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Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults
Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults A comparative study demonstrating clinical and immunopathologic overlap Fenella Wojnarowska, M.A., B.Sc., B.M., Reh.COxon), M.R.C.P.CUK.),* R. A. Marsden, M.B., Ch.B., M.R.C.P.,** B. Bhogal, FIMLS,*** and M, M. Black, M.D., F.R.C.P.(London)*** Oxford and London, England Linear IgA disease of adults, chronic bullous disease of childhood, and the rare childhood cicatricial pemphigoid currently are regarded as separate clinical entities despite their many shared features. All are sulfone-responsive subepidermal bullous diseases associated with linear IgA deposition at the basement membrane zone. In this paper we present a long-term study of 25 cases of adult linear igA disease, 25 cases of chronic bullous disease of childhood, and four cases of childhood Cicatricial pemphigoid, which has revealed further similarities among all three groups. The morphology and distribution of the cutaneous and mucosal lesions were similar; mucosal involvement was present in 80% of patients with adult linear IgA disease, 64% of those with chronic bullous disease of childhood, and 100% of those with childhood cicatricial pemphigoid, and ocular scarring affected patients in all groups. Remission occurred in 64% of those with chronic bullous disease of childhood (the disease was active in 12% after puberty), 48% of those with adult linear IgA disease, and in no cases of childhood cicatricial pemphigoid. HLA B8 and circulating IgA anti-basement membrane zone antibody were more common in chronic bullous disease of childhood than adult linear IgA disease. There were no absolute differences among the three groups, and we suggest that adult linear IgA disease, chronic bullous disease of childhood, and childhood cicatricial pemphigoid are the same disease, with childhood Cicatricial pemphigoid being a more severe form of chronic bullous disease of childhood. (J AM ACAD DERMATOL 1988;19:792-805.)
From the Department of Dermatology.s The Slade Hospital, Oxford, the,Department of Dermatology, ...... S1. George's Hospital, London, and the Institute of Dermatology.wv St. John's Hospital for Diseases of the Skin, London. The data in this article have been presented as Poster Exhibits at the American Academy of Dermatology meetings in 1983, 1984, and 1986; awarded Gold Awards in 1983 (Teaching Value) and 1986 {Original Investigation). Accepted for publication Feb. 8, 1988. Reprint requests to: Dr. Fenella Wojnarowska, Department of Dermatology, The Slade Hospital, Oxford OX3 7 JH, England.
792
Linear IgA deposition at the dermoepidermal junction is found in three characteristic clinical syndromes: linear IgA diseaseof adults (synonyms: linear IgA bullous dermatosis and linear dermatitis herpetiformis),'? chronic bullous disease of childhood (synonyms: benign chronic bullous dermatosis of childhood and juvenile dermatitis herpetiformis)6,7 and childhood cicatricial pemphigoid.8.9 Linear IgA disease of adults, chronic bullous
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 793
I
6
1
2
1
4
5
•
7
•
•
Pr...pub.rtal Post ..pub.rtal
10 15 20 25 10 15 4D 45 50 55
eo
15 70 75 10 15
Age (years)
Fig. 1. Age of onset of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease.
disease of childhood, and childhood cicatricial pemphigoid have been regarded as separate entities. 3• 6, B Adult linear IgA disease, which is distinguished by frequent mucosal involvement, persists indefinitely.vv'? Chronic bullous disease of childhood has previously been regarded as being limited to the skin and remitting before puberty, 11, 12 and childhood cicatricial pemphigoid initially resembles chronic bullous disease of childhood but later progresses to ocular scarring. All, however, are subepidermal bullous diseases that are responsive to dapsone and sulfonamides. A long-term study of 54 patients with linear IgA dermatoses was therefore undertaken to determine the prognosis of this condition and whether the marked differences among the groups previously described': 1, 8 were maintained. PATIENTS AND METHODS
Patients The study consisted of 54 patients with acquired bullous diseases, with linear IgA at the basement membrane zone in clinically uninvolved skin. In 42 patients IgA was the sole immunoreactant, and in 12 IgG, IgM, or C3 was present in addition to IgA. In none were there circulating IgG or C3 antibasement zone antibodies alone. The cases of all patients were studied by one of us, and the patients were followed up for at least 2 years. Although reports of some of these cases have been previously published.' 7, 8, II, 13 additional data are now available. Eleven children and 18 adults were assessed by an ophthalmologist.
