Bullous Autoimmune Dermatoses
Clinical Features, Diagnostic Evaluation, and Treatment Options
Background: Bullous autoimmune dermatoses are a clinically and immunopathologically heterogeneous group of diseases, characterized clinically by blisters or erosions of the skin and/or mucous membranes. In Germany, their prevalence is approximately 40 000 cases nationwide, and their incidence approximately 20 new cases per million people per year.
Methods: This review is based on publications that were retrieved by a selective search of the literature focusing on the current German and European guidelines.
Results: Recent years have seen the publication of guidelines, controlled prospective clinical trials, and multicenter diagnostic studies improving both diagnosis and therapy. Specific monovalent and multivariate serological test systems and pattern analysis of tissue-bound autoantibodies allow identification of the target antigens in 80–90% of patients. This enables the precise classification of disease entities, with implications for treatment selection and disease outcome. In 2019, the anti-CD20 antibody rituximab was approved by the European Medicines Agency for the treatment of moderate and severe pemphigus vulgaris, with an ensuing marked improvement in the care of the affected patients. To treat mild and moderate bullous pemphigoid, topical clobetasol proprionate is recommended, in severe disease, combined with systemic treatment, i.e. usually (a) prednisolone p.o. at an initial dose of 0.5mg/kg/d , (b) an immunomodulant, e.g. dapsone or doxycycline, or (c) prednisolone plus an immunomodulant.
Conclusion: The early recognition and precise diagnostic evaluation of bullous autoimmune dermatoses now enables improved, often interdisciplinary treatment, in accordance with the available guidelines. Current research projects are focused on new treatment approaches, an improved understanding of the underlying pathophysiology, and further refinements of diagnostic techniques.
Autoimmune bullous diseases (AIBD) are prototypical autoantibody-mediated autoimmune diseases in which the effects of the autoantibodies are directly visible on the skin and/or on mucous membranes. If left untreated, these diseases are potentially life-threatening due to superinfection, fluid loss, and severely restricted food intake (1, 2, 3, 4, e1, e2).
Clinically, depending on the disease entity, vesicles, blisters, pustules, erosions, excoriations, and erythema on the skin and mucous membranes can be seen. In AIBD, autoantibodies are directed against structural proteins of the skin; in pemphigus diseases, they are directed against desmosomal proteins, which connect neighboring keratinocytes/epithelial cells, and in pemphigoid diseases, against proteins of the basement membrane zone, which connect the epidermis/epithelium and the dermis/lamina propria (Figure 1).
The frequency of AIBD differs significantly depending on the geographic region and population evaluated (2, e3, e4). In Germany and central Europe, bullous pemphigoid is by far the most common AIBD (5, e5, e6, e7, e8, e9, e10) (Table 1), with an increasing incidence in recent decades (e8, e11, e12, e13). Possible causes for the increasing incidence of bullous pemphigoid may include an aging population, the association with increasingly frequent neurological diseases and certain medications (see below), and a greater awareness of atypical variants without blistering (overview in [e4]).
The most common AIBDs in children are linear IgA dermatosis and pemphigus vulgaris (6, e14). An association with the human leukocyte antigens HLA-DRB1*04 and HLA-A*10 and a polymorphic variant in the ST18 gene have been described for pemphigus vulgaris, while an overrepresentation of HLA-DQB1*03:01 and polymorphism in the mitochondrial ATP8 gene has been described for bullous pemphigoid (1, 2, e3, e15, e16).
Pemphigus diseases can be classified in 4 main forms based on clincial and immunopathological features: pemphigus vulgaris, in about 70–80% of patients; pemphigus foliaceus, in about 20%; paraneoplastic pemphigus, in about 5%; and IgA pemphigus, in 1–3% (Table 2) (2).
In pemphigus vulgaris, the mucous membranes close to the surface are always affected, including primarily the oral cavity (Figure 2a). Erosions predominate and can also manifest on the mucosa of the pharynx, larynx, esophagus, and genitalia (2, 3). In about half of the cases, flaccid blisters and erosions also appear on the skin, which may involve large areas. This led to a mortality of over 80% before the introduction of the corticosteroids (2, e3, 5). At present, the mortality of patients with pemphigus vulgaris is still two to three times higher than in the general population (e3, 5).
