The authors present their experience related to the diagnosis, treatment, and followup of 431 patients with bullous pemphigoid, 14 patients with juvenile bullous pemphigoid, and 273 patients with pemphigus. The detection of autoantibodies plays an outstanding role in the diagnosis and differential diagnosis. Paraneoplastic pemphigoid is suggested to be a distinct entity from the group of bullous pemphigoid in view of the linear C3 deposits along the basement membrane of the perilesional skin and the “ladder” configuration of autoantibodies demonstrated by western blot analysis. It is proposed that IgA pemphigoid should be differentiated from the linear IgA dermatoses. Immunosuppressive therapy is recommended in which the maintenance dose of corticosteroid is administered every second day, thereby reducing the side effects of the corticosteroids. Following the detection of IgA antibodies (IgA pemphigoid, linear IgA bullous dermatosis, and IgA pemphigus), diamino diphenyl sulfone (dapsone) therapy is preferred alone or in combination. The clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis is stressed.
The most frequent autoimmune bullous skin disorders are bullous pemphigoid (BP) and pemphigus vulgaris (PV). The diagnosis of both diseases relies not only on the clinical features but also on the detection of skin- or membrane-bound and circulating autoantibodies. We first diagnosed subepidermal bullous dermatosis in 1970 [
Since 1970, we have diagnosed and treated 431 patients with BP (age range 38–102 years, mean 71.6 years), 14 children with juvenile BP (age range 3–14 years, mean 7.5 years), and 273 patients with pemphigus (age range 21–83 years, mean 53.9 years). All clinical investigations were conducted with the understanding and the consent of the patients. We are currently treating 47 patients with pemphigus and 45 with BP. The diagnoses were based on the clinical features and routine histological and immunohistological examinations [
The diseases of the pemphigoid group are associated with tissue-bound and circulating autoantibodies against the protein components of hemidesmosomes. BP230 is an intracellular protein of 230-kDa that belongs to the plakin family of cytolinkers [
Autoantibodies in sera from epidermolysis bullosa acquisita (EBA) patients will bind to a 290-kDa band, the alfa chain of collagen VII, whereas this is not the case with sera from all other primary blistering diseases. A second band, of 145 kDa, will often be labeled with EBA antibodies. In most patients with linear IgA dermatoses (LABD), the recognized target antigens are constituted by 97-kDa or 120-kDa proteins, two fractions of BP180. LABD is characterized by circulating IgA antibodies against a 230-kDa antigen of dermal extracts, while in patients with IgA pemphigoid there is no reactivity against this antigen [
In mucous membrane pemphigoid (MMP), the target antigens vary; subsets of patients affected exclusively by oral and ocular mucosal diseases have autoantibodies targeting BP180, laminin332,
Most types of pemphigus antibodies are directed against the desmosomal cadherins known as Dsg1 and Dsg3. The PV antigen is a protein complex of 230 kDa which contains Dsg3 with a molecular weight of 130 kDa and plakoglobin with a molecular weight of 80 kDa. These two proteins are colligated by a disulfide bridge. Dsg3 is expressed primarily in the basal epidermal layers throughout the mucosa, while Dsg1 is expressed primarily in the upper levels of both the mucosa and the epidermis. Dsg3 alone is therefore able to maintain the mucosal integrity, and the impairment of Dsg1 does not cause mucosal lesions. If the patient has only mucocutaneous symptoms, anti-Dsg3 antibodies can be detected. In the event of skin and mucous membrane involvement, antibodies can be found against both Dsg1 and Dsg3. In PV there are always antibodies against Dsg3, while in pemphigus foliaceus (PF) only Dsg1 can be detected. In cases of paraneoplastic pemphigus, there are autoantibodies against some other desmosomal proteins, such as desmoplakin1, desmoplakin2, envoplakin, periplakin, plectin, BP230, BP180, and a not-further-characterized 170 kDa protein [
The diagnosis of autoimmune blistering diseases can be confirmed by histological and immunopathological studies [
BP is most commonly seen in the elderly [
Bullous pemphigoid and pemphigus vulgaris. (a) The clinical picture of generalized pemphigoid with tense blisters, crusts, and erythematous plaques. (b) The histological picture of BP; subepidermal blister. (c) Linear basement zone deposits of IgG in BP. (d) Circulating IgG antibodies bind to the epidermal site of SSS in a patient with BP. (e) The flaccid blister in PV. (f) The histological picture of PV with intraepidermal blister. (g) DIF analysis demonstrates binding of C3 to the intercellular cement substance (ICS) in the upper stratum Malpighii. (h) An IIF study with monkey esophagus as substrate demonstrates the presence of anti-ICS antibody with antihuman IgG conjugate.