Investigations Biopsy specimens of a blister or other skin lesion from 46 patients were used for diagnosis, and the results of histologic findings were classified as similar to or combining features of dermatitis herpetiformis or bullous pemphigoid.' A biopsy specimen was taken from clinically uninvolved or perilesional skin in each case, and standard immunofluorescence techniques were used to detect deposition of IgA, IgG, IgM, C3, and fibrin. Indirect immunofluorescence examination for IgG, IgA, and complement-fixing antibodies was performed with the use of normal human skin and rabbit esophagus as substrate. Typing for human leukocyte antigen (HLA) was determined for 46 patients. Autoantibody screens for both organ- and non-organ-specific antibodies were performed in 40 patients, and serum immunoglobulin levels were estimated in 27 patients. Gluten-sensitive enteropathy. Evidence for glutensensitive enteropathy was sought by clinical history, measurement of serum folate (37 patients) and of IgG and IgA antigliadin antibodies (31 patientsj.lv" and screening for antireticulin antibody (39 patients). Jejunal biopsies were performed in 28 patients, with intraepithelial lymphocyte counts determined in 24 patients.
RESULTS
Clinical features Clinical classification of the 54 cases showed 25 cases of chronic bullous disease of childhood, 4 of childhood cicatricial pemphigoid (onset before puberty), and 25 of adult linear 19A disease (onset
Journal of the American Academy of Dermatology
794 Wojnarowska et al.
Table I. Patients with linear IgA disease of adults, chronic bullous disease of childhood, and childhood cicatricial pemphigoid: clinical and immunologic data Clinical features
Patient No.
Sex
Age at onset
Cutaneous eruption
Chronic bullous disease oj childhood 1 M 2 2 M 6 2Jh 3 F IJh 4 F F 5 5 6 F 10 7 M Y2 7Y2 8 F 9 M 1 10 F 3 11 lY2 M 12 6 M 13 F 2 14 M 3 15 F 6 16 F 3V2 17 M 3Y2 18 M 3 19 F 9 20 F 7 21 M 8
22 23 24 25
5
F F F
8 3V2
M
3Y2
Mucosal involvement
+ + + + +
+
+
+
+ + + + + + + + + + + + + + + + +
after puberty). The clinical features are shown in Table I. Age of onset. The age of onset is shown in Fig. 1 and Table I; there were two peaks, one at 0 to 5 years and one at 60 to 65 years. Chronic bullous disease of childhood commenced at ages ranging from 6 months to 10 years, with a mean of 41h years. There was a similar age of onset with childhood cicatricial pemphigoid from 21h years to 101h years, with a mean of 5 years. There was a wide range of age of onset in adult linear IgA disease, from 14 to 83 years, with a mean of 52 years. Sex distribution. Female patients were more commonly affected than were male patients (1.6: 1) in all groups.
