantibody production and participate in the recruitment and activation of eosinophils (Fig. 2). Eosinophils also contribute to the maintenance of Th2-type inflammatory responses by further producing IL-4, IL-5 and IL-13 [60]. IL-13 can directly stimulate peripheral nerve fibers and indirectly recruit IL-31-secreting eosinophils to the site of skin lesions and is therefore involved in BP-associated itch (Fig. 2) [61].

Dupilumab, a fully human monoclonal antibody, binds to the alpha subunit of the IL-4 receptor. This subunit is shared by both IL-4 and IL-13, therefore dupilumab inhibits IL-4 and IL-13 signaling [39, 62]. Hence, it downregulates eosinophil chemotaxis, B-cell proliferation and autoantibody production (Fig. 2) [60]. Dupilumab may further improve pruritus in BP by directly reducing IL-13 and by indirectly downregulating IL-31 production by eosinophils [61]. It is approved for the treatment of moderate to severe atopic dermatitis and is currently being studied for many other Th2 inflammatory diseases.

In a case series involving 13 BP patients from five academic centers receiving dupilumab, 92.3% (12/13) of the patients achieved disease clearance or satisfactory response (defined as documented improvement noted by clinicians and the patient's willingness to continue the medication without reaching complete clearance) [63]. Among the patients, 53.8% (7/13) achieved total clearance of BP, and no adverse events were reported during the treatment [63].

In the documented case of a 72-year-old woman with BP, dupilumab treatment not only alleviated pruritus and improved skin lesions but also resulted in the normalization of anti-BP180 antibodies [55]. Additionally, following dupilumab therapy, there was a reduction in the percentages of circulating CD4 T cells producing IL-4, IL-13, IL-17, and IL-31 [55]. Notably, there were no significant changes in the proportions of interferon (IFN)-γ-producing CD4 and CD8 T cells before and after treatment [55]. These findings suggest that the effectiveness of dupilumab may primarily be attributed to its suppression of Th2 cytokines [55].

BP patients who receive dupilumab in combination with conventional therapies achieve faster clinical response and reduction of the cumulative corticosteroid dose, when compared with those treated only with conventional therapies [64, 65]. A case report indicated that combination of omalizumab with dupilumab demonstrated high efficacy in a patient with refractory BP [66]. Two case reports have demonstrated that dupilumab is promising for the treatment of highly refractory, rituximab-resistant or immune checkpoint inhibitor-induced BP [67, 68]. Regarding the studies involving immune checkpoint inhibitors, a notable limitation is the absence of discussion on the role of IL-4 blockade in tumor immunity, giving rise to safety concerns. Consequently, these promising results should be interpreted cautiously, as many questions remain unanswered.

In a recent retrospective cohort study conducted by the National Autoimmune Bullous Diseases Cooperative Group of China, 146 patients diagnosed with BP were administered a dosage of dupilumab 300 mg every 2 weeks, following an initial 600 mg dose [69]. Among these patients, 127 (87.0%) attained disease control within 4 weeks, defined as the absence of new lesions and itching, as well as the healing of existing lesions [69]. The median (interquartile range [IQR]) time for achieving this control was 14 (7–14) days [69]. Additionally, 52 (35.6%) patients experienced complete remission, while 13 (8.9%) BP patients relapsed during the observation period [69]. The most common adverse events were infections and eosinophilia [69]. Anti-BP180 antibody levels >50 relative units/mL, as well as female sex, were associated with better response to treatment [69].

Dupilumab may be administered at the dosing scheme approved for atopic dermatitis: 600 mg subcutaneously initially, followed by 300 mg subcutaneously every other week. However, some BP patients may need a maintenance dose more frequently than every other week, suggesting the need for higher doses [63].

Clinical trials are needed to further confirm the efficacy of dupilumab in patients with BP and its long-term effect. Additionally, more studies are also required to establish the optimal dosage and the treatment intervals for the maximal benefit. Currently, there is an ongoing phase III randomized, double-blind, placebo-controlled trial for the use of dupilumab in BP (NCT04206553) [70].

2.3 Eosinophil-Related Molecules

Eosinophil infiltration is a common characteristic in BP skin lesions, and these cells are attracted by various chemokines present in blister fluid, such as IL-5, eotaxin, and galectin-9 [71]. Moreover, more than 50% of untreated BP patients exhibit elevated levels of blood eosinophils, which have been found to be positively correlated with disease severity and itch intensity [72,73,74,75,76]. Recent studies have identified increased levels of the eotaxin receptor CCR3 and its ligand, eotaxin, in BP, suggesting their involvement in the condition [77,78,79]. Eotaxin-1 and eotaxin-3, significantly upregulated in the serum and blister fluid of BP patients, are strongly linked to eosinophil numbers and activation [75, 80]. Notably, eotaxin-1 has been coined as the ‘aging factor’ due to its age-dependent rise in serum levels and its recent association with aging and neurocognitive decline [75, 80].

BP patients with eosinophilia are typically older and often exhibit more extensive palmoplantar involvement than others [74]. Moreover, the levels of eosinophilic cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and major basic protein (MBP) released by eosinophils are higher in the serum and blister fluid of BP patients compared with healthy controls [81]. ECP and EDN can induce blister formation by disrupting the detachment of keratinocytes from the extracellular matrix [81]. Eosinophils also stimulate the secretion of matrix metalloproteinase (MMP)-9, which facilitates the degradation of BP180 and cleavage of the DEJ [82,83,84]. Additionally, eosinophils are considered the primary source of IL-31 in BP, a well-known pruritogen and promoting factor for blister formation [85]. Therefore, targeting eosinophils holds promise as a potential treatment strategy for BP.

Bertilimumab is a humanized monoclonal antibody targeting eotaxin-1 (CCL-11). By binding to this chemokine, bertilimumab impairs eosinophil migration to the skin. Currently, it has not received approval for treating any other conditions. However, the FDA has recently granted bertilimumab orphan drug designation for the treatment of BP. In a phase II, open-label clinical trial of patients with newly diagnosed moderate to extensive BP (NCT02226146), disease severity decreased by 81% 13 weeks after the use of bertilimumab. Subjects received only three doses of bertilimumab (on days 0, 14 and 28) [86]. The molecule was also well tolerated, indicating that bertilimumab is a well tolerated and efficacious treatment for BP [86]. Limitations of this trial included lack of a control group, a small number of patients (n = 9) and a short duration of treatment (4 weeks) [86].

AKST4290 is an antagonist of the CCR3 eotaxin receptor on eosinophils. In a phase II, double-blinded clinical trial (NCT04499235), patients with BP were administered 400 mg of AKST4290 twice, in combination with mometasone furoate. The treatment exhibited efficacy, resulting in disease control [87].

Nemolizumab is an anti-IL-31 receptor A antibody that is licensed in Japan to treat atopic dermatitis and awaits worldwide approval for prurigo nodularis, as it strongly reduces pruritus (Fig. 2) [88]. Consequently, it might be considered a potential additional medication for controlling pruritus in BP in the future. However, no clinical trials have been planned thus far [22].

IL-5 is a Th2 cell-induced cytokine detected in blister fluid of patients with BP and is present in the acute phase of BP [56, 57]. It contributes to eosinophilic maturation, activation and chemotactic activity by increasing CCR3 expression [61, 89,