PV, the most common form of pemphigus, affects a younger population. PV can involve the skin and/or mucous membranes. Histological studies on cutaneous and mucosal biopsies reveal acantholysis in the suprabasilar part of the epidermis (Figure
The sera of patients with PV typically bind to a 130-kDa protein (Dsg3). The binding of sera to a 160-kDa protein (Dsg1) is seen in patients with PV, but to desmocollin 1 and to Dsg3 in patients with IgA pemphigus. Autoantibodies in paraneoplastic pemphigus typically target Dsg3 and proteins of the plakin family, including envoplakin, periplakin, plectin, desmoplakin, BP180, BP230, and a not-further-characterized 170-kDa protein [
Western blot investigations. (a) A “ladder” configuration can be seen in paraneoplastic pemphigus. (b) A “ladder” configuration of paraneoplastic pemphigoid on western blot analysis.
The recombinant ectodomains of Dsg1 and Dsg3 have been utilized to develop highly sensitive and specific ELISA assays. While the Dsg ectodomains are expressed in insect cells in two of the ELISA systems (MBI, Nagoya, Japan), the ectodomains in the other two available ELISA tests are generated in human HEK293 cells (Euroimmun, Lübeck, Germany) with a high potential of correct expression of conformational epitopes and the advantage that only the mature protein forms are expressed [
BP diseases are subepidermal blistering illnesses with an incidence of 10 new cases per 1 million persons per year [
BP can be classified into two main groups: typical and atypical pemphigoid. In the typical type, generalized, localized, seborrheic, mucous membrane and paraneoplastic variants can be distinguished
In most cases in the BP group we found the linear basement membrane zone deposition of IgG and C3 (365 patients), but in 20 patients linear basement membrane zone reactions with IgA and also with C3 were visible, and in 33 patients only C3, the third component of the complement could be observed. In 13 patients there was linear basement fluorescence with all Ig’s and also with C3.
The localized form is characterized by some solitary eruptions on the head or on the extensor surface of the extremities, without causing complaints
In certain cases of localized pemphigoid, it is not necessary to use systemic corticosteroids; topical corticosteroid therapy can lead to total recovery.
Seborrheic pemphigoid generally presents in older women with erythema and crusting in the seborrheic area [
In MMP, also known as CP, the oral cavity, conjunctiva, and laryngeal, nasal, or genital mucosa may be involved. With the exception of the oral mucosa, it usually heals with scars. In the mouth, desquamative gingivitis is the most frequent form. In cases of eye involvement, blindness can be the most serious complication, due to scarring.
Since the 1970s, we have had 37 patients with tumors (gastrointestinal, gynecological, urological, pulmonary, or endocrine) in BP. In some of these cases, the “ladder” configuration was seen on immunoblot analysis, between the typical 180 and 230 kDA bands of BP; the linear basement zone deposition of C3 was detected only with DIF (Figure
In some of our patients, we observed linear basement zone deposits of IgA together with deposits of C3; in these cases, antibodies against BP180 and BP230 could be detected. We consider that this type should be distinguished from LABD, which is a unique entity both clinically and by western blot analysis.
The atypical group of pemphigoid includes LABD, linear IgM dermatosis, HG, VBSLE, EBA, and juvenile BP or drug-induced pemphigoid [
LABD is predilected on the face, especially periorally, on the scalp, and around the ears. Initially, pruritic, erythematous plaques and papules occur, which later display an annular or herpetiform pattern. New blisters may appear around an older lesion, forming a rosette-like shape [
HG, which occurs most commonly in the third trimester of pregnancy and rarely in the postpartum period, causes intense pruritus. Many patients exhibit urticarial plaques, papules, or multiform lesions on the abdomen, but small herpetiform vesicles are rare, and differential diagnostic problems can therefore arise.
In EBA, inflammation predominates at the beginning, after which scarring and fragility of the skin can be seen. The clinical signs are located at the pressure-exposed areas (Figures
Epidermolysis bullosa aquisita. (a) Erosions in the oral cavity in EBA. (b) Blisters on the wrist in EBA. ((c) and (d)) Blisters on the fingertips in EBA.