Paraneoplastic pemphigus is associated with neoplasia and may clinically resemble pemphigus vulgaris. Characteristic features are pronounced stomatitis, lip involvement, and polymorphic, often lichenoid, skin changes (2, 7, e17). With a mortality of 75–90%, the prognosis is unfavorable, primarily due to neoplasm and bronchiolitis obliterans, which occurs in 5–20% of cases (e3, e18, e19).
In IgA pemphigus, pustules and erosions are the most prominent lesions (e20, e21, e22) (Table 2). Furthermore, neonatal pemphigus, pemphigus herpetiformis, and endemic pemphigus foliaceus are described as separate entities; pemphigus vegetans is considered a clinical variant of pemphigus vulgaris with predominant involvement of the axillary and inguinal areas. (2, 3, e23).
The differential diagnoses of pemphigus vulgaris and paraneopalstic pemphigus are severe drug reactions, such as Steven–Johnson syndrome, toxic epidermal necrolysis, stomatitis due to herpes simplex virus, hereditary epidermolysis, mucosal lichen planus, and mucous membrane pemphigoid (MMP). Pemphigus foliaceus must be differentiated from seborrheic dermatitis and impetigo, and IgA pemphigus, from pustular psoriasis as well as from pustular reactions to drugs.
Bullous pemphigoid presents with tense blisters (Figure 2b), erosions, and urticarial erythema. Non-bullous forms are found in around 20% of cases (e24, e25). Characteristic features are the often severe pruritus and manifestation in old age (mean age of onset, 78 years). Therefore, bullous pemphigoid should be excluded in case of chronic pruritus in old age. Mucosal involvement can be seen in 10–20% of patients (8, 9, 10, e26).
Associated diseases that have been described include cardiovascular diseases, psoriasis, diabetes mellitus, hematological malignancies, and degenerative neurological diseases, the latter mostly preceding the skin disease and affecting 30–50% of patients (11, 12, e27, e28, e29). Associations with the use of dipeptidyl peptidase IV inhibitors have also been observed, particularly with vildagliptin, as well as (although to a lesser degree) with spironolactone, loop diuretics, and drugs for Parkinson’s disease (13, e27, e29, e30, e31, e32, e33). Gliptins should be replaced by other antidiabetic drugs in any case, and the other drugs switched to alternatives when possible. The 1-year mortality rates have been reported to range between 8% and 41% (1, e7, e10, e13, e34, e35). Differential diagnoses are bullous erysipelas, impetigo contagiosa, adverse drug reactions, herpes zoster, urticarial eczema, bullous reactions to insect stings, artifactual changes, hereditary epidermolysis, and other pemphigoid diseases.
Predominant involvement of mucous membranes supports the clinical diagnosis of MMP (Figures 2d, e). The mucous membranes of the mouth and the conjunctiva are particularly affected, as well as (less frequently) mucous membranes of the nose, pharynx, anogenital region, larynx, esophagus, and trachea. About 25–30% of patients present with additional erosions and blisters on the skin (1, 14).
Lesions of the conjunctiva, nose, larynx, esophagus and trachea in particular heal with scarring, which can lead to blindness, chronic hoarseness, difficulties in breathing and dysphagia, respectively. The main autoantigens are BP180 (in around 75% of patients) and laminin 332 (in up to 25%). Anti-laminin 332 MMP is associated with malignancy in 25–30% of cases, and in these patients, a tumor search is required (14, 15, e36). MMP has a differential diagnosis similar to that of pemphigus vulgaris.
Pemphigoid gestationis usually occurs in the third trimester of pregnancy, with severe pruritus and urticarial erythematous plaques, initially mainly in the periumbilical region. The disease resolves postpartum but usually recurs in subsequent pregnancies (1, e2, e37). As main differential diagnoses, polymorphic eruption of pregnancy and urticaria are to be distinguished. Linear IgA disease is characterized by tense vesicles and blisters, often arranged in an annular pattern, but may also resemble bullous pemphigoid and is a common AIBD in childhood (6, e14). In adults, induction by drugs should be considered; notably, about half of the drug-induced cases are caused by vancomycin (e38). Anti-p200 pemphigoid clinically resembles bullous pemphigoid but shows more palmoplantar involvement (e39). In epidermolysis bullosa acquisita, the inflammatory variant mimics bullous pemphigoid, MMP, or linear IgA disease. In the mechanobullous variant, which is present in a third of patients, blisters appear on areas most stressed by mechanical forces, such as elbows, knees, and feet. Involvement of the mucous membranes and healing with scarring are common in this variant (16, 17, e40); the most important differential diagnosis is porphyria cutanea tarda.