+ + + + + + + + +
+
NK NK
+
+ + + + +
Response to dapsone or sulfonamidcs
+ + + + + + + + + + + + +
+ + + + + + + + + + + +
Duration (yr)
1 6 6 16 7 V2 V2
Remission
+ + + +
7
2 9
10 4 2 3
1 12 6 3
4 5 lh
2 14 2 1
+ +
+
NK + + + + + +
+
+ +
Prodromal events. Many patients reported a preceding illness or ingestion of drugs shortly before the onset of their disease. Thirty-eight percent of the children and 26% of adults had a preceding infection that ranged in severity from an upper respiratory tract infection to typhoid, brucella, and tetanus. Thirty-one percent of patients had taken nonsteroidal anti-inflammatory drugs or antibiotics before onset of the eruption. Some patients noted transient pruritus before their eruption. Three adult patients had a prolonged period of prodromal itching, which in one patient lasted 1 year. Distribution of the eruption. Distribution of the eruption in the three groups is shown in Table II. Chronic bullous disease of childhood. The
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 795
Immunopathology
IgA
+ + + + + + + + + + + + + + + + + + + + + + + + +
C3
+ + +
+
Indirect: Antibasement membrane zone antibodies (titer)
+IgA +IgA +IgA +IgA
(1:4) (1:8) (1:4) (l :64)
+IgA +IgA +IgA +IgA +IgA
(1:4) (1 :8) (1 :8) (1: 16) (l :8)
ND +IgA +IgA +IgA
ND
+IgA (l :32) +IgA (1 :32) +IgA (1: 16)
ND +IgA (1 :8) +
+
+ +IgA (1:32) +IgA (l :8)
majority of patients had involvement of the perineum (84%) (Fig. 2) and the perioral area (60%). This distribution was seen particularly in children under 5 years. The face were involved in 72%, and the ears in 34%. Involvement of the trunk (Fig. 3) and limbs was most common (96%), and many (80%) had involvement of the hands and feet. Older children had a more widespread bullous pemphigoid-like disease (Fig. 3). Childhood cicatricial pemphigoid. Three cases began with a generalized eruption that involved the face, trunk, limbs, hands, and feet; the fourth was typical of chronic bullous disease of childhood. In two long-standing cases that were reviewed in adult life, lesions were restricted to the face and upper body after puberty.
Fig. 2. Chronic bullous disease of childhood: involve-
ment of the perineum with annular vesicular lesions. (From Marsden RA. Clin Exp Dermatol 1982;7:65363.)
Adult linear IgA disease. The trunk (96%) (Figs. 4 and 5) and limbs (88%) were the most commonly affected areas. Dermatitis herpetiformis-like involvement of the limbs, restricted to the extensor surfaces of the knees and elbows, was noted in only two patients. The hands and feet were affected in half the patients, but only three had pompholyx-like involvement. Involvement of the perineum (32%), the face (40%), perioral area (36%), and ears (16%) were less frequent than in the children. Skin lesions. The eruption was usually symptomatic and was described as pruritic or burning. The lesions were variable and changed with time. The earliest lesions were urticated lesions (24%) or annular, polycyclic, or target lesions (30%) (Figs. 3 and 4). These were equally common in adults (32%) and children (32%) (100% of those with childhood cicatricial pemphigoid and 16% of those with chronic bullous disease of childhood); they were so striking in four adults that the initial diagnosis was erythema multiforme. Large bullae, occasionally hemorrhagic, were the most common lesions and occurred in 72% of children and of adults. In the children they were often grouped in the classical "cluster of jewels" sign (Fig. 2). Patients whose eruption was incompletely suppressed by therapy often had urticarial lesions. In both adults and children blisters and vesicles were observed at the edge of annular lesions, creating the "string of beads" sign. Small vesicles
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796 Wojnarowska et al.
Table I. Cont'd Clinical features
Patient No.
Sex
Age at onset
Childhood cicatricial pemphigoid 26 F 2\6 27 F 10\6 28 F 5 29 F 4 Linear IgA disease oj adults 30 F 27 F 31 45 32 M 29 33 F 67 34 F 72 35 M 59 36 M 58 37 62 F 38 57 M 39 F 63 40 F 14 41 F 18 42 F 46 43 F 61 44 M 50 45 M 64
46 47 48 49 50 51 52 53 54
M F F F
F M M F M
28 65 30 69 45 83 79 33 67
Cutaneous eruption
Mucosal involvement
+ +
+ +
+
+
+
+ + + + + + + + +
+ +
+ + + +
+ + + + + + + +
+
+
+
+ + + +
+ + + + + +
+ +
+ + + +
+ + +
Response to dapsone or sulfonamides
+
+ + +
+ + + + + + + + (+) + + + + + + + + + + + + + NT NT
+
Duration (yr)
Remission
3 2 17 33 \6 l,h
\6 2 2 2
<10 2 2 2
+ + + + +
+
+ +
10 40 34 3 3 2
+
10
<\6
+
2
2 5
1
+
+
+, Positive; -, negative; NK, not known; ND, not done; NT, not tested.
