Skin immunofluorescence in the diagnosis of primary bullous diseases—a review of 279 cases

Immunofluorescence (IF) findings are reviewed in 279 consecutive patients with a suspected primary bullous disorder (PBD), IF substantiated the diagnosis of PBD in 51%. The most frequent disorders were bullous pemphigoid (44%), dermatitis herpetiformis (25%) and pemphigus (13%) A diagnosis of PBD was refuted in 29% of cases with bullae; whereas 18% of cases presenting with an itchy papular eruption were shown to have a PBD. All 19 patients with intercellular epidermal IgG ± C3 on direct IF had a clinical and histological diagnosis of pemphigus. Thirty-five patients with granular sub-epidermal IgA ± C3 had dermatitis herpetiformis. Of the 72 with linear C3 ± IgG at the dermo-epidermal junction (DEJ), 62 had bullous pemphigoid, seven herpes gestationis, two cicatricial pemphigoid, and one epidermolysis bullosa acquisita. The 13 patients with linear IgA as the predominant immunoglobulin at the DEJ appeared to form a distinct clinical group, i.e. linear IgA disease. Deposition of IgA at the DEJ appeared to be a marker for mucosal disease in the series as a whole. The presence of a second immunoglobulin at the DEJ (in addition to IgG) in patients with bullous pemphigoid was associated with more severe disease. In 50%, of the biopsies IF was either negative or showed non-specific patterns of staining which did not associate with any particular clinical feature: of these, the most common were diffuse dermal IgG, dermal fibrinogen, granular C3 at the DEJ and vascular deposits. IF examination is of considerable value in the diagnosis and management of PBD provided that non-specific patterns of deposition are interpreted appropriately.     

Immunofluorescence and immunoperoxidase: a comparison for sensitivity in cutaneous immunopathology (author's transl)]

A comparative study of the sensitivities of the immunofluorescence (IF) and immunoperoxydase (IPo) techniques was undertaken. The material used was biopsies of various skin lesions and especially pemphigus, bullous pemphigoid, lupus erythematosus and dermatitis herpetiformis. Direct and indirect methods were performed for the detection of fixed immunoglobulins and complement deposits. With large deposits, immunoperoxydase and immunofluorescence show an equal sensibility and the labeling obtained with IPo is never more intensive than the labeling obtained with IF. In contrast, with small deposits, IPo was less sensitive than IF and appears negative in the majority of the cases and especially in dermatitis herpetiformis. These results are confirmed in using increasing dilutions of conjugates and can be explained by the difficulty in doing the observation of small positive deposits with IPo.     

IgA bullous pemphigoid: a distinct blistering disorder

We report a patient with an eccrine carcinoma who developed localized blistering which clinically resembled pemphigoid, histologically showed subepidermal blistering with features of both dermatitis herpetiformis and bullous pemphigoid, responded to dapsone and exhibited linear IgA deposition on direct immunofluorescence. The nosological position of patients with linear IgA deposition and subepidermal blistering is not clear. A review of the literature reveals that in adults linear IgA deposition may occur in three separate situations: dermatitis herpetiformis, bullous pemphigoid and a third condition of which our case is an example which is best termed IgA bullous pemphigoid. This condition is distinguished from cases of dermatitis herpetiformis with linear IgA by the clinical features and the site of IgA deposition on immunoelectronmicroscopy. It is distinguished from cases of bullous pemphigoid with linear IgA by the absence of circulating IgG antibasement membrane zone antibody, the therapeutic response to dapsone and the frequent occurrence of circulating IgA antibasement membrane zone antibody. IgA bullous pemphigoid has not previously been reported with a carcinoma but the association lends further support to the concept that this eruption represents a variant of pemphigoid.     

A study of benign chronic bullous dermatosis of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood

Eighteen patients with benign chronic bullous dermatosis of childhood were studied and the findings compared with those of dermatitis herpetiformis (twenty-two cases) and bullous pemphigoid (five cases) beginning in childhood. The patients with benign chronic bullous dermatosis of childhood had a moderately pruritic bullous eruption with maximal involvement of the pelvic and perioral regions which tended to occur at an earlier age than either dermatitis herpetiformis or bullous pemphigoid. In contrast to dermatitis herpetiformis one-third of the cases with benign chronic bullous dermaiosis of childhood went into remission. Evidence of coeliac disease was only found in the dermatitis herpetiformis group. Surprisingly both diseases shared HLA-B8. A linear BMZ band of IgA was detected on direct immunofluorescence in all but one of the cases with benign chronic bullous dermatosis of childhood and circulating antibodies were detectable in two-thirds. Routine histopathology was of little value in distinguishing between benign chronic bullous dermaiosis of childhood and dermatitis herpetiformis or bullous pemphigoid. Several paradoxes have yet to be explained before it can be determined whether benign chronic bullous dermatosis of childhood is a variant of dermatitis herpetiformis or linear IgA disease.     

