Linear IgA Bullous Dermatosis of Adults TADEUSZ P. CHORZELSKI, MD STEPHANIA JABkOr;JSKA, MD EWA MACIEJOWSKA
Historical
Review
The skin disorder designated as linear IgA bullous dermatosis (LABD), identified in 1979 (l), had been for many years a matter of controversy. This controversy was due mainly to its clinical diversity, as some cases closely resemble dermatitis herpetiformis (DH), some cases are indistinguishable from bullous pemphigoid (BP), and still other cases combine features of both (2). No wonder that some authors considered this disease as DH or its variety (3 - 6), others as BP (7,8), and yet others as intermediate or mixed forms of DH and BP (2,9). In support of the relationship with DH were the skin immune deposits of immunoglobulin A (IgA) class and, as a rule, a dramatic response to sulfones. Supporting the relationship with BP were the linear pattern of IgA deposits along the basement membrane zone (BMZ) and, occasionally, the concomitant presence of complement in the same distribution (1,2,9). Furthermore, at least in some cases, the ultrastructural depositions of IgA, in the lamina lucida, similar to that in BP, suggested some relationship between LABD and BP (10 - 12). In a proportion of cases of LABD, the linear IgA deposits are found below the basal lamina (12-14) or in both locations (6,11,12,15). The main difference from BP is the IgA-class skin deposits, papillary microabscesses in the histology, and, as a rule, a good response to sulfones. The most important reason for separation of LABD from DH is that LABD is not associated with gluten-sensitive enteropathy and, as could be expected, a glutenfree diet is not effective treatment for LABD (16). Recognition of LABD as a distinct entity, despite the clear-cut differences from DH and BP, took a long time until more data on immunoelectron microscopy, serology, genetics, From the Department of Dermatology, Warsaw Academy of Medicine, Warsaw, Poland. Address correspondence to: S. Jablonska, MD, Department ofDertnatology, Warsaw Academy of Medicine, Koszykowa HA, 02-008, Warsaw, Poland.
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and antigen analysis became available; however, some cases still defy strict classification, as they combine immunological features of LABD and BP; that is, both IgA and IgG immune deposits are present (2,9,17,18).
Clinical
Characteristics
Characteristics of LABD as compared with other bullous diseases are summarized in Table 1. The skin lesions are variable: papular, vesicular, bullous, erythematous, edematous, and erythema multiforme-like. Depending on their combination and distribution, the clinical picture may resemble DH, BP, or both (Figs 1 - 3). As in BP, the vesicles and bullae may be tense and of different size, may appear in clusters and on the erythematous and edematous base or on uninvolved skin, and may be symmetric or irregularly distributed all over the body. In some cases the symmetric distribution is confined to the areas typical of DH (buttocks, elbows, knees, dorsa of the hands, scapular region, scalp and face), and if the papular eruption predominates, the initial clinical diagnosis may be suggestive of DH. If the eruption is mainly vesicular, clinical distinction from vesicular pemphigoid is not possible, and if there is, in addition, a herpetiform arrangement in some areas the initial clinical diagnosis might be herpetiform pemphigus (19). The difficulties in clinical diagnosis of LABD are illustrated in Table 2, which lists the initial diagnoses of the cases referred to us for immunologic studies. LABD may appear as a localized variety, for example, in the neck and head areas (20,21). In rare instances, vesiculobullous eruptions may also involve palms and soles, resembling dyshydrotic eczema or pompholyx (22). The mucosal involvement appears to be much more common in LABD than recognized. Although the oral manifestations are usually not prominent, there is one report of a case with predominant oral lesions that preceded skin lesions by 5 years (23). In the British series, 9 of
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Table 1. Differentiation
of Linear 1gA Bullous Dermatosis From Dermatitis Herpetiformis LABD, CBDC*
Clinical features
Vesicular and bullous eruption in cluster, chiefly on lower trunk, groin, lower extremities, facial skin around mouth Variable Chronic, lasting several months or years, possible spontaneous remissions Subepidermal bullae, features characteristic of both DH and BP in some biopsy specimens or even in the same specimen In some places bulla forms below basal lamina as in DH; in some, above it as in BP
PlUlitUS
Course
Histology
Electron microscopy
lmmunofluorescence of biopsy specimens of normal skin Lesional skin
lmmunofluorescence studies
Immunoelectron
serum
microscopy
Jejunal changes
In adults, 33% HLA-BS, HLADQWl and -DRw6
HLA types Response to treatment Sulfones and/or sulfapyridine
Prednisone Combined treatment with sulfones and prednisone Gluten-free
Linear IgA, occasionally also C3 deposits at the BMZ, possible admixture of other immunoglobulins Linear IgA deposits at the BMZ, occasionally also linear C3 deposits No IgG anti-BMZ antibodies, IgA anti-BMZ antibodies, increased frequency on splitskin substrate IgG deposits below the basal lamina and/or in the lamina lucida Usually no changes
diet
Usually favorable but often high doses are needed to control the disease, in the long run may not be satisfactory Usually not satisfactory Treatment of choice if sulfones or sulfapyridine do not control the disease No effect
and Bullous Pemphigoid , _
DH Papular and vesicular eruption in herpetiform arrangement, typical distribution-elbows, knees, buttocks, etc Very severe and burning Chronic, duration of several years; may persist after puberty Subepidermal bulla, polymorphonuclear microabscesses in dermal papillae, leukocytoclasia Bulla in the dermis below the basal lamina, fibrin deposits and inflammatory infiltrates beneath the basal lamina IgA granular deposits in dermal papillae
Deposits may not be detectable, polymorphonuclear leukocytes loaded with IgA No BMZ antibodies; IgA-EmA in cases with flat mucosa
IgA deposits in dermal papillae below BMZ In about 70% of cases, flattening of villi and lymphocytic infiltrates in the lamina propria and in the epithelium HLA-B8, -DRW3, -DR2, and -DQW2 in over 70% of cases
34 patients had oral ulcerations
(23), and some of them also had symptoms of cicatrizing conjunctivitis indistinguishable from benign cicatricial pemphigoid (Cl’) (24). This is why some pathogenetic relationship between LABD and CP has been suggested (17,25 - 28). The pruritus is variable from mild to very severe, with burning and pain, as in DH. Some patients in remission
Large tense bullae on normal or erythematous skin, no characteristic distribution Variable Chronic, duration of several months, possible spontaneous remissions Subepidermal bullae, numerous eosinophils, rare microabscesses consisting mainly of eosinophils Bulla forms between basal laminae as in DH; in some, above it as inBP Linear IgG and C3 deposits at BMZ
Linear IgG and C3 deposits at BMZ
In most cases IgG anti-BMZ antibodies
IgG and C3 deposits on hemidesmosomes and/or in the lamina lucida No changes
No characteristic HLA type in adults, in children not established
Dramatic
In most cases no response, in some favorable but not as dramatic as in DH
Not satisfactory Not needed
Favorable In some cases satisfactory
Favorable
ZABD, linear IgA bullous dermatosis; CBDC, chronic bullous disease of childhoc pd; DH, dermatitis herpetiformis; basement membrane zone. Source. Modified fromChonelski et al (59). l
BP
No effect BP, bulbouspemphigoid;
&A, immunogfobulin
A; BMZ,
claim that they can predict the reappearance of the lesions as the pruritus and burning precede the relapse by several hours or a few days. The natural course of the disease cannot be satisfactorily evaluated because of the long-lasting controversy concerning the recognition of the disease and the very short follow-up. In our experience, most patients go into
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Figure 1. Dermatitis herpetiformis-like, vesiculoerythematous, symmetrically distributed lesions in a 23-year-old man. clinical remission after several months months to 11 years, mean 5.6 years).
or years (10
Atypical Cases In general, systemic manifestations do not occur in LABD. There are anecdotal cases with severe arthralgia, muscle pain, sore throat, and fever (29), and/or severe arthralgia Figure 2. Some vesicular lesions in herpetiform arrangement and some larger, bullous pemphigoid-like bullae on an erythematous base in a 64-year-old woman.
Figure 3. Eythematous and vesicular eruption in herpetiform arrangement in a 59-year-old woman, clinically difficult to classify. Unlike in dermatitis herpetiformis, the eruption is localized in the axilla, and unlike in subcorneal pustular dermatosis, the vesicles are tense. only (30). It is possible that in these cases the blistering eruption could have been induced by drugs applied for arthralgia or other symptoms, and at least in one case the nonsteroidal anti-inflammatory agents were implicated as a provoking factor (30,31). There are some well-documented reports on drug-inTable 2. Initial Clinical Diagnoses in Cases of Linear InA Bullous Dermatosis Initial Clinical Diagnosis
Number of Patients
Linear IgA bullous dermatosis Bullous pemphigoid Dermatitis herpetiformis Pemphigus herpetiformis Erythema multifoxme Total
9 16 16’ 2 1
44
l In one case, dermatitis herpetiformis coexisted with linear IgA bullous demntosis (details in the text).