Dermatitis herpetiformis, which is the cutaneous manifestation of celiac disease, is characterized by severe pruritus, excoriated papules, and vesicles with predilection for knees, elbows, and buttocks (4, 18).
AIBD cannot be diagnosed on the basis of the clinical picture alone. Rather, detection of tissue-bound and/or circulating autoantibodies is required (10).
Tissue-bound autoantibodies (primarily IgG and IgA) and complement deposits are detected using direct immunofluorescence (IF) in a perilesional skin/mucosal biopsy and continue to represent the gold standard in AIBD diagnostics (9, 10, 17, 18, 19, 20, 21). Direct IF allows a differentiation between pemphigoid diseases with linear deposits on the basement membrane (Figure 3a, b), pemphigus diseases with intercellular fluorescence in the epithelium (Figure 3c), and dermatitis herpetiformis with granular deposits of IgA along the basement membrane and/or in the tips of the dermal papillae. Linear and intercellular fluorescence together indicate paraneoplastic pemphigus (7, e17).
Of the pemphigoid diseases, linear IgA disease can be differentiated based on predominant IgA deposits along the basement membrane, and epidermolysis bullosa acquisita, based on serration pattern analysis (1). Almost all pemphigoid diseases show an n-serrated pattern (Figure 3a); except epidermolysis bullosa acquisita and bullous lupus erythematosus which reveal a u-serrated pattern (Figure 3b) (22, e41, e42).
Circulating autoantibodies can be detected in the serum of about 90% of AIBD patients. In contrast, this is only possible for about half of the patients with epidermolysis bullosa acquisita or MMP (16, 17, e43). A serological diagnosis in combination with the clinical picture allows an exact assignment to the individual entities and thus a tailored therapy and a more precise prognosis. Anti-laminin 332 MMP and paraneoplastic pemphigus are both facultative and obligatory paraneoplasia, respectively, and a search for an underlying malignancy is indicated (7, 15, e36, e44).
To screen for suspected AIBD, an indirect IF on monkey esophagus and 1 M NaCl–split skin is carried out, which enables a differentiation into pemphigus and pemphigoid diseases (Figure 4a–c). The salt-split skin allows a subdivision of binding to the epidermal roof (in the case of autoantibodies against BP180 and BP230) or to the floor (autoantibodies against p200 antigen, laminin 332, and type VII collagen) of the artificial split (Figures 1 and 4a–c, Table 2) (1, 2, 10, 18, 19, e45).
For the detection of autoantibodies against the most important target antigens of AIBD, sensitive and specific enzyme-linked immunosorbent assays (ELISA) using the recombinant immunodominant regions of the target antigens are available (Euroimmun, Lübeck; MBL, Nagoya, Japan; Table 2) (10, e46, e47, e48, e49, e50, e51, e52). For instance, ELISA can detect circulating antibodies against desmoglein 3 in the sera of patients with pemphigus vulgaris, and circulating antibodies against desmoglein 1 in patients with pemphigus foliaceus, in >95% of the cases (3, 23, e47, e52). Serum IgG antibodies against BP180 NC16A can be detected in 80–90% of the sera from patients with bullous pemphigoid.
The diagnostic sensitivity of bullous pemphigoid can be increased by 5–8% by the additional use of the BP230 ELISA, with which 50–60% of patients react (e46, e53). Serum autoantibodies against BP180 NC16A are also found in patients with pemphigoid gestationis as well as in 30–50% of patients with MMP who have serum antibodies against the epidermal side of human split skin (e54, e55, e56, e57).
For circulating autoantibodies against desmoglein 1, desmoglein 3, BP180 NC16A, and type VII collagen, a correlation with disease activity has been shown (3, e47, e48, e58, e59); their determination via ELISA during the course of the disease is recommended to be indcluded in therapeutic decisions (17, 21, 24). Instead of a step-by-step diagnostic approach, multivariate ELISA systems can be used in which autoantibodies against several target antigens are analyzed in parallel (e51, e60). The indirect IF-based BIOCHIP technology offers a comparable option. It assembles several substrates in so-called BIOCHIP mosaics in a single incubation field of a standard laboratory slide (15, 23, e61, e62, e63) (Figures 3d and 4d–f).