or papulovesicles (Fig. 5) were more common in adults (44%) than children (28%). The initial diagnosis in two children and five adults was dermatitis herpetiformis. Six children, as they grew older, had a shift from large bullae to papulovesides, which often were confined to the head and upper trunk. Milia were noted in four patients. Mucous membrane involvement. Mucous membrane involvement occurred in 74% patients (Tables I and III). It was ahnost equally common in those with chronic bullous disease of childhood
(64%) as in those with adult linear IgA disease (80%). Chronic bullous disease of childhood. On direct questioning 40% of the children had ocular symptoms, that is, pain, grittiness, discharge, and redness. They had had disease for 5 to 16 years, and two (of seven examined by an ophthahnologist) had unequivocal signs of fine scarring; 48% had oral involvement with recurrent and troublesome mouth ulcers. One child reported nasal symptoms. The perineal area and external genitalia were
Volume 19 Number 5, Part 1 November 1988
Bullous disease of childhood, childhood pemphigoid, and linear IgA disease
797
Immunopathology
C3
IgA
+ + + +
Indirect: Antibasement membrane zone antibodies (titer)
+IgA (l :8) +
(+)
+ +IgA (neat) +lgA (1:4)
+ + + + + + +
+ + +
+ +
+
+ +
+
+IgA (1:2)
+
+
+
+IgA (l :8) +IgA (1:40) +IgA (1 :2) +C3 (1 :2)
+
+ + + + + +
+ Fig. 3. Chronic bullous disease of childhood: widespread annular bullous eruption that resembles bullous pemphigoid and demonstrates the "string of pearls" sign.
ND + +
+ + +
+ +
+IgA (1:8) +
involved in 72%, but only one child had urinary symptoms. Childhood cicatricial pemphigoid. All four children had ocular scarring, which manifested as symblepharon in three (Fig. 6), with entropion in one and such severe corneal scarring in one that she was registered as blind by the age of 12 years (Fig. 7). Oral ulceration occurred in all four, and in one it was continuous and caused scarring of the lower lip. One had episodes of hoarseness, probably a result of involvement of the larynx, and one
Fig. 4. Adult linear IgA disease: annular lesions on the trunk. (Courtesy H. R. Vickers, Oxford, England.)
Journal of the American Academy of Dermatology
798 Wojnarowska et a/.
Table II. Distribution of cutaneous lesions Clinical diagnosis and number of patients
Chronic bullous disease of childhood: 25 Childhood cicatricial pemphigoid: 4 Linear IgA of disease of adults: 25 Total
Face
Perioral
18
15 (60) 3 (75) 9 (36) 27 (50)
(72) 4 (100) 10 (40) 32 (60)
Hands
24 (96) 4 (100) 24 (96)
2L (96)
21 (84)
1 (25) 8 (32) 30 (56)
24 (96) 4 (l00) 22 (88) ~ (93)
20 (80) 4 (100) 13 (52)
.n. (69)
Table III. Mucous membrane involvement in patients with linear IgA disease of adults, chronic bullous disease of children, and childhood cicatricial pemphigoid No. of patients, with site ,of involvement Clinical diagnosis and number of patients
Ocular (scarring)
Chronic bullous disease of children: 25 Childhood cicatricial pemphigoid: 4 Linear 19A disease of adults: 25 Total
10 (2) 4 (4) 18 (10)
32
Genital
Nasal"
Total· excluding genitals
12
18
16
4
2
4
16
10
5
20
32
30
7
40
(16) • Ascertained in 19 patients.