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duced LABD with regression of the lesions after withdrawal of therapy and reappearance of the eruption on reinstitution of therapy. Various drugs were reported to precipitate the disease: diclofenac (32), lithium carbonate (33), vancomycin (34), intravenous contrast drugs used for urography (35). In all these cases sulfones controlled the blistering eruption. Sunlight has also been suggested as a possible aggravating factor for LABD lesions located mostly in sun-exposed areas. In the described case, the role of UVA was supported by a strongly positive phototest followed by reproduction of bullous lesions (36).
Association With Other Autoimmune Diseases There are some conflicting reports concerning the possible coexistence of LABD and systemic lupus erythematosus (SLE) (37). The presence at the BMZ of IgA in addition to other immunoglobulins that are a part of the LE band makes the interpretation arbitrary. A dramatic response to sulfones could favor such a coexistence; however, cases of bullous SLE without an IgA component may also respond as well. Thus, an association between LABD and SLE remains to be determined after the antigens and circulating IgA anti-BMZ antibodies are defined. There is at least one described case of coexistent SLE and LABD, in which circulating IgA anti-BMZ antibodies were detected reacting with the epidermal side of the split skin (38), as occurs in typical LABD cases; however, the authors could not define the 97-kd antigen as characterized by Zone et al (39), probably because of the low titer of antibody. We have seen one case of an association between LABD and DH. LABD was confirmed on the basis of the linear IgA immune deposits at the BMZ and circulating BMZ antibodies of the IgA class, and DH on the basis of the granular IgA deposits in the papillae and the circulating antiendomysial antibodies of the IgA class (IgAEmA). The patient was a 31-year-old man in whom LABD developed 4 years after DH was diagnosed, while he was on a gluten-free diet and maintenance dose of sulfones. The biopsy showed two patterns of IgA deposits, linear and granular, in some areas one or other predominating. The large bullae of LABD subsided within several weeks, whereas the DH persisted. In another man 50 years of age, LABD preceded by several years the development of pemphigus vulgaris of the oral mucosa. The diagnosis of pemphigus was contirmed by immunopathology of the mucous membranes and circulating pemphigus antibodies of IgG and IgA classes, both in titers of 160. On an increase in the dose of sulfones, the pemphigus disappeared and did not recur, whereas the LABD exacerbated occasionally on maintenance doses of sulfones.
Figure 4. Histology. To the right, subepidermal bulla as in bullous pemphigoid; to the leff, inflammatory infiltrates in dermal papillae with numerous polymorphonuclear leukocytes. H&E, X250.
Association With Internal Malignancies Although very rare, LABD has been reported to develop in patients with internal malignancies, specifically in four cases of Hodgkin’s disease (40-43). The connection between these two disorders was suggested by the parallel course of blistering disease and malignancy in three of the described cases; it was not clear in one case, in which Hodgkin’s disease preceded LABD by several years (41). In single cases, LABD has been reported to be associated with other lymphomas, multiple myelomas, and carcinomas (20,44-48); however, so far there is no convincing evidence for a causal relationship between LABD and any of these malignancies.
Histopathology The bulla in LABD is subepidermal, resembling closely BP or DH in some biopsy specimens from the same patient and/or combining features of both in the same specimen(s) (49) (Table 1 and Fig 4). Papillary microabscesses are usually present, especially if multiple biopsies are taken. The papillary microabscesses and cutaneous infiltrates consist mainly of neutrophils, but may have an admixture of eosinophils, as in BP. Fibrin at the tips of the papillae is less common than in DH (4). Although the neutrophil microabscesses may be indistinguishable from those of DH, such a differentiation is, according to Smith et al (50), possible by use of the camera lucida technique. With this method, the authors found the number of pap& lary neutrophil microabscesses and the length of the epidermal BMZ associated with them to be greater in DH than in LABD, whereas the number of rete tips with neutrophils in basal vacuoles and the length of BMZ asso-
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negative on monkey esophagus as a substrate, two became positive when the “split-skin method’ of Gammon et al (52) was applied. Thus, “split skin” proved to be a more sensitive technique for all BMZ antibodies, both those of the IgG class and those of the IgA class.
Immunoelectron Microscopic Studies
Figure 5. Direct immunofluorescence. Linear &A deposits at the basement membrane zone. X400.
ciated with them were greater in LABD. Smith et al (50) claim that with this technique a correct histologic diagnosis can be made in almost all cases. These studies are of interest because they support the distinctness of LABD; however, for diagnostic purposes such a special histopathologic procedure is not necessary as immunopathology provides a most reliable diagnostic criterion.
Immune Deposits Immune IgA deposits are homogeneous and occur in a linear distribution along the BMZ (Fig 5); in about 25% of biopsies complement components may also be detected in the same pattern. In some cases, granular IgA deposits of DH in linear arrangement along the BMZ can be mistaken for LABD; however, multiple sections will show, in some areas, the typical granular papillary pattern. The biopsies should be taken from the vicinity of the bullae, but typical immunofluorescence patterns can also be found in the normal skin at other sites of the body.
Circulating Anti-Basement Membrane Zone Antibodies of IgA Class Anti-BMZ antibodies of the IgA class are not a frequent finding in LABD. They were detected in 2 of 13 patients by Bhogal et al (51) and in 3 of 37 patients by Chorzelski et al (1). In the latter study, however, of four LABD sera
Immunoelectron microscopic studies have provided conflicting results. In the majority of reported cases, the IgA deposits have been located below the lamina densa (3,13,51,53). In the study of Bhogal et al (51), all 15 cases of LABD showed such a localization. Other authors found deposits in the lamina lucida in some cases and in the sublamina densa in other cases (5,10-12,53-55). There are also reports of deposits in both locations in the same areas (12,15,56,57). Using immunoelectron microscopy, Bhogal et a1 (51) found that in LABD the antibody reacts with the antigen in the sublamina densa region of the basement membrane zone; while using the suction blister method these authors stated that LABD and chronic bullous disease of childhood (CBDC) antigens are present in the lamina lucida (28). These results are difficult to interpret. Prost et al (15) described in 11 cases an electron microscopic pattern claimed to be specific to the disease. The linear deposits formed “a mirror image on each side of the lamina densa from which they were separated by a clear space.” This double localization of IgA immune deposits corresponds to previous findings in two cases (12) (Fig 6) (see article by Jabkonska et al also in this issue).
Unclassified Cases Although cases of LABD may show a variety of clinical symptoms of DH and BP, with large bullae and/or small vesicles, there are cases with similar clinical features differing in immunopathology. The immune deposits consist not only of IgA but show, in addition, IgG and complement components. Such puzzling cases (7) have been previously interpreted as atypical pemphigoid and described under the name polymorphic pemphigoid (8). Jablonska et al have reported unusual cases of this type and called them, initially, intermediate and mixed forms of dermatitis herpetiformis and bullous pemphigoid (2,9). Further experience with similar cases in which exclusively IgA deposits were detected led these authors to recognize this bullous disorder as a new entity designated as LABD (1,58-61); however, cases displaying the concomitant presence of IgA and IgG skin deposits, and sometimes also anti-BMZ circulating antibodies of both classes, remain a problem. Such a case was interpreted by Miyagawa et al (62) as an immunologic overlap of BP and
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Figure 6. Immunoelectron microscopy. 1gA immune deposits are localized mainly in the sublamina densa, partly on the anchoring fibers, and also in the lamina lucida and on hemidesmosomes. X 56,000.
DH. The present authors believe that in the Miyagawa et al case, although exact classification was not possible, true DH can be excluded as the IgA immune deposits were linear and not granular. In another unclassified case reported by Toda et al (63), there were linear IgG, IgA, and C3 deposits in the skin and circulating IgG and IgA BMZ antibodies, found on electron microscopy to bind to the anchoring fibers; however, the ultrastructural dermoepidermal separation occurred in the lamina lucida. In those authors’ opinion, their case cannot be classified in any known category of bullous dermatoses. It is worth stressing that in this case the response to sulfones was not satisfactory and it was necessary to introduce systemic steroids. In one of the present authors’ cases of this type, there was also only a minimal response to sulfones alone, and steroids had to be given in a dose of up to 100 mg a day. Another unusual case was described by Petersen et al (18). The disease presented initially with predominant IgG deposits and circulating IgG BMZ antibodies. After 3 years, IgA deposits predominated, and circulating antibodies were not detectable anymore. As the IgG BMZ antibody did not react with the 220-kd protein, Petersen and co-workers claimed that the antigen differed from that of BP. The present authors have observed nine unclassified cases with linear deposits of IgA, IgG, and complement, and in two, there were circulating BMZ antibodies of both classes; the authors believe that the recognition of such a subset of LABD is important from a practical, and especially therapeutic, point of view as these patients usually do not respond to sulfones alone
and require addition of larger doses of corticosteroids than used in typical LABD. There are no strict criteria for delineating these unusual cases from either LABD or BP. The immunoelectron microscopic “mirror image pattern” on each side of the lamina densa of immune deposits, found also in these cases and supposedly characteristic of LABD, would suggest a relationship between such cases and LABD (15). The nosologic position of unclassified cases remains to be clarified.
