Patience and expertise are required for bullous pemphigoid

Direct and indirect immunofluorescence are still the gold standard for the detection of specific antibodies and autoantibodies in bullous pemphigoid. Highly effective topical steroids or systemic corticosteroids are recommended as first-line therapy. In the event of a lack of response or contraindications, immunomodulatory and immunosuppressive drugs can be used. According to several case reports, omalizumab and dupilumab have proven to be effective treatment options and further biologics are currently being researched.

Bullous pemphigoid (BP) is characterized by subepidermal blistering, i.e. blistering within the dermoepidermal junction zone (Fig. 1, Fig. 2) [1]. It is the most common bullous autoimmune dermatosis in Switzerland and Europe, reported Prof. Dr. med. Luca Borradori, Clinic Director and Chief Physician, University Clinic for Dermatology, Inselspital Bern [2]. In recent decades, an increase in the incidence of BP has also been observed in this country. An ageing population, the association with increasingly common neurological diseases and certain medications, as well as an increased awareness of atypical variants without blistering are discussed as possible causes for this [28]. The treatment of BP aims to bring the disease under control, alleviate itching symptoms and improve the quality of life of those affected. The treatment methods depend primarily on the severity of the disease. According to Prof. Borradori, attention should be paid to a favorable risk-benefit profile of the respective treatment.

Clinical suspicion of BP: serology provides certainty

The diagnosis of BP is based on a combination of criteria, including clinical features, light microscopic findings and detection of autoantibodies in the skin by direct immunofluorescence (DIF) [3]. The classic clinical manifestation of BP is a very itchy rash with generalized blistering (bulging, itchy blisters of varying sizes filled with serous fluid). In early stages or in atypical variants, however, only localized or generalized excoriated, eczematous or urticarial lesions may be present [4]. The mucous membranes are affected to 10-30%. The typical finding in direct immunofluorescence is the detection of linear immunoglobulin (Ig)G bound to the dermo-epidermal junction zone, more rarely also IgM and IgA. These autoantibodies primarily bind the proteins BP180 and BP230, which are components of the hemidesmosomes. These represent an important cellular connection and have an essential function for the mechanical stability of the skin [1].

In order to confirm the suspected diagnosis of BP, the following further laboratory diagnostic clarification steps are recommended in the s2K guidelines of an EADV expert group, updated in 2022 [3]:

Detection of circulating IgG autoantibodies against the basement membrane zone (BMZ) by indirect immunofluorescence microscopy (IIF) using normal human skin cleaved with NaCl solution.
Detection of anti-BP180-NC16A IgG autoantibodies and/or anti-BP230 IgG autoantibodies by ELISA (enzyme-linked immunosorbent assay).
The novel “multivariate” tests are also recommended for the detection of circulating anti-BMZ IgG autoantibodies. These BIOCHIP mosaic assays combine different antigenic substrates. In the rare cases of BP in which circulating anti-BMZ antibodies are not detectable by either indirect immunofluorescence microscopy or commercially available ELISA, it is recommended that additional testing be performed to increase diagnostic sensitivity and rule out other autoimmune diseases of the dermo-epidermal junction (especially anti-P200 pemphigoid or epidermolysis bullosa acquisita). An overview of the relevant tests can be found in the s2K guidelines published in JEADV [3].

Pathophysiology: complement-independent mechanisms also involved

The pathophysiological relationships in BP are very complex [4]. On the one hand, activation of the complement system with the production of anaphylatoxins and activation of the innate immune response with subsequent recruitment and activation of basophils, eosinophils, neutrophils, monocytes/macrophages and mast cells play a key role in BP [5,6, 28-31]. On the other hand, researchers have increasingly discovered complement-independent inflammatory mechanisms in connection with BP antibodies in recent years. Keratinocytes in particular appear to be able to secrete a large number of proinflammatory pathogenetically relevant cytokines [4,7,32].