reported nasal symptoms. Two had involvement of the vulval area, and one also had dysuria. Adult linear IgA disease. Of the 72% of patients with ocular involvement, 60% had symptoms and 40% had definite scarring with symblepharon; an additional 20% had minor scarring. Four patients with scarring had no eye symptoms. In one patient the eye symptoms became the dominant part of his disease. Oral symptoms were noted by 64% patients and in three were very troublesome, with persistent painful ulceration (Fig. 8). Two had symptoms despite suppression of the skin eruption, and the third never had clinical skip involvement (patient No. 53). One patient had severe gingivitis that cleared with dapsone. Two patients had episodes of hoarseness; 20% of patients had nasal symptoms of stuffiness, crusting, and bleeding. In 40% of patients the genitals were involved with erosions and blisters. Associated diseases. Many patients had other
diseases. Five had atopic symptoms and three had autoimmune diseases. There were no marked disease associations. Two adults had carcinomas, one a lymphoma, and one a myeloma. Investigations Histopathology. Biopsy specimens from 46 patients were reviewed, of which only 37 showed a subepidermal blister. Chronic bullous disease oj childhood. Fourteen biopsy specimens showed a subepidermal blister. Eight had. a dermatitis herpetiformis-like appearance (with neutrophils predominating), one was bullous pemphigoid-like (predominantly eosinophils), two showed mixed results, and three findings were unhelpful Childhood cicatricial pemphigoid. One biopsy specimen was dermatitis herpetiforrnis-like and two bullous pemphigoid-like. Adult linear IgA disease. Histologic findings for
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 799
Fig. 5. Adult linear IgA disease: papulovesicular plaque on the trunk.
Fig. 6. Childhood cicatricial pemphigoid: conjunctivitis and symblepharon formation.
six patients showed a dermatitis herpetifonnis-like appearance. More patients showed bullous pemphigoid (eight) or mixed histology (four) than did those with chronic bullous disease of childhood. Two studies were unhelpful. Immunopathology. Immunopathology findings are summarized in Tables I and IV. Linear IgA deposition at the basement membrane zone was present in all patients; in 78% it was the sole immunoreactant. Chronic bullous disease of childhood. IgM was found in five patients, one of whom showed IgM, IgG, and C3 (this pattern was constant for 5
years). Of the patients tested 72% had a circulating IgA antibody in titers ranging from 1: 4 to 1: 64. Childhood cicatricial pemphigoid. One patient showed IgM, IgG, and C3. Three had circulating IgA antibodies present in low titers (neat-l :4). Adult linear IgA disease. IgG and C3 were found together in three patients, one of whom also showed IgM; three patients showed IgG, and 20% of patients had circulating IgA antibody. In two patients the antibodies were transient and related to clinical exacerbation. The titers were low (1 : 2~ 1: 64). One patient had serum that bound C3 at the dermoepidermal junction, without IgG or C3 all
800
Journal of the American Academy of Dermatology
Wojnarowska et ai.
Fig. 7. Childhood cicatricial pemphigoid: end-stage cicatrizing conjunctivitis and symblepharon. (Courtesy P. Wright, London, England.)
direct immunofluorescence. The presence of IgM in addition to IgA did not correlate with mucous membrane involvement, prognosis, or duration of disease. Serum immunoglobulins. Serum IgA was normal in all but four patients. There were minor transient abnormalities in three, and one showed low IgA in association with an IgM paraproteinemia and lymphoma. In all other patients there were only minor abnormalities of IgG and IgM. Autoantibodies. Organ-specific antibodies, mainly thyroid, were present in 23% of patients. They were more common in patients with adult linear IgA disease (27%) than those with chronic bullous disease of childhood (14%) «15% in the normal population). Antinuclear antibodies were present in low titers (1 : 10-1 :40) in 20% of patients with chronic bullous disease of childhood and adult linear IgA disease (similar to our normal population). Immunogenetics. There was a striking difference between the incidence of HLA B8 in chronic bullous disease of childhood, in which the incidence was 76% (16/21) of patients (four of whom were homozygous), in childhood cicatricial pemphigoid, in which it was absent, and in adult linear IgA disease, in which the incidence was 28% (6/21) (20% of the normal population of the United Kingdom have HLA B8). HLA B 12 was present in 16% of those with chronic bullous disease of
childhood, in 25% of those with childhood cicatricial pemphigoid, and in 25% of those with adult linear IgA disease (HLA B12 in the normal population of the United Kingdom, 30%). Gluten-sensitive enteropathy. There was no evidence to support a close association between the linear IgA dermatoses and gluten-sensitive enteropathy. Four patients (three children) had gastrointestinal symptoms, and three patients had raised intraepithelial lymphocyte counts. Two adults had antireticulin antibodies, four raised IgA antigliadin antibodies, and three had transient low folates. Treatment The treatments that were given are shown in Tables I and V. Most patients were maintained on regimens of dapsone, sulfapyridine, or sulfamethoxypyridazine. They responded within 72 hours but relapsed on stopping the drug. Seventeen patients also received steroids. In five the initial diagnosis was bullous pemphigoid, and prednisolone controlled the eruption at doses above 30 mg daily. The value of the addition of low-dose steroids to the therapy of patients whose disease was partially controlled was difficult to assess, inasmuch as the effect was neither rapid nor dramatic. Two patients never received systemic therapy. The mucous membranes responded less well to dapsone and sulfonamides. It was common for
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 801
mucosal activity to persist despite control of the skin lesions. Seven patients adhered to a gluten-free diet for up to 2 years without benefit.