Genetics Initial studies focused on HLA-B8, which was found to be present in LABD either as frequently as in the general population (54) or significantly more frequently, up to about 55% versus 30% in the controls and 88% in DH (57,64). The role of genetic factors in both DH and LABD is suggested by the low frequency of HLA-B8 in the Japanese population, resulting in the very rare occurrence of true DH and celiac disease. Cases described previously in Japan as DH proved to be LABD (65). The recent findings on class II antigens point to significant immunogenetic differences between LABD and DH, especially in the DQ region. DQwl is in LABD associated with DRw6, and in DH with DR2 (66). The difference in frequencies of DR3 and DQwl in LABD as compared with DH could provide further evidence for the distinctness of LABD; however, in a more recent paper by the British group, no significant association was found between the disease and the HLA type of the A, B, C, and DR loci (67).
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Pathogenesis Origin of the ZgADeposits Initial studies suggested qualitative differences in the immunoglobulins between LABD and DH (68). In DH, the IgA deposits were found to be dimeric, containing J chain and binding purified secretory piece in vitro (69). In contrast, in the majority of LABD cases, J chain was absent. The authors concluded that in DH, contrary to LABD, IgA originated in the gut mucosa. Studies on IgA subclasses using monoclonal antibodies indicated that IgA deposits in DH are mainly or exclusively of the IgAl subclass (70 - 74). This has not been confirmed in a recent study with the use of polyclonal antibodies prepared in sheep and rabbits, which showed that both DH and LABD patients have a similar distribution of IgAl and IgA2 subclasses (74). Although these results proved not to be correct (personal communication), LABD and DH appear not to differ in respect to the origin of IgA immune deposits. Also, a study on the production of IgA by peripheral blood lymphocytes did not show any differences between LABD and DH (75). Thus, the site of production of IgA deposits in LABD and DH remains to be determined.
No Evidence of Enferopafhy There is still some controversy concerning the occurrence of enteropathy in LABD. Some authors have reported negative findings in all cases studied (54), whereas others have found enteropathy in single cases (20) or even in as many as 25% of cases (64). The discrepancy might be due to the criteria of evaluation of gut mucosa, as the mere presence of lymphocyte infiltration in the epithelium and/or grade I/II flattening of the villi was taken as sufficient evidence for classification as enteropathy. Chorzelski et al did not find any significant changes in the gut of eight patients with LABD (76). The absence of jejunal changes is also supported by invariably negative findings of IgA-EmA, which is a specific marker of gluten-sensitive enteropathy (76). The most important evidence is provided by complete failure of the gluten-free diet (16; Chorzelski et al, unpublished observations).
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sera. These authors showed that the LABD antigen, in contrast to the BP antigen, was not produced by keratinocytes alone, and required the presence of skin fibroblasts. The molecular weight of the LABD antigen reported by the British group was 285 kd (77,78). The reason for such a major discrepancy requires clarification. Immunofluorescence (IF) studies on different substrates showed that the LABD antigen is expressed on various stratified epithelia, except bladder, that contain BP but not EBA antigens. On the other hand, LABD and BP antibodies were found to react with placenta to which EBA antibodies do not bind (79). IgAl subclass antibody bound in vivo to placenta of two patients with LABD, as IgGl does in herpes gestationis. In the latter, however, major histocompatibility complex (MHC) class II subregion molecules, which are absent in LABD, are expressed (77). The in vivo binding of IgA BMZ antibodies may be of pathogenic importance (see below) and merits further studies on the possible transmission of the disease to the newborn, as observed in some cases of herpes gestationis (80,81).
Pathogenic Potential of Basement Membrane Zone lmmunoglobulin A Antibodies An experimental study on the use of normal human skin organ culture and sera from three patients with LABD showed the binding of IgA antibody to the basement membrane, with the resulting dermoepidermal separation (82). Sera from two patients with DH did not produce this effect; however, such a control appears not to be sufficient, as even LABD serum without anti-BMZ antibodies would behave similarly. The dermoepidermal separation did not require complement, as heating of the serum did not affect the results. The proteinase inhibitors added to the cultures prevented the separation of the epidermis, and this provides evidence that proteinases are involved in the formation of the bulla. It is conceivable that proteinases are released from the neutrophils, as it has been shown that IgA deposits in LABD can function as ligands for neutrophil adherence (83). The pathogenic role of IgA anti-BMZ antibodies remains to be confirmed by other experiments, such as passive transfer to the experimental animals.
Antigen of Linear ZgABullous Dermafosis Information on the antigen(s) against which the IgA BMZ antibody is directed is scarce. All available data strongly suggest that the antigen(s) differs from those of BP and EBA (epidermolysis bullosa acquisita). According to Zone et al (39), the IgA antibody of LABD failed to react with the epidermal extract, but did react with the 97-kd band from dermal extract not recognized by normal and BP
Therapy The therapy of choice comprises sulfones (dapsone) or sulfapyridine. These drugs should be applied in every case at the time of diagnosis. The average daily dosage of sulfones ranges from 100 to 150 mg, and that of sulfapyridine, 1.0 to 1.5 g, until the symptoms regress completely. In general, improvement is rapid, and takes no
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more than several days. Gradually the dosage is reduced to 50 mg, and the patient is usually maintained on this dosage for several weeks or months. If the response is not satisfactory, small doses of corticosteroids (30,20, 10 mg daily) should be added (1,18,58,76,84). The combined therapy can also be used from the start, as it allows the dose of sulfones to be reduced, thus avoiding the toxic side effects of sulfones or sulfapyridine. The alternate treatment is sulfamethoxypyridazine, in doses similar to those of sulfapyridine, or salazopyrine in doses of 5.0 to 6.0 g daily, which may be beneficial in some cases, in conjunction with small doses of corticosteroids (85). Single cases responded to antibiotics, such as erythromycin (86; Chorzelski et al, unpublished observation). Colchicine (1.5 mg daily for several weeks) was reported by Aram (87) to be effective in a case in which dapsone could not be continued because of pronounced hemolysis. The action of colchicine was confirmed a year later, when it was reapplied because of a relapse. It produced a dramatic improvement over a 4-day period and complete resolution within 14 days. The present authors’ experience is not that good. It should be stressed that therapy with sulfones, alone or in conjunction with corticosteroids, is in general effective, but the doses and the duration of therapy vary considerably from patient to patient. Some patients require treatment with small doses repeatedly over several years, and some become symptom free after several weeks, but usually reinstitution of drugs is needed for relapses.
Conclusions Linear IgA bullous dermatosis is a subepidermal bullous disease combining clinical and histologic features of DH and BP, and characterized by continuous IgA deposits along the basement membrane zone. In some cases, antiBMZ antibodies of the IgA class are also found in the circulation. Immunoelectron microscopy shows IgA deposits to be localized in the lamina lucida, below the lamina densa, and/or in both locations. The main difference from DH is the absence of gluten-sensitive enteropathy. The therapy of choice consists of sulfones alone or in
herpetiformis (Duhring): munoelectronmicroscopic 1977;69:490-3.
Immunofluorescence studies. J Invest
and imDermatol
4. Pehamberger H, Konrad K, Holubar K. Juvenile dermatitis herpetiformis: An immunoelectron-microscopic study. Br J Dermatol 1979;101:271-7. 5. Yaoita H, Katz SI. Circulating IgA anti-basement membrane zone antibodies in dermatitis herpetiformis. J Invest Dermatol 1977;69:558-60. 6. Meurer M, Schmoeckel C, Braun-Falco 0. Dermatitis herpetiformis Duhring mit linearen Ablagerungen von IgA (lineare IgA-Dermatose). Hautarzt 1984;35:230-9. 7. Honeyman JF, Honeyman A, Lobitz WC, et al. The enigma of bullous pemphigoid and dermatitis herpetiformis. Arch Dermatol 1972;106:22-5. 8. Honeyman JF, Honeyman AR, de la Para MA, et al. Polymorphic pemphigoid. Arch Dermatol 1979;115:423-7. 9. Jablonska S, Chorzelski TP, Blaszczyk M. uberlappungssyndrome bei bull&en Dermatosen. In: Braun-Falco 0, Wolf HH, editors. Fortschritte der praktischen Dermatologie und Venerologie. Berlin: Springer-Verlag, 1975;9:95106. 10. Yaoita H, Katz SI. Immunoelectron microscopic localization of IgA in skin of patients with dermatitis herpetiformis. J Invest Dermatol 1976;67:502-6. 11. Dabrowski J, Chorzelski TP, Jabkonska S, et al. The ultrastructural localization of IgA in skin of a patient with mixed form of dermatitis herpetiformis and bullous pemphigoid. J Invest Dermatol 1978;70:76-9. 12. Dabrowski J, Chorzelski T, Jablonska S, et al. Immunoelectron microscopic studies in IgA linear dermatitis. Arch Dermatol Res 1979;265:289-98. 13. Rantala I, Hietanen J, Soidinmaki H, et al. Immunoelectron microscopic findings in oral mucosa of patients with dermatitis herpetifonnis and linear IgA disease. Stand J Dent Res 1985;93:243-8. 14
Bhogal B, Wojnarowska F, Marsden RA, et al. Linear IgA bullous dermatosis of adults and children: An immunoelecnon microscopic study. Br J Dermatol 1987;117:289 -96.