Juvenile bullous pemphigoid and bullous eruption of systemic lupus erythematosus. ((a) and (b)) Tense blisters and hemorrhagic crusts on the extremities of a 5-year- old boy with juvenile BP. (c) Erythematous plaques and some blisters in a VBSLE patient. (d) Circulating IgG antibodies bind to the dermal site of SSS in VBSLE.
Infants and children can also be affected; the signs of juvenile BP are similar to those of bullous impetigo (Figures
Subjects with VBSLE have small grouped blisters on the light-exposed skin (Figure
Diseases in the pemphigus group are rare, but often life threatening; they manifest intraepidermal blistering with suprabasal acantholysis. The various forms of pemphigus are differentiated on the basis of their clinical, immunopathological, and molecular biological features [
The most common form is PV, which is characterized by extensive flaccid blisters, mucocutaneous erosions, and a hemorrhagic crust (Figure
Pemphigus vegetans is suspected of being the infectious form of PV [
PF is the superficial and less severe variant of PV [
PE, also called Senear-Usher disease, is similar to PF, but characterized by an additional “lupus band” of granular deposits of IgG and complement along the epidermal basement membrane zone. The clinical symptoms begin with erythematous patches on sun-exposed areas.
The atypical pemphigus group comprises drug-induced, paraneoplastic, IgA pemphigus and PH.
Drug-induced pemphigus can be caused by penicillamine, angiotensin-converting enzyme inhibitors, and pyrazolone derivatives. It displays the symptoms of PF or PE.
In paraneoplastic pemphigus, there are polymorphic cutaneous lesions ranging from blisters to erosions, and even denudation on the trunk and the extremities, but also on the palms and soles. Severe, hemorrhagic, painful oral erosions are typical. This form tends to be associated with hematologic neoplasms. We have diagnosed 2 patients with this disease.
IgA pemphigus has two variants. The subcorneal pustular type is characterized by flaccid pustules which coalesce, leading to annular or polycyclic scaled lesions. The disease which is often associated with IgA gammopathy has a good prognosis. The second intraepidermal neutrophilic type is localized to the intertriginous regions and trunk.
PH combines the clinical features of dermatitis herpetiformis with the immunopathological features of PV. The patients have small grouped vesicle and experience intense pruritus.
For the treatment of autoimmune bullous diseases, we use immunosuppressive therapy and systemic corticosteroid as recommended in the literature [
It may occur that the corticosteroid therapy alone is not sufficient for the attainment of the complete remission. In these cases, and especially in pemphigus, we supplement the therapy with 2.5 mg/body weight/day of azathioprine. In severe or certain special cases, other medicaments and therapies may be suggested, in accordance with the literature (cytostatic drugs, intravenous Ig, and plasmapheresis). Novel targeted treatments such as immunoadsorption or rituximab, an anti-CD20 monoclonal antibody, have recently proven to be highly effective in severe and refractory autoimmune blistering diseases [
Our experience of more than 40 years with several hundred patients with autoimmune bullous disease may be summarized as follows. In the BP group, DIF most frequently reveals linear deposits of IgG and C3 at the dermoepidermal junction, but sometimes linear basal membrane zone deposits of IgA and C3. These cases correspond to classical BP both clinically and by western blot assay, and in some of them circulating antibodies are detected with antihuman IgA conjugate on IIF analysis. We regard these cases as IgA pemphigoid. LABD, which also manifests the linear deposition of IgA, is a separate, unique entity with very low prevalence. Via the typical clinical symptoms and western blotting it can be well differentiated from IgA pemphigoid. We consider it is reasonable to list IgA pemphigoid in another group. Almost all of our juvenile BP cases were IgA pemphigoid. Diamino diphenyl sulfone has a role in the treatment of both diseases. Regarding the literature argument as to whether BP is a paraneoplastic disease [ The ELISA technique has practical importance in the primary diagnosis of both BP and pemphigus. Our investigations have indicated that the methodically chosen antigenic epitope or a combination of epitopes can substitute the total antigen structure immunologically and their production can be solved with the recombinant fusion technique [ With a new method for the treatment of both BP and pemphigus, the corticosteroid side effects were greatly reduced, without loss of the therapeutic effect. We suggest administration of the maintenance corticosteroid dose only every second day in both bullous diseases. The autoantibodies have an outstanding role in both the diagnosis and the differential diagnosis. The detection of tissue-bound autoantibodies by DIF remains of great value in the diagnosis of bullous dermatoses; the ELISA technique is now playing a major part. The detection of circulating autoantibodies (IIF, western blotting, and SSS) is important from the aspect of the differential diagnosis of certain special disease forms. In brief, the technique developed by Lever [