Histology of linear IgA disease, dermatitis herpetiformis, and bullous pemphigoid

The histologic appearances of cutaneous biopsy specimens from 30 patients with linear IgA disease with a continuous band of IgA along the basement membrane, four patients with a linear pattern of granular IgA along the basement membrane, 26 patients with dermatitis herpetiformis who had IgA in the papillary dermis, and 23 patients with bullous pemphigoid who had IgG and/or C3 along the basement membrane were compared. Those with linear and granular IgA and dermatitis herpetiformis differed from those with bullous pemphigoid in five respects. Multiple microabscesses and fibrin at tips of papillae and leukocytoclasis were less common in bullous pemphigoid, whereas a dense infiltrate of eosinophils in and below bullae and a linear infiltrate of eosinophils along the basement membrane were more common in bullous pemphigoid. Also, multilocular bullae and acantholysis were more common in dermatitis herpetiformis than in bullous pemphigoid. Linear IgA disease differed from dermatitis herpetiformis in two respects. Acantholysis and fibrin at the tips of papillae and leukocytoclasis were more common in dermatitis herpetiformis. The specimens from patients with granular IgA did not differ significantly from those with linear IgA or dermatitis herpetiformis. The appearances of biopsy specimens of patch tests with potassium iodide taken from 11 patients with dermatitis herpetiformis and linear or granular IgA disease were similar to those taken from spontaneous lesions.     

The ultrastructural localization of IgA deposits in chronic bullous disease of childhood (CBDC).

A case of bullous disease in a child with linear IgA immune deposits at the basement membrane zone and with some clinical, histological, and electron microscopic characteristics both of dermatitis herpetiformis and bullous pemphigoid, is described. The bulla formed between the basal lamina and basal cell membranes as in bullous pemphigoid, but at the same time there were numerous inflammatory cells in the dermis just below the partly destroyed basal lamina and also abundant fibrin deposits in very recent bulla and in the skin, all of which is rather characteristic of dermatitis herpetiformis. Ultrastructurally, the IgA deposits were located chiefly below the lamina basalis (the dermal type) but also, though less abundantly, in the lamina lucida, very much as we have seen them to be in adult cases with linear IgA immune deposits at the basement membrane zone. The investigations have supplied further evidence showing the chronic bullous disease of childhood to be actually a counterpart of the form in adults with the same linear localization of IgA deposits.     

Adult linear IgA bullous dermatosis: report of three cases

Linear immunoglobulin A bullous dermatosis is a rare autoimmune disease that usually has an excellent prognosis in childhood; however, its control is more difficult in adults. It presents heterogeneous clinical manifestations and is frequently confused with other bullous diseases such as bullous pemphigoid and Duhring’s dermatitis herpetiformis. Dermatologists’ awareness of this disease contributes to early diagnosis and appropriate treatment. We thus report three cases of linear immunoglobulin A dermatosis in adults.     

Electron microscopic studies in dermatitis herpetiformis in relation to the pattern of immune deposits in the skin

Summary Electron microscopic studies were made in 12 cases of dermatitis herpetiformis: 6 of them with a continuous immunofluorescence line of IgA deposits at the dermo-epidermal junction, and the other 6 with granular IgA deposits in the dermal papillae. Six cases of bullous pemphigoid with a continuous immunofluorescence line of IgG deposits at the dermo-epidermal junction were examined similarly for comparison.In dermatitis herpetiformis with the continuous IgA line the ultrastructural characteristics both of dermatitis herpetiformis and bullous pemphigoid were present, even when the histological and clinical features as well as response to sulphapyridine and sulphones were typical of dermatitis herpetiformis. The ultrastructural pattern was essentially the same as in the cases with clinical and histological characteristics of the mixed dermatitis herpetiformis-bullous pemphigoid form, although in the latter there was some predominance of the characteristics of bullous pemphigoid.

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Zusammenfassung Elektronenmikroskopische Untersuchungen wurden in 12 Fällen von Dermatitis herpetiformis durchgeführt. In 6 Fällen waren IgA-Ablagerungen in der dermo-epidermalen Zone linear und in 6 Fällen granulär, in den dermalen Papillen lokalisiert. Zum Vergleich wurden auch 6 Fälle von bullösem Pemphigoid mit typischen IgG linearen Ablagerungen in der dermoepidermalen Zone untersucht.Bei Dermatitis herpetiformis mit linearer IgA-Immunofluorescenz waren die charakteristischen Merkmale sowohl von Dermatitis herpetiformis, als auch von bullösem Pemphigoid vorhanden, sogar wenn das histologische und klinische Bild und die Ansprechbarkeit auf Sulfapyridin oder Sulfone charakteristisch für Dermatitis herpetiformis waren. Das ultrastrukturelle Muster war grundsätzlich dasselbe in Fällen von typischer Dermatitis herpetiformis mit linearen IgA-Ablagerungen und in Fällen von gemischter Form Dermatitis herpetiformis — bullöses Pemphigoid, obwohl in den letzten die Merkmale von bullösem Pemphigoid mehr ausgeprägt waren.