15. Prost C, de Leca AC, Combemale I’, et al. Diagnosis of adult linear IgA dermatosis by immunoelectron microscopy in 16 patients with linear IgA deposits. J Invest Dermatol 1989;92:39-45.
with small doses of corticosteroids.
16. Leonard JN, Griffiths CEM, Powles AV, et al. Experience with a gluten free diet in the treatment of linear IgA disease. Acta Derm Venereol (Stockh) 1987;67:145-8.
Chorzelski TP, Jablonska S, Beutner EH. Linear IgA bullous dermatosis. Adult form of linear IgA bullous dermatotis. In: Beutner EH, Chorzelski TP, Bean SF, editors. Immunopathology of the skin. New York; Wiley, 1979:315-9. Jablonska S, Chorzelski TI’, Beutner EH, et al. Dermatitis herpetiformis and bullous pemphigoid. Intermediate and mixed forms. Arch Dermatol 1976;112:45-8. Pehamberger H, Konrad K, Holubar K. Circulating IgA antibasement membrane antibodies in linear dermatitis
17. Peters MS, Rogers RS III. Clinical correlations of linear IgA deposition at the cutaneous basement membrane zone. J Am Acad Dermatol 1989;20:761- 70.
combination
References
18. Petersen MJ, Gammon RW, Briggaman RA. A case of linear IgA disease presenting initially with IgG immune deposits. J Am Acad Dermatol 1986;14:1014-9. 19. Jablonska S, Chorzelski TP, Beutner EH, et al. Herpetiformis pemphigus: A variable pattern of pemphigus. Int J Dermatol 1975;14:353-9.
Clinics in Dermatology 2992;9:383-392 20. Mobacken H, Kastrup W, Ljunghall H, et al. Linear IgA dermatosis: A study of ten adult patients. Acta Derm Venereol (Stockh) 1983;63:123-8. 21. Viet-Porges MF, Abi-Rached G, Flaguel B, et al. Dermatite a IgA lineaire a localisation cervicofaciale. Ann Derm Venereol 1987;114:1458-60. 22. Barth JH, Venning VA, Wojnarowska F. Palmo-plantar involvement in auto-immune blistering disordersPemphigoid, linear IgA disease and herpes gestationis. Clin Exp Dermatol 1988;13:85-6. 23. Chan LS, Regezi JA, Cooper KD. Oral manifestation of linear IgA disease. J Am Acad Dermatol 1990;22:362-5. 24. Fuligni A, DiBlasi A, Borgogni L, et al. A peculiar case of linear IgA bullous dermatitis. Arch Dermatol 1991;127:126-7. 25. Leonard JN, Wright P, Williams DM, et al. The relationship between linear IgA disease and benign mucous membrane pemphigoid. Br J Dermatol 1984;110:307-14. 26. Kumar V, Rogozinski T, Yarbrougn C, et al. A case of cicatricial pemphigoid or cicatricial linear IgA bullous dermatosis. J Am Acad Dermatol 1980;2:327-31. 27. Tamaki K, Nashiro K, Ishii A. Cicatricial pemphigoid with IgA deposits. J Dermatol (Tokyo) 1990;17:317-21. 28. Aboobaker J, Bhogal B, Wojnarowska F, et al. The localization of the binding site of circulating IgA antibodies in linear IgA disease of adults, chronic bullous disease of childhood and childhood cicatricial pemphigoid. Br J Dermatol 1987;116:293-302. 29. Leigh G, Marsden RA, Wojnarowska F. Linear IgA dermatosis with severe arthralgia. Br J Dermatol 1988;119:78992. 30. Williams REA. Linear IgA dermatosis with severe arthralgia. Br J Dermatol 1989;121:541-2.
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LABD OF ADULTS 38. Lau M, Kaufmann-Griinzinger I, Raghunath M. A case report of a patient with features of systemic lupus erythematosus and linear IgA disease. Br J Dermatol 1991;124:498502. 39. Zone JJ, Taylor TB, Kadunce DE’, et al. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 1990;85:812-20. 40. Vignon D, Guillaume JC, Revuz J, et al. Association maladie de Hodgkin et dermatose a IgA lineaire. Nouv Presse Med 1982;11:603-4. 41. Kienzler JL, Blanc D, Laurent R, et al. Dermatose bulleuse a IgA lineaire et maladie de Hodgkin. Ann Dermatol Venereol 1983;110:727-8. 42. Bamadas MA, Brunet S, Rodriguez JL. Linear IgA bullous dermatosis associated with Hodgkin’s disease. J Am Acad Dermatol 1988;19:1122-4. 43. Jacyk WK, Nagel GJ, van der Hoven AE. Linear IgA dermatosis and Hodgkin’s lymphoma. Report of a case in an African and review of the literature. J Dermatol (Tokyo) 1990;17:633-7. 44. Polla L, Chavaz D, Didierjean L, et al. Dermatose a IgA lineaire et lymphadenopathie angio-immunoblastique. Dermatologica 1983;167:182-3. 45. Russell-Jones JR, Coolamali SK. IgA bullous pemphigoid: A distinct blistering disorder. Br J Dermatol 1980;102:71925. 46. Godfrey K, Wojnarowska F, Leonard J. Linear IgA disease of adults: Association with lymphoproliferative malignancy and possible role of other triggering factors. Br J Dermat01 1990;123:447-52. 47. McEvoy MT, Connolly SM. Linear IgA dermatosis: Association with malignancy. J Am Acad Dermatol 1990;22:5963.
31. Wojnarowska F, Marsden RA, Bhogal B, et al. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. J Am Acad Dermatol 1988;19:792-805.
48. Sekula SA, Tschen JA, Bean SF. Linear IgA bullous disease in a patient with transitional cell carcinoma of the bladder. Cutis 1986;38:354-62.
32. Gabrielsen TO, Staerfelt F. Drug-induced bullous dermatosis with linear IgA deposits along the basement membrane. Acta Derm Venereol (Stockh) 1981;61:439-41.
49. Blenkinsopp WK, Fry L, Haffenden GP, et al. Histology of IgA disease, dermatitis herpetiformis and bullous pemphigoid. Am J Dermatopathol 1983;5:547-54.
33. McWhirter JD, Hashimoto K, Fayne S, et al. Linear IgA bullous dermatosis related to lithium carbonate. Arch Dermat01 1987;123:1120-2.
50. Smith SB, Harrist TJ, Murphy GF, et al. Linear IgA bullous dermatosis vs dermatitis herpetiformis. Arch Dermatol 1984;120:324-8.
34. Baden L, Apovian C, Imber MJ, et al. Vancomycin-induced linear IgA bullous dermatosis. Arch Dermatol 1988;124:1186-8.
51. Bhogal B, Wojnarowska F, Marsden RA, et al. Linear IgA bullous dermatosis of adults and children: An immunoelectron microscopic study. Br J Dermatol 1987;117:289-96.
35. Lemarchand-Venencie F, Vigouroux F, Blanc F, et al. Dermatose bullouse a IgA lmeaire au d&ours immCdiat dune urographie intra-veineuse. Ann Dermatol Venereol 1987;114:1423-5.
52. Gammon WR, Briggaman RA, Inman AO, et al. Diierentiating anti-lamina lucida and anti-sublamina densa antiBMZ antibodies by indirect immunofluorescence on 1 .O M sodium chloride-separated skin. J Invest Dermatol 1984;82:139-44.
36. Bruley C, Gauchy 0, Beltzer-Garelly E, et al. Dermatose a IgA lineaire photo-aggravee. Ann Dermatol Venereol 1987;114:1358-9. 37. Thaipisuttikul Y, Piamphongsant T, Suwandwela N. Coexistence of linear IgA dermatitis herpetiformis and systemic lupus erythematosus. J Dermatol (Tokyo) 1983;10:161-6.