The detection of specific autoantibodies that are not (yet) included in commercial assays is carried out in some specialized laboratories (Table 2 and Box).
The pathophysiology of pemphigus and pemphigoid diseases has been presented in detail in recent reviews (1, 2, 3, 25, e1, e64, e65, e66, e67). A common feature of all AIBDs is the presence of T cells and pathogenetically relevant autoantibodies against the respective autoantigens in genetically susceptible individuals (e68, e69, e70, e71, e72, e73, e74, e75). The trigger factors that lead to a breach of tolerance are still largely unknown.
In pemphigus, autoantibody binding is followed by the desmogleins being depleted from the cell surface and further signal transducing events, among others via the p38MAP kinase. Both lead to a weakening of the cell–cell interactions and to the separation of the keratinocytes/epithelial cells called acantholysis (3, 25, e1, e64).
In pemphigoid diseases, the binding of the autoantibodies leads to the local activation of complement and subsequently to the infiltration of inflammatory cells, such as eosinophils, neutrophils, macrophages, and T cells, into the upper dermis. The release of specific proteases from granulocytes, macrophages, and activated mast cells ultimately results in degradation of the proteins of the dermal–epidermal junction, which appears histologically as subepidermal clefts and clinically as tense blisters and erosions (1, e76). C5aR1, leukotriene B4, the neonatal Fc receptor, eotaxin, the IL-5 receptor, and IL-17A have been identified as key mediators of pemphigoid diseases; clinical studies are currently underway in which some of these are investigated (26, 27, 28, 29, e67, e77, e78, e79, e80, e81, e82, e83).
German and/or European guidelines have been formulated for bullous pemphigoid, pemphigus vulgaris/foliaceus, MMP, and dermatitis herpetiformis (9, 18, 21, 24, 30, 31, e84) (eTables 1 and 2). In addition to an interdisciplinary approach with ENTs, ophthalmologists, gynecologists, general practitioners, infectiologists, paediatricians, and, if necessary, other specialist disciplines, cooperation with patient support groups is recommended, for example with the German Pemphigus und Pemphigoid Selbsthilfegruppe (www.pemphigus-pemphigoid-selbsthilfe.de) or the International Pemphigus and Pemphigoid Foundation (www.pemphigus.org).
First-line therapy for pemphigus vulgaris/foliaceus has changed significantly following the approval of the anti-CD20 antibody rituximab for the treatment of moderate and severe pemphigus vulgaris by the European Medicines Agency (EMA) and the US American Food and Drug Administration (FDA). Joly et al. demonstrated that treatment of patients with newly diagnosed pemphigus vulgaris/foliaceus with rituximab (2 × 1 g plus 0.5 g each, in months 12 and 18) plus prednisolone (0.5–1.0 mg/kg/day p.o. for three to six months) was significantly more effective and safer than therapy with oral prednisolone 1.0–1.5 mg/kg/day for 12–18 months (55% difference, 95% confidence interval: [38.4; 71, 7]; p < 0.0001) (32). For moderate and severe pemphigus vulgaris/foliaceus, administration of rituximab (2 × 1 g at an interval of 2–3 weeks) is recommended in combination with systemic corticosteroids (tapering over 3–6 months). Alternatively, conventional therapy with prednisolone p.o. 1.0 mg/kg/day plus azathioprine or mycophenols can be applied (eTable 2) (24). As an alternative to oral corticosteroids, intravenous corticosteroid pulses can be used (24, 31). The guideline recommends another infusion of rituximab (1 g) after six months in the event of relapse or incomplete remission; in refractory patients, the guideline also recommends high-dose intravenous immunoglobulins (IVIg) or immune apheresis (eTable 2) (24, 31).
Currrent clinical trials for treatment of pemphigus are evaluating efficacy and safety of inhibition of the Bruton tyrosine kinase or the neonatal Fc receptor, depletion of desmoglein 3–specific B cells using chimeric autoantibody receptor T cells (CAART), and tolerance induction by nanoparticles (27, 33, e1, e85, e86).