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Offprint requests to: Prof. Dr. Stefania Jabloska (address see above)     

Dermatitis herpetiformis and bullous pemphigoid: a developing association confirmed by immunoelectronmicroscopy

Summary We report a case of dermatitis herpetiformis associated with bullous pemphigoid in which the clinical, histopathological and immunopathological findings were corroborated by direct immunoelectronmicroscopy performed on normal and peri–lesional skin biopsies. Western immunoblotting detected the 180kDa BPAG2 consistent with bullous pemphigoid. HLA–typing confirmed the DR3 DQ2 haplotype associated with dermatitis herpetiformis.     

IgA linear dermatosis of childhood (chronic Bullous disease of childhood)

Of twenty-seven cases of subepidermal blistering disease of children twelve corresponded clinically, histologically and immunologically to dermatitis herpetiforms of adults, six to bullous pemphigoid, and eight to chronic bullous disease of childhood (CBDC), i.e. IgA linear dermatosis. This latter disease seems to be a distinct entity, different from both dermatitis herpetiformis and bullous pemphigoid, and is characterized immunopathologically by linear IgA deposits at the basement membrane zone. These cases usually do not show intestinal involvement and respond well to combined treatment with sulphones and corticosteroids, whereas sulphones or sulphapyridine alone are, even in very high doses, not sufficient for full control of the disease. CBDC or IgA linear dermatosis of childhood may be regarded as a counterpart of IgA linear dermatosis of adults.     

Chronic bullous dermatosis of childhood.

A case of chronic bullous dermatosis of childhood in a 3-year-old boy is described. Immunoflourescence tests were negative and biopsy of the jejunal mucosa showed marked villous atrophy. The dermatosis was brought under control by a combination of diaminodiphenylsulphone and systemic steroids. The relationship with other bullous eruptions of childhood such as dermatitis herpetiformis and bullous pemphigoid is discussed.     

Juvenile dermatitis herpetiformis and chronic acquired bullous disease in children

Eight children with chronic acquired bullous disease were studied by direct immunofluorescence. Multiple jejunal biopsies were examined as well as tissue antigens (HLA-andthcDRw₃ B cell allo-antigen). Juvenile dermatitis herpetiformis (JDH) was diagnosed in seven patients and chronic bullous disease of childhood (CBDC) in one. The use of these different laboratory techniques may make it possible to differentiate more clearly between the different chronic acquired bullous diseases seen in childhood.     

Conjunctival involvement in the autoimmune blistering dermatoses: a clinical and histopathological study

The conjunctiva was examined by slit lamp microscopy and biopsy for direct immunofluorescence (IF) in patients with cicatricial pemphigoid (CP), bullous pemphigoid (BP), pemphigoid gestationes (PG), linear IgA dermatosis (LAD), pemphigus and dermatitis herpetiformis (DH).
In CP, five of 13 patients had definite scarring, seven equivocal, and one no signs. IF showed linear deposition of IgG and/or C₃ along the BMZ in 45%.
In BP, six of 18 patients had fine conjunctival scarring. IF showed linear IgG IgA and/or C₃ in 73 %. Scarring was not observed in one PG patient.
In LAD, three of seven patients had conjunctival scarring, one with marked symblepharon. IF in five patients showed linear IgG without IgA in three.
In pemphigus, neither of two patients had scarring. IF in both showed IgG and/or C3 between epithelial cells.
In DH, one of three patients had fine scarring.
These findings demonstrate that conjunctival involvement may occur in autoimmune bullous dermatoses other than CP and LAD.     

Indirect immunofluorescence testing in bullous diseases

Sera from patients with bullous pemphigoid, pemphigus vulgaris and other bullous conditions have been tested for auto-antibodies by the indirect immunofluorescence (IIF) method. Positive confirmation of the initial diagnosis was obtained in approximately 75% of both pemphigus and pemphigoid cases. It is suggested that the major source of error in the IIF test lies in the existence of ‘pemphigus-like antibodies’; and clinically, in diagnosing some cases of dermatitis herpetiformis as pemphigoid.     