53. Tanita Y, Masu S, Kato T, et al. Linear IgA bullous dermatosis clinically simulating pemphigus vulgaris. Arch Dermatol 1986;122:246-8. 54. Lawley TJ, Strober W, Yaoita H, et al. Small intestinal biopsies and HLA types in dermatitis herpetiformis patients
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with granular and linear IgA skin deposits. J Invest Dermato1 1980;74:9-12.
72. Olbricht S, Flotte T, Collins B, et al. Dermatitis herpetiformis. Arch Dermatol 1986;122:418-21.
55. Haffenden GP, Ring NP, Leonard JN, et al. Immunoelectron microscopic studies in patients with linear IgA deposits. J Invest Dermatol 1983;80:363A.
73. Egelrud T. Dermatitis herpetiformis: Selective deposition of immunoglobulin Al in granular deposits in clinically normal skin. Acta Dermatovenereol (Stockh) 1986;66:11-5.
56. YamasakiY, HashimotoT, NishikawaT. Dermatitis herpetiformis with linear IgA deposition: Ultrastructural localization of in vivo bound IgA. Acta Derm Venereol (Stockh) 1982;62:401-5.
74. Barghuthy FS, Kumar V, Valeski E, et al. Identification of IgA sub-classes in skin of dermatitis herpetiformis patient. Int Arch Allergy Appl Immunol 1988;85:268-71.
57. Leonard JN, Haffenden GP, Ring NE’, et al. Linear IgA bullous dermatosis in adults-The St Mary’s view. In: Beutner EH, Chorzelski TP, Kumar V, editors. Immunopathology of the skin. New York: Wiley, 1987:421-9. 58. Jabkonska S, Chorzelski T. Dermatose a IgA lineaire. Ann Dermatol Venereol 1979;106:651-5. 59. Chorzelski TP, Jablonska S, Beutner EH, et al. Linear IgA bullous dermatosis. In: Marks R, Christophers E, editors. The epidermis in disease. Lancaster, England: MTP Press, 1981:577-84. 60. Wilson DB, Beutner EH, Kumar V, et al. Linear IgA bullous dermatosis. Int J Dermatol 1985;24:569 - 74. 61. Chorzelski T, JabIoiiska S. Evolving concept of IgA linear dermatosis. Semin Dermatol 1988;7:225-32. 62. Miyagawa S, Kiriyama Y, Shirai T, et al. Chronic bullous disease with coexistent circulating IgG and IgA anti-basement membrane zone antibodies. Arch Dermatol 1981;117:349-53. 63. Toda K, Moriguchi Y, Imamura S. A unique case of subepidermal bullous disease. J Dermatol (Tokyo) 1986;13:1416. 64. Leonard JN, Haffenden GP, Ring NP, et al. Linear IgA disease in adults. Br J Dermatol 1982;102:301-16. 65. Hashimoto K, Miki Y, Nishioka K, et al. HLA antigens in dermatitis herpetiformis among Japanese. J Dermatol (Tokyo) 1980;7:289-91. 66. Sachs JA, Leonard JN, Awad J, et al. A comparative serological and molecular study of linear IgA disease and dermatitis herpetiformis. Br J Dermatol 1988;118:759-64. 67. Venning VA, Taylor CJ, Ting A, et al. HLA type in bullous pemphigoid, cicatricial pemphigoid and linear IgA disease. Clin Exp Dermatol 1989;14:283-85. 68. Leonard JN, Haffenden GP, Unsworth D, et al. Evidence that the IgA in patients with linear IgA disease is qualitatively different from that of patients with dermatitis herpetiformis. Br J Dermatol 1984;110:315-21. 69. Unsworth DJ, Manuel I’D, Walker-Smith JA, et al. A immunofluorescent test for gluten sensitivity. Arch Child 1981;56:864-8. 70. Hall RF’, Nelson DL, Lawley TJ. Identification of IgA classes in skin of patients with dermatitis herpetiformis stract]. J Invest Dermatol 1983;80:364.
new Dis sub[ab-
71. Hall RP, Lawley TJ. Characterization of circulating and cutaneous IgA immune complexes in patients with dermatitis herpetiformis. J Immunol 1985;135:1760-5.
75. Wojnarowska F, Per1 S. Normal IgA production by peripheral blood lymphocytes in dermatitis herpetiformis and linear IgA dermatosis. Arch Dermatol Res 1989;280:494-6. 76. Chorzelski TP, JabIonska S, Beutner EH, et al. Linear IgA bullous dermatosis. In: Beutner EH, Chorzelski TP, Kumar V, editors. Immunopathology of the skin. New York: Wiley, 1987:407-20. 77. Kelly SE, Wojnarowska F. The use of chemically split tissue in the detection of circulating anti-basement membrane zone antibodies in bullous pemphigoid and cicatricial pemphigoid. Br J Dermatol 1988;118:31-40. 78. Wojnarowska F, Whitehead I’, Leigh IM, et al. Identitication of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults. Br J Dermatol 1991;124:157-62. 79. Pothupitiya GM, Wojnarowska F, Bhogal BS, et al. Distribution of the antigen in adult linear IgA disease and chronic bullous dermatosis of childhood suggests that it is a single and unique antigen. Br J Dermatol 1988;118:175-82. 80. Chorzelski TP, Jablonska S, Beutner EH, et al. Herpes gestationis with identical lesions in the newborn. Arch Dermato1 1976;112:1121-9. 81. Katz A, Minta JO, Toole JWP, et al. Immunopathologic study of herpes gestationis in mother and infant. Arch Dermatol 1977;113:1069-72. 82. Akahosi Y, Kanola G, Anan S, et al. Dermato-epidermal blister formation by linear IgA dermatosis sera in normal human skin in organ culture. J Dermatol (Tokyo) 1987;14:552-8. 83. Hendrix JD, Mangum KL, Zone JJ, et al. Cutaneous IgA deposits in bullous disease function as ligands to mediate adherence of activated neutrophils. J Invest Dermatol 1990;94:667- 72. 84. Schiffner JH. Therapy of childhood linear IgA dermatitis herpetiformis. J Am Acad Dermatol 1982;6:403 -4. 85. McFadolen JP, Leonard JN, Pawles AV, et al. Sulphamethoxypyridazine for dermatitis herpetiformis, linear IgA discicatricial pemphigoid. Br J Dermatol ease and 1989;121:759-62. 86. Janniger CK, Wiltz H, Schwartz RA. Adult linear IgA bullous dermatosis: A polymorphic disorder. Cutis 1990;45:37-42. 87. Aram H. Linear IgA bullous dermatosis. Successful treatment with colchicine. Arch Dermatol 1984;120:9601.
Historical
Review
The skin disorder designated as linear IgA bullous dermatosis (LABD), identified in 1979 (l), had been for many years a matter of controversy. This controversy was due mainly to its clinical diversity, as some cases closely resemble dermatitis herpetiformis (DH), some cases are indistinguishable from bullous pemphigoid (BP), and still other cases combine features of both (2). No wonder that some authors considered this disease as DH or its variety (3 - 6), others as BP (7,8), and yet others as intermediate or mixed forms of DH and BP (2,9). In support of the relationship with DH were the skin immune deposits of immunoglobulin A (IgA) class and, as a rule, a dramatic response to sulfones. Supporting the relationship with BP were the linear pattern of IgA deposits along the basement membrane zone (BMZ) and, occasionally, the concomitant presence of complement in the same distribution (1,2,9). Furthermore, at least in some cases, the ultrastructural depositions of IgA, in the lamina lucida, similar to that in BP, suggested some relationship between LABD and BP (10 - 12). In a proportion of cases of LABD, the linear IgA deposits are found below the basal lamina (12-14) or in both locations (6,11,12,15). The main difference from BP is the IgA-class skin deposits, papillary microabscesses in the histology, and, as a rule, a good response to sulfones. The most important reason for separation of LABD from DH is that LABD is not associated with gluten-sensitive enteropathy and, as could be expected, a glutenfree diet is not effective treatment for LABD (16). Recognition of LABD as a distinct entity, despite the clear-cut differences from DH and BP, took a long time until more data on immunoelectron microscopy, serology, genetics, From the Department of Dermatology, Warsaw Academy of Medicine, Warsaw, Poland. Address correspondence to: S. Jablonska, MD, Department ofDertnatology, Warsaw Academy of Medicine, Koszykowa HA, 02-008, Warsaw, Poland.
0
1992 by Elsevier Science Publishing
Co., Inc.
l
0738-081x/92/$5.00
and antigen analysis became available; however, some cases still defy strict classification, as they combine immunological features of LABD and BP; that is, both IgA and IgG immune deposits are present (2,9,17,18).