One study showed that both BP-IgG and BP-IgE are able to bind directly to the surface of cultured human keratinocytes, with subsequent loss of hemidesmosomes at the basement membrane zone [8]. Eosinophils are involved in BP pathogenesis by mediating the effects of anti-BP180 IgE antibodies and contributing to dermo-epidermal separation. In the presence of IgG or IgE, eosinophils can directly mediate dermo-epidermal separation [9,10]. Freire et al. found elevated levels of both anti-BP180 and anti-BP230 IgE using ELISA and immunofluorescence compared to healthy controls [11].

Anti-BP180 IgE autoantibodies are present in the majority of BP patients, and their levels correlate with disease activity [12–15]. In addition, direct immunofluorescence studies have shown that the majority of BP patients had IgE+ cells in their skin, in contrast to healthy controls. Overall, the evidence suggests that there is an additional complement-independent, Th2-dependent, eosinophil-mediated pathway that contributes to tissue damage and clinical features in BP [4].

“Treat-to-target” with progress monitoring and follow-up

– The EADV expert group generally recommends a treatment duration of between 9 and 12 months for BP [3].

– Discontinuation of treatment is recommended in patients who have been symptom-free for at least 1-6 months on minimal therapy with oral prednisone (0.1 mg/kg/day), clobetasol propionate (10 g/week) or immunosuppressants. Discontinuation of treatment is also influenced by the patient’s general condition and the presence of certain comorbidities.

– anti-BP180 ELISA (i.e. >27 U/mL as determined by the MBL** test) and to a lesser extent ^DIF$ studies have been reported to have predictive value for the occurrence of relapse after discontinuation of treatment [24]. It may be worth considering using these tests before discontinuing treatment.

– In addition, attention should be paid to possible adrenal insufficiency caused by the use of exogenous corticosteroids (CS) (also after the use of topical CS).

A follow-up examination is recommended in the third month after discontinuation of treatment. This period appears to be sufficient to detect most BP relapses [24–26]. Irrespective of this, recurrence of itching, excoriations and/or inflammatory skin lesions should always be clarified by a doctor.

** MBL= Medical & Biological Laboratories
^$ DIF=Direct Immunofluorescence

New treatment options: Biologics as an alternative therapy

Table 1 [3] provides an overview of the currently available treatment options. The guidelines continue to recommend the use of superpotent topical corticosteroids (TCS) or systemic steroids (prednisolone 0.5 mg/kg/d) as first-line therapy. In many cases, the symptoms can be contained, but “you have to be patient,” explained Prof. Borradori [2]. The estimated duration of treatment is 9-12 months. However, there are also patients for whom standard therapy is not effective or is contraindicated. “We need good, new and effective therapies,” emphasized the speaker [2]. The observation that patients with BP often have elevated serum IgE levels and circulating BP180- and BP230-specific IgE autoantibodies supports the idea that IgE plays a role in BP pathogenesis [16,17]. The use of omalizumab, a humanized monoclonal antibody that inhibits IgE binding to its high-affinity receptor (FcεRI), is therefore an obvious choice. Case reports show that omalizumab therapy leads to a strong decrease in FcεRI expression on circulating basophils and a strong reduction of FcεRI + cells in the skin of treated patients [16].

Other biologic targeted therapies that have shown promise in BP include dupilumab, a human IgG4 monoclonal antibody that binds to the α-subunit of the IL-4 receptor, thereby inhibiting IL-4/IL-13 signaling pathways [18–21]. “We have many case series that show that dupilumab has a good effect in patients with bullous pemphigoid,” reported Prof. Borradori [19,22]. The biologic proved to be effective both as monotherapy and in combination with a standard therapy. Following successful clinical testing in Phase II, the efficacy and safety of dupilumab in BP is currently being investigated in the Phase III LIBERTY-BP study (NCT04206553) [23].

Congress: Joint advanced training BE-BS-ZH

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