Polymorphic pemphigoid. Is it still worth using this terminology?

The term polymorphic pemphigoid has been used in the literature as a variant of bullous pemphigoid. But this term is imprecise and now obsolete, since patients with linear IgA dermatosis have been reported under this terminology. The patients who develop an atypical subepidermal bullous disease with clinical and histological features of both bullous pemphigoid and dermatitis herpetiformis may actually be classified into three groups: (1) vesicular variant of bullous pemphigoid; (2) linear IgA dermatosis, and (3) mixed subepidermal bullous disease.     

Complement activation in bullous skin diseases.

Pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, and herpes gestationis are members of the chronic vesiculobullous skin diseases of man. The complement system, including both the classical and alternative pathways, may be important in the pathogenesis of these diseases. In pemphigus, early complement components (C1, C4, and C2) appear to be activated in addition to later components (C3 and C5), suggestive of classical pathway activation. Participation of properdin in addition to early complement components suggests local activation of both complement pathways in bullous pemphigoid and cicatricial pemphigoid. Herpes gestationis and dermatitis herpetiformis may be bullous skin diseases entirely mediated by the alternate or properdin pathway. The specific immunopathologic findings in these diseases are discussed.     

Diagnosis of autoimmune bullous diseases

Autoimmune bullous disorders (AIBDs) are a heterogeneous group of rare diseases clinically characterized by erosions and/or blisters on the skin and mucous membranes. AIBDs can be categorized into two groups: pemphigus diseases, characterized by intraepidermal blistering and autoantibodies against desmosomal proteins such as desmoglein (Dsg) 1, Dsg3, members of the plakin family, and subepidermal AIBDs, comprised of pemphigoid diseases and dermatitis herpetiformis. Autoantibodies in dermatitis herpetiformis target transglutaminases 2 and 3, while in pemphigoid disease, autoantibodies are directed against structural proteins of the dermal‐epidermal junction. Although analysis of a perilesional biopsy with direct immunofluorescence (IF) microscopy is still the diagnostic gold standard, several assays have become widely available that allow serological diagnosis in the majority of patients. Standard serological diagnosis includes indirect IF on monkey esophagus and salt‐split human skin. Assays to further characterize autoantibody specificity include ELISA systems based on recombinant forms of the immunodominant regions of the target antigens as well as multivariant indirect IF microscopy tests with several miniature substrates. These serological assays are complemented by various in‐house assays using immunoblotting and ELISA, which are only available in specialized laboratories. Here we review new developments in the diagnosis of AIBDs and describe state‐of‐the‐art diagnostic procedures for this group of diseases.     

Linear arrangement of neutrophils along the Basal layer in bullous pemphigoid: a unique histological finding

Bullous pemphigoid is an inflammatory autoimmune subepidermal bullous disease with distinct immunohistological features. We report an unusual case of a 59-year-old woman with a bullous eruption whose lesional skin biopsy showed a subepidermal blister with a linear arrangement of neutrophils, mimicking linear IgA bullous dermatosis. However, direct immunofluorescence studies demonstrated IgG and C3 linear deposition along the basement membrane zone, compatible with bullous pemphigoid. We suggest that bullous pemphigoid should therefore be considered in the differential diagnosis of neutrophil-rich subepidermal bullous diseases along with dermatitis herpetiformis and linear IgA.     

Linear IgA Bullous Dermatosis

Linear IgA bullous dermatosis (LABD) can mimic bullous pemphigoid (BP) and/or dermatitis herpetiformis (DH) both clinically and histologically. LABD, however, can be distinguished from BP and DH by direct immunofluorescent (IF) demonstration of linear IgA deposits along the basement membrane zone. A retrospective study of 234 cases of BP, 27 cases of LABD, 60 cases of DH, and 20 cases of cicatricial pemphigoid (CP) revealed that BP patients are significantly older than LABD or DH patients and LABD patients are significantly older than DH patients. BP and CP occur more frequently in women (65-70%) than LABD or DH (44-48%). The frequencies of C3 deposits in the basement membrane zone (BMZ) are significantly higher in BP (85%) compared with LABD (18.5%) and DH (28.3%). LABD patients varied in their response to various therapeutic agents. Some responded to corticosteroids and some to sulfones alone, whereas others required a combination of corticosteroids and sulfones.     

BULLOUS PEMPHIGOID IN CHILDHOOD: REPORT OF THREE CASES AND A REVIEW OF LITERATURE

Three proven cases of bullous pemphigoid in childhood which responded to dapsone are reported. The clinical and immunological criteria for diagnosis were similar to those in the aged. This report emphasizes that the condition is a distinctive clinical entity and entirely different from dermatitis herpetiformis and benign chronic bullous dermatosis of childhood.