Clinical
Characteristics
Characteristics of LABD as compared with other bullous diseases are summarized in Table 1. The skin lesions are variable: papular, vesicular, bullous, erythematous, edematous, and erythema multiforme-like. Depending on their combination and distribution, the clinical picture may resemble DH, BP, or both (Figs 1 - 3). As in BP, the vesicles and bullae may be tense and of different size, may appear in clusters and on the erythematous and edematous base or on uninvolved skin, and may be symmetric or irregularly distributed all over the body. In some cases the symmetric distribution is confined to the areas typical of DH (buttocks, elbows, knees, dorsa of the hands, scapular region, scalp and face), and if the papular eruption predominates, the initial clinical diagnosis may be suggestive of DH. If the eruption is mainly vesicular, clinical distinction from vesicular pemphigoid is not possible, and if there is, in addition, a herpetiform arrangement in some areas the initial clinical diagnosis might be herpetiform pemphigus (19). The difficulties in clinical diagnosis of LABD are illustrated in Table 2, which lists the initial diagnoses of the cases referred to us for immunologic studies. LABD may appear as a localized variety, for example, in the neck and head areas (20,21). In rare instances, vesiculobullous eruptions may also involve palms and soles, resembling dyshydrotic eczema or pompholyx (22). The mucosal involvement appears to be much more common in LABD than recognized. Although the oral manifestations are usually not prominent, there is one report of a case with predominant oral lesions that preceded skin lesions by 5 years (23). In the British series, 9 of
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Table 1. Differentiation
of Linear 1gA Bullous Dermatosis From Dermatitis Herpetiformis LABD, CBDC*
Clinical features
Vesicular and bullous eruption in cluster, chiefly on lower trunk, groin, lower extremities, facial skin around mouth Variable Chronic, lasting several months or years, possible spontaneous remissions Subepidermal bullae, features characteristic of both DH and BP in some biopsy specimens or even in the same specimen In some places bulla forms below basal lamina as in DH; in some, above it as in BP
PlUlitUS
Course
Histology
Electron microscopy
lmmunofluorescence of biopsy specimens of normal skin Lesional skin
lmmunofluorescence studies
Immunoelectron
serum
microscopy
Jejunal changes
In adults, 33% HLA-BS, HLADQWl and -DRw6
HLA types Response to treatment Sulfones and/or sulfapyridine
Prednisone Combined treatment with sulfones and prednisone Gluten-free
Linear IgA, occasionally also C3 deposits at the BMZ, possible admixture of other immunoglobulins Linear IgA deposits at the BMZ, occasionally also linear C3 deposits No IgG anti-BMZ antibodies, IgA anti-BMZ antibodies, increased frequency on splitskin substrate IgG deposits below the basal lamina and/or in the lamina lucida Usually no changes
diet
Usually favorable but often high doses are needed to control the disease, in the long run may not be satisfactory Usually not satisfactory Treatment of choice if sulfones or sulfapyridine do not control the disease No effect
and Bullous Pemphigoid , _
DH Papular and vesicular eruption in herpetiform arrangement, typical distribution-elbows, knees, buttocks, etc Very severe and burning Chronic, duration of several years; may persist after puberty Subepidermal bulla, polymorphonuclear microabscesses in dermal papillae, leukocytoclasia Bulla in the dermis below the basal lamina, fibrin deposits and inflammatory infiltrates beneath the basal lamina IgA granular deposits in dermal papillae
Deposits may not be detectable, polymorphonuclear leukocytes loaded with IgA No BMZ antibodies; IgA-EmA in cases with flat mucosa
IgA deposits in dermal papillae below BMZ In about 70% of cases, flattening of villi and lymphocytic infiltrates in the lamina propria and in the epithelium HLA-B8, -DRW3, -DR2, and -DQW2 in over 70% of cases
34 patients had oral ulcerations
(23), and some of them also had symptoms of cicatrizing conjunctivitis indistinguishable from benign cicatricial pemphigoid (Cl’) (24). This is why some pathogenetic relationship between LABD and CP has been suggested (17,25 - 28). The pruritus is variable from mild to very severe, with burning and pain, as in DH. Some patients in remission
Large tense bullae on normal or erythematous skin, no characteristic distribution Variable Chronic, duration of several months, possible spontaneous remissions Subepidermal bullae, numerous eosinophils, rare microabscesses consisting mainly of eosinophils Bulla forms between basal laminae as in DH; in some, above it as inBP Linear IgG and C3 deposits at BMZ
Linear IgG and C3 deposits at BMZ
In most cases IgG anti-BMZ antibodies
IgG and C3 deposits on hemidesmosomes and/or in the lamina lucida No changes
No characteristic HLA type in adults, in children not established
Dramatic
In most cases no response, in some favorable but not as dramatic as in DH
Not satisfactory Not needed
Favorable In some cases satisfactory
Favorable
ZABD, linear IgA bullous dermatosis; CBDC, chronic bullous disease of childhoc pd; DH, dermatitis herpetiformis; basement membrane zone. Source. Modified fromChonelski et al (59). l
BP
No effect BP, bulbouspemphigoid;
&A, immunogfobulin
A; BMZ,
claim that they can predict the reappearance of the lesions as the pruritus and burning precede the relapse by several hours or a few days. The natural course of the disease cannot be satisfactorily evaluated because of the long-lasting controversy concerning the recognition of the disease and the very short follow-up. In our experience, most patients go into
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Figure 1. Dermatitis herpetiformis-like, vesiculoerythematous, symmetrically distributed lesions in a 23-year-old man. clinical remission after several months months to 11 years, mean 5.6 years).
or years (10
Atypical Cases In general, systemic manifestations do not occur in LABD. There are anecdotal cases with severe arthralgia, muscle pain, sore throat, and fever (29), and/or severe arthralgia Figure 2. Some vesicular lesions in herpetiform arrangement and some larger, bullous pemphigoid-like bullae on an erythematous base in a 64-year-old woman.
Figure 3. Eythematous and vesicular eruption in herpetiform arrangement in a 59-year-old woman, clinically difficult to classify. Unlike in dermatitis herpetiformis, the eruption is localized in the axilla, and unlike in subcorneal pustular dermatosis, the vesicles are tense. only (30). It is possible that in these cases the blistering eruption could have been induced by drugs applied for arthralgia or other symptoms, and at least in one case the nonsteroidal anti-inflammatory agents were implicated as a provoking factor (30,31). There are some well-documented reports on drug-inTable 2. Initial Clinical Diagnoses in Cases of Linear InA Bullous Dermatosis Initial Clinical Diagnosis
Number of Patients
Linear IgA bullous dermatosis Bullous pemphigoid Dermatitis herpetiformis Pemphigus herpetiformis Erythema multifoxme Total
9 16 16’ 2 1
44
l In one case, dermatitis herpetiformis coexisted with linear IgA bullous demntosis (details in the text).
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duced LABD with regression of the lesions after withdrawal of therapy and reappearance of the eruption on reinstitution of therapy. Various drugs were reported to precipitate the disease: diclofenac (32), lithium carbonate (33), vancomycin (34), intravenous contrast drugs used for urography (35). In all these cases sulfones controlled the blistering eruption. Sunlight has also been suggested as a possible aggravating factor for LABD lesions located mostly in sun-exposed areas. In the described case, the role of UVA was supported by a strongly positive phototest followed by reproduction of bullous lesions (36).
Association With Other Autoimmune Diseases There are some conflicting reports concerning the possible coexistence of LABD and systemic lupus erythematosus (SLE) (37). The presence at the BMZ of IgA in addition to other immunoglobulins that are a part of the LE band makes the interpretation arbitrary. A dramatic response to sulfones could favor such a coexistence; however, cases of bullous SLE without an IgA component may also respond as well. Thus, an association between LABD and SLE remains to be determined after the antigens and circulating IgA anti-BMZ antibodies are defined. There is at least one described case of coexistent SLE and LABD, in which circulating IgA anti-BMZ antibodies were detected reacting with the epidermal side of the split skin (38), as occurs in typical LABD cases; however, the authors could not define the 97-kd antigen as characterized by Zone et al (39), probably because of the low titer of antibody. We have seen one case of an association between LABD and DH. LABD was confirmed on the basis of the linear IgA immune deposits at the BMZ and circulating BMZ antibodies of the IgA class, and DH on the basis of the granular IgA deposits in the papillae and the circulating antiendomysial antibodies of the IgA class (IgAEmA). The patient was a 31-year-old man in whom LABD developed 4 years after DH was diagnosed, while he was on a gluten-free diet and maintenance dose of sulfones. The biopsy showed two patterns of IgA deposits, linear and granular, in some areas one or other predominating. The large bullae of LABD subsided within several weeks, whereas the DH persisted. In another man 50 years of age, LABD preceded by several years the development of pemphigus vulgaris of the oral mucosa. The diagnosis of pemphigus was contirmed by immunopathology of the mucous membranes and circulating pemphigus antibodies of IgG and IgA classes, both in titers of 160. On an increase in the dose of sulfones, the pemphigus disappeared and did not recur, whereas the LABD exacerbated occasionally on maintenance doses of sulfones.