For bullous pemphigoid, the current German AWMF guideline recommends a whole-body application of topical 0.05% clobetasol propionate (40 g/day), a superpotent glucocorticosteroid of class IV, for mild as well as moderate cases, if necessary; for severe cases, this is usually recommended in combination with systemic treatment (24). In a controlled randomized study, topical 0.05% clobetasol propionate (40 g/day) had a comparable effect in patients with bullous pemphigoid as prednisolone (0.5 mg/kg/day) (disease control in moderate cases, topical 100% [95; 100]) versus oral 95% [87; 99], p = 0.06; in severe cases, topical 99% [94; 100] versus oral 91% [83; 96], p = 0.02) (34). As a systemic treatment, prednisolone is given orally at 0.5 mg/kg/day, possibly in combination with the (potentially steroid-sparing) agents azathioprine, dapsone, doxycycline, methotrexate, mycophenolate mofetil, or mycophenolate sodium. Alternatively, dapsone, doxycycline, or methotrexate can also be used as the only systemic treatment without oral corticosteroid (24) (see further details, eTable 1). In randomized controlled trials in patients with bullous pemphigoid, doxycycline was associated with significantly fewer serious adverse events than oral prednisolone (difference 19.0% [7.9; 30.1], p = 0.001), and dapsone was associated with a lower cumulative corticosteroid dose than azathioprine (p = 0.06) (35, 36). IVIg, immunoadsorption, rituximab, cyclophosphamide, or omalizumab can be used in refractory patients (eTable 1) (24, 37, 38, 39, e87).
The severity of MMP is distinguished on the basis of the risk of scarring, as mild/moderate with exclusive involvement of the skin and oral mucosa, or as severe, with involvement of the eyes, nasal mucosa, pharynx, larynx, esophagus, or trachea (30, e84). In the case of mild/moderate MMP, topical treatment with highly potent topical glucocorticoids, possibly in combination with immunomodulators, is often sufficient. For severe MMP, treatment with dapsone combined with systemic corticosteroid (prednisolone, either orally 0.5–1.5 mg/kg/day or as an intravenous pulse therapy) or cyclophosphamide (orally or intravenously) is recommended (e84). In the case of eye involvement, topical treatments that can be used in addition to lubricants include corticosteroids, tetracyclines, and cyclosporine (e84). Timely interdisciplinary treatment of inflammation is crucial before irreversible scarring occurs, especially in the eyes.
The systemic treatments for refractory MMP and other pemphigoid diseases and dermatitis herpetiformis are summarized in eTable 1.
We would like to thank Carolin Mahlerwein (Lübeck) for the schematic overview figure, Ingeborg Atefi and Marina Kongsback-Reim (Lübeck) for help in preparing the flourescent images, and the patients for the clinical images. This work was supported by the strukturelle Förderung des Exzellenz Cluster Precision Medicine in Chronic Inflammation (EXC2167) This work was supported by structural funding from the Cluster of Excellence Precision Medicine in Chronic Inflammation (PMI) (grant number EXC 2167) from the German Research Foundation.
Conflict of Interest Statement
Dr. van Beek has received reimbursement of meeting participation fees and travel expenses from Actelion, speaking honoraria from Infinite Science, and support for shared research projects from Euroimmun.
Prof. Zillikens has received consulting honoraria from Almirall, arGEN-X, Pincell, Roche Pharma, and UCB, speaking honoraria and reimbursement of travel expenses and conference fees from Novartis, Roche Pharma, Abbvie, UCB, Janssen, Almirall, and Fresenius, and support for shared research and development projects from Dompe, Euroimmun, and Fresenius.
Prof. Schmidt has received consulting honoraria from Argen X, UCB, AstraZeneca, Roche, Topas, Almirall, and Thermo Fischer, reimbursement of meeting participation fees and travel expenses as well as speaking honoraria from Biotest, Novartis, and Fresenius, and research support (third-party funds) from UCB, Biotest, Incyte, Novartis, Euroimmun, Argen X, AstraZeneca, Dompe, Admirx, Synthon/Biondis, and Fresenius.
Manuscript received on 3 August 2020, revised version accepted on 27 January 2021.
Translated from the original German by Veronica A. Raker, PhD
Dr. med. Nina van Beek
Department of Dermatology, Venereology, and Allergology
University Medical Center Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160
23538 Lübeck, Germany
Cite this as:
van Beek N, Zillikens D, Schmidt E: Bullous autoimmune dermatoses: clinical features, diagnostic evaluation, and treatment options. Dtsch Arztebl Int 2021; 118: 413–20. DOI: 10.3238/arztebl.m2021.0136
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Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany: Prof. Dr. med. Dr. rer. nat. Enno Schmidt
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