Figure 4. Histology. To the right, subepidermal bulla as in bullous pemphigoid; to the leff, inflammatory infiltrates in dermal papillae with numerous polymorphonuclear leukocytes. H&E, X250.
Association With Internal Malignancies Although very rare, LABD has been reported to develop in patients with internal malignancies, specifically in four cases of Hodgkin’s disease (40-43). The connection between these two disorders was suggested by the parallel course of blistering disease and malignancy in three of the described cases; it was not clear in one case, in which Hodgkin’s disease preceded LABD by several years (41). In single cases, LABD has been reported to be associated with other lymphomas, multiple myelomas, and carcinomas (20,44-48); however, so far there is no convincing evidence for a causal relationship between LABD and any of these malignancies.
Histopathology The bulla in LABD is subepidermal, resembling closely BP or DH in some biopsy specimens from the same patient and/or combining features of both in the same specimen(s) (49) (Table 1 and Fig 4). Papillary microabscesses are usually present, especially if multiple biopsies are taken. The papillary microabscesses and cutaneous infiltrates consist mainly of neutrophils, but may have an admixture of eosinophils, as in BP. Fibrin at the tips of the papillae is less common than in DH (4). Although the neutrophil microabscesses may be indistinguishable from those of DH, such a differentiation is, according to Smith et al (50), possible by use of the camera lucida technique. With this method, the authors found the number of pap& lary neutrophil microabscesses and the length of the epidermal BMZ associated with them to be greater in DH than in LABD, whereas the number of rete tips with neutrophils in basal vacuoles and the length of BMZ asso-
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negative on monkey esophagus as a substrate, two became positive when the “split-skin method’ of Gammon et al (52) was applied. Thus, “split skin” proved to be a more sensitive technique for all BMZ antibodies, both those of the IgG class and those of the IgA class.
Immunoelectron Microscopic Studies
Figure 5. Direct immunofluorescence. Linear &A deposits at the basement membrane zone. X400.
ciated with them were greater in LABD. Smith et al (50) claim that with this technique a correct histologic diagnosis can be made in almost all cases. These studies are of interest because they support the distinctness of LABD; however, for diagnostic purposes such a special histopathologic procedure is not necessary as immunopathology provides a most reliable diagnostic criterion.
Immune Deposits Immune IgA deposits are homogeneous and occur in a linear distribution along the BMZ (Fig 5); in about 25% of biopsies complement components may also be detected in the same pattern. In some cases, granular IgA deposits of DH in linear arrangement along the BMZ can be mistaken for LABD; however, multiple sections will show, in some areas, the typical granular papillary pattern. The biopsies should be taken from the vicinity of the bullae, but typical immunofluorescence patterns can also be found in the normal skin at other sites of the body.
Circulating Anti-Basement Membrane Zone Antibodies of IgA Class Anti-BMZ antibodies of the IgA class are not a frequent finding in LABD. They were detected in 2 of 13 patients by Bhogal et al (51) and in 3 of 37 patients by Chorzelski et al (1). In the latter study, however, of four LABD sera
Immunoelectron microscopic studies have provided conflicting results. In the majority of reported cases, the IgA deposits have been located below the lamina densa (3,13,51,53). In the study of Bhogal et al (51), all 15 cases of LABD showed such a localization. Other authors found deposits in the lamina lucida in some cases and in the sublamina densa in other cases (5,10-12,53-55). There are also reports of deposits in both locations in the same areas (12,15,56,57). Using immunoelectron microscopy, Bhogal et a1 (51) found that in LABD the antibody reacts with the antigen in the sublamina densa region of the basement membrane zone; while using the suction blister method these authors stated that LABD and chronic bullous disease of childhood (CBDC) antigens are present in the lamina lucida (28). These results are difficult to interpret. Prost et al (15) described in 11 cases an electron microscopic pattern claimed to be specific to the disease. The linear deposits formed “a mirror image on each side of the lamina densa from which they were separated by a clear space.” This double localization of IgA immune deposits corresponds to previous findings in two cases (12) (Fig 6) (see article by Jabkonska et al also in this issue).
Unclassified Cases Although cases of LABD may show a variety of clinical symptoms of DH and BP, with large bullae and/or small vesicles, there are cases with similar clinical features differing in immunopathology. The immune deposits consist not only of IgA but show, in addition, IgG and complement components. Such puzzling cases (7) have been previously interpreted as atypical pemphigoid and described under the name polymorphic pemphigoid (8). Jablonska et al have reported unusual cases of this type and called them, initially, intermediate and mixed forms of dermatitis herpetiformis and bullous pemphigoid (2,9). Further experience with similar cases in which exclusively IgA deposits were detected led these authors to recognize this bullous disorder as a new entity designated as LABD (1,58-61); however, cases displaying the concomitant presence of IgA and IgG skin deposits, and sometimes also anti-BMZ circulating antibodies of both classes, remain a problem. Such a case was interpreted by Miyagawa et al (62) as an immunologic overlap of BP and
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Figure 6. Immunoelectron microscopy. 1gA immune deposits are localized mainly in the sublamina densa, partly on the anchoring fibers, and also in the lamina lucida and on hemidesmosomes. X 56,000.
DH. The present authors believe that in the Miyagawa et al case, although exact classification was not possible, true DH can be excluded as the IgA immune deposits were linear and not granular. In another unclassified case reported by Toda et al (63), there were linear IgG, IgA, and C3 deposits in the skin and circulating IgG and IgA BMZ antibodies, found on electron microscopy to bind to the anchoring fibers; however, the ultrastructural dermoepidermal separation occurred in the lamina lucida. In those authors’ opinion, their case cannot be classified in any known category of bullous dermatoses. It is worth stressing that in this case the response to sulfones was not satisfactory and it was necessary to introduce systemic steroids. In one of the present authors’ cases of this type, there was also only a minimal response to sulfones alone, and steroids had to be given in a dose of up to 100 mg a day. Another unusual case was described by Petersen et al (18). The disease presented initially with predominant IgG deposits and circulating IgG BMZ antibodies. After 3 years, IgA deposits predominated, and circulating antibodies were not detectable anymore. As the IgG BMZ antibody did not react with the 220-kd protein, Petersen and co-workers claimed that the antigen differed from that of BP. The present authors have observed nine unclassified cases with linear deposits of IgA, IgG, and complement, and in two, there were circulating BMZ antibodies of both classes; the authors believe that the recognition of such a subset of LABD is important from a practical, and especially therapeutic, point of view as these patients usually do not respond to sulfones alone
and require addition of larger doses of corticosteroids than used in typical LABD. There are no strict criteria for delineating these unusual cases from either LABD or BP. The immunoelectron microscopic “mirror image pattern” on each side of the lamina densa of immune deposits, found also in these cases and supposedly characteristic of LABD, would suggest a relationship between such cases and LABD (15). The nosologic position of unclassified cases remains to be clarified.
Genetics Initial studies focused on HLA-B8, which was found to be present in LABD either as frequently as in the general population (54) or significantly more frequently, up to about 55% versus 30% in the controls and 88% in DH (57,64). The role of genetic factors in both DH and LABD is suggested by the low frequency of HLA-B8 in the Japanese population, resulting in the very rare occurrence of true DH and celiac disease. Cases described previously in Japan as DH proved to be LABD (65). The recent findings on class II antigens point to significant immunogenetic differences between LABD and DH, especially in the DQ region. DQwl is in LABD associated with DRw6, and in DH with DR2 (66). The difference in frequencies of DR3 and DQwl in LABD as compared with DH could provide further evidence for the distinctness of LABD; however, in a more recent paper by the British group, no significant association was found between the disease and the HLA type of the A, B, C, and DR loci (67).
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Pathogenesis Origin of the ZgADeposits Initial studies suggested qualitative differences in the immunoglobulins between LABD and DH (68). In DH, the IgA deposits were found to be dimeric, containing J chain and binding purified secretory piece in vitro (69). In contrast, in the majority of LABD cases, J chain was absent. The authors concluded that in DH, contrary to LABD, IgA originated in the gut mucosa. Studies on IgA subclasses using monoclonal antibodies indicated that IgA deposits in DH are mainly or exclusively of the IgAl subclass (70 - 74). This has not been confirmed in a recent study with the use of polyclonal antibodies prepared in sheep and rabbits, which showed that both DH and LABD patients have a similar distribution of IgAl and IgA2 subclasses (74). Although these results proved not to be correct (personal communication), LABD and DH appear not to differ in respect to the origin of IgA immune deposits. Also, a study on the production of IgA by peripheral blood lymphocytes did not show any differences between LABD and DH (75). Thus, the site of production of IgA deposits in LABD and DH remains to be determined.
No Evidence of Enferopafhy There is still some controversy concerning the occurrence of enteropathy in LABD. Some authors have reported negative findings in all cases studied (54), whereas others have found enteropathy in single cases (20) or even in as many as 25% of cases (64). The discrepancy might be due to the criteria of evaluation of gut mucosa, as the mere presence of lymphocyte infiltration in the epithelium and/or grade I/II flattening of the villi was taken as sufficient evidence for classification as enteropathy. Chorzelski et al did not find any significant changes in the gut of eight patients with LABD (76). The absence of jejunal changes is also supported by invariably negative findings of IgA-EmA, which is a specific marker of gluten-sensitive enteropathy (76). The most important evidence is provided by complete failure of the gluten-free diet (16; Chorzelski et al, unpublished observations).
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sera. These authors showed that the LABD antigen, in contrast to the BP antigen, was not produced by keratinocytes alone, and required the presence of skin fibroblasts. The molecular weight of the LABD antigen reported by the British group was 285 kd (77,78). The reason for such a major discrepancy requires clarification. Immunofluorescence (IF) studies on different substrates showed that the LABD antigen is expressed on various stratified epithelia, except bladder, that contain BP but not EBA antigens. On the other hand, LABD and BP antibodies were found to react with placenta to which EBA antibodies do not bind (79). IgAl subclass antibody bound in vivo to placenta of two patients with LABD, as IgGl does in herpes gestationis. In the latter, however, major histocompatibility complex (MHC) class II subregion molecules, which are absent in LABD, are expressed (77). The in vivo binding of IgA BMZ antibodies may be of pathogenic importance (see below) and merits further studies on the possible transmission of the disease to the newborn, as observed in some cases of herpes gestationis (80,81).
Pathogenic Potential of Basement Membrane Zone lmmunoglobulin A Antibodies An experimental study on the use of normal human skin organ culture and sera from three patients with LABD showed the binding of IgA antibody to the basement membrane, with the resulting dermoepidermal separation (82). Sera from two patients with DH did not produce this effect; however, such a control appears not to be sufficient, as even LABD serum without anti-BMZ antibodies would behave similarly. The dermoepidermal separation did not require complement, as heating of the serum did not affect the results. The proteinase inhibitors added to the cultures prevented the separation of the epidermis, and this provides evidence that proteinases are involved in the formation of the bulla. It is conceivable that proteinases are released from the neutrophils, as it has been shown that IgA deposits in LABD can function as ligands for neutrophil adherence (83). The pathogenic role of IgA anti-BMZ antibodies remains to be confirmed by other experiments, such as passive transfer to the experimental animals.
Antigen of Linear ZgABullous Dermafosis Information on the antigen(s) against which the IgA BMZ antibody is directed is scarce. All available data strongly suggest that the antigen(s) differs from those of BP and EBA (epidermolysis bullosa acquisita). According to Zone et al (39), the IgA antibody of LABD failed to react with the epidermal extract, but did react with the 97-kd band from dermal extract not recognized by normal and BP
Therapy The therapy of choice comprises sulfones (dapsone) or sulfapyridine. These drugs should be applied in every case at the time of diagnosis. The average daily dosage of sulfones ranges from 100 to 150 mg, and that of sulfapyridine, 1.0 to 1.5 g, until the symptoms regress completely. In general, improvement is rapid, and takes no
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more than several days. Gradually the dosage is reduced to 50 mg, and the patient is usually maintained on this dosage for several weeks or months. If the response is not satisfactory, small doses of corticosteroids (30,20, 10 mg daily) should be added (1,18,58,76,84). The combined therapy can also be used from the start, as it allows the dose of sulfones to be reduced, thus avoiding the toxic side effects of sulfones or sulfapyridine. The alternate treatment is sulfamethoxypyridazine, in doses similar to those of sulfapyridine, or salazopyrine in doses of 5.0 to 6.0 g daily, which may be beneficial in some cases, in conjunction with small doses of corticosteroids (85). Single cases responded to antibiotics, such as erythromycin (86; Chorzelski et al, unpublished observation). Colchicine (1.5 mg daily for several weeks) was reported by Aram (87) to be effective in a case in which dapsone could not be continued because of pronounced hemolysis. The action of colchicine was confirmed a year later, when it was reapplied because of a relapse. It produced a dramatic improvement over a 4-day period and complete resolution within 14 days. The present authors’ experience is not that good. It should be stressed that therapy with sulfones, alone or in conjunction with corticosteroids, is in general effective, but the doses and the duration of therapy vary considerably from patient to patient. Some patients require treatment with small doses repeatedly over several years, and some become symptom free after several weeks, but usually reinstitution of drugs is needed for relapses.
Conclusions Linear IgA bullous dermatosis is a subepidermal bullous disease combining clinical and histologic features of DH and BP, and characterized by continuous IgA deposits along the basement membrane zone. In some cases, antiBMZ antibodies of the IgA class are also found in the circulation. Immunoelectron microscopy shows IgA deposits to be localized in the lamina lucida, below the lamina densa, and/or in both locations. The main difference from DH is the absence of gluten-sensitive enteropathy. The therapy of choice consists of sulfones alone or in
herpetiformis (Duhring): munoelectronmicroscopic 1977;69:490-3.
Immunofluorescence studies. J Invest
and imDermatol
4. Pehamberger H, Konrad K, Holubar K. Juvenile dermatitis herpetiformis: An immunoelectron-microscopic study. Br J Dermatol 1979;101:271-7. 5. Yaoita H, Katz SI. Circulating IgA anti-basement membrane zone antibodies in dermatitis herpetiformis. J Invest Dermatol 1977;69:558-60. 6. Meurer M, Schmoeckel C, Braun-Falco 0. Dermatitis herpetiformis Duhring mit linearen Ablagerungen von IgA (lineare IgA-Dermatose). Hautarzt 1984;35:230-9. 7. Honeyman JF, Honeyman A, Lobitz WC, et al. The enigma of bullous pemphigoid and dermatitis herpetiformis. Arch Dermatol 1972;106:22-5. 8. Honeyman JF, Honeyman AR, de la Para MA, et al. Polymorphic pemphigoid. Arch Dermatol 1979;115:423-7. 9. Jablonska S, Chorzelski TP, Blaszczyk M. uberlappungssyndrome bei bull&en Dermatosen. In: Braun-Falco 0, Wolf HH, editors. Fortschritte der praktischen Dermatologie und Venerologie. Berlin: Springer-Verlag, 1975;9:95106. 10. Yaoita H, Katz SI. Immunoelectron microscopic localization of IgA in skin of patients with dermatitis herpetiformis. J Invest Dermatol 1976;67:502-6. 11. Dabrowski J, Chorzelski TP, Jabkonska S, et al. The ultrastructural localization of IgA in skin of a patient with mixed form of dermatitis herpetiformis and bullous pemphigoid. J Invest Dermatol 1978;70:76-9. 12. Dabrowski J, Chorzelski T, Jablonska S, et al. Immunoelectron microscopic studies in IgA linear dermatitis. Arch Dermatol Res 1979;265:289-98. 13. Rantala I, Hietanen J, Soidinmaki H, et al. Immunoelectron microscopic findings in oral mucosa of patients with dermatitis herpetifonnis and linear IgA disease. Stand J Dent Res 1985;93:243-8. 14
Bhogal B, Wojnarowska F, Marsden RA, et al. Linear IgA bullous dermatosis of adults and children: An immunoelecnon microscopic study. Br J Dermatol 1987;117:289 -96.
15. Prost C, de Leca AC, Combemale I’, et al. Diagnosis of adult linear IgA dermatosis by immunoelectron microscopy in 16 patients with linear IgA deposits. J Invest Dermatol 1989;92:39-45.
with small doses of corticosteroids.
16. Leonard JN, Griffiths CEM, Powles AV, et al. Experience with a gluten free diet in the treatment of linear IgA disease. Acta Derm Venereol (Stockh) 1987;67:145-8.
Chorzelski TP, Jablonska S, Beutner EH. Linear IgA bullous dermatosis. Adult form of linear IgA bullous dermatotis. In: Beutner EH, Chorzelski TP, Bean SF, editors. Immunopathology of the skin. New York; Wiley, 1979:315-9. Jablonska S, Chorzelski TI’, Beutner EH, et al. Dermatitis herpetiformis and bullous pemphigoid. Intermediate and mixed forms. Arch Dermatol 1976;112:45-8. Pehamberger H, Konrad K, Holubar K. Circulating IgA antibasement membrane antibodies in linear dermatitis
17. Peters MS, Rogers RS III. Clinical correlations of linear IgA deposition at the cutaneous basement membrane zone. J Am Acad Dermatol 1989;20:761- 70.
combination
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