Prognosis Remission, defined as absence of cutaneous lesions or mucous membrane symptoms without treatment, occurred in 52% patients. The duration of the disease varied from a few weeks to 40 years. Chronic bullous disease of childhood. In 64% (16) of patients remission occurred, in most cases within 2 years. Three female patients with active disease are now postpubertal at ages 14, 17, and 22 years. Childhood cicatricial pemphigoid. The skin cleared completely in two patients, but mucous membrane activity continued. Two patients, now 23 and 38 years of age, have active skin disease and severe and cumulative ocular scarring. Adult linear IgA disease. In 48% (12) of patients remission occurred, all except two within 2 years (40% within 1 year); in two the disease was present for only a few weeks. In those cases in which remission did not occur, the mean duration of disease was 7 years (range, 2-40 years). Immunopathologic findings during remission. In both chronic bullous disease of childhood and adult linear IgA disease, the majority of patients lost their immunoreactants from both skin (12/17) and serum (5/9, initially positive). This loss occurred within 6 months in one patient; however, circulating antibody persisted for 4 years after remission in one patient with chronic bullous disease of childhood. DISCUSSION
The relationship of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease is unclear. The diseases have a common immunopathology, differing only in frequency of circulating IgA antibasement zone antibodies. There have been considered to be very marked clinical differences, not only in age of onset but also in extent of mucosal involvement and prognosis. Chronic bullous disease of childhood has been regarded as benign, that is, without any long-term sequelae of mucosal scarring and with an
Fig. 8. Adult linear IgA disease: persistent painful erosion on the tongue.
excellent prognosis, with rermssion occurring before puberty.7.I1,12,16.17 Adult linear IgA disease is characterized by mucosal involvement, 10,13, 18 and remission has been regarded as rare-"; however, IgA deposition also is seen in cicatricial pemphigoid." Contrary to previous reports, this study has shown substantial clinical overlap between chronic bullous disease of childhood and adult linear IgA disease. The high incidence of mucosal involvement and ocular scarring in adult linear IgA disease'? has been confirmed but also has been demonstrated in chronic bullous disease of childhood, which suggests that childhood cicatricial pemphigoid is a severe form of chronic bullous disease of childhood. Remission before puberty has been shown not to be universal in chronic bullous disease of childhood and was more common in patients with adult linear IgA disease than previously reported. The remission rate of the adults (48%), however is less than
Journal of the American Academy of Dermatology
802 Wojnarowska et al.
Table IV. Immunopathologic findings in patients with linear IgA disease of adults, chronic bullous disease of children, and childhood cicatricial pemphigoid No, of patients with linear deposition at dermoepidermal junction
I
Direct
Clinical diagnosis and number of patients
IgA
Chronic bullous disease of childhood: 25 Childhood cicatricial pemphigoid: 4 Linear IgA disease of adults: 25
j
IgG
I
C3
I
IgM
25
5
4
1
25
6
1
3
I
Indirect IgA
18* (1:4-1 :64) 3 (neat-I:4)
5t
I
IgG
I
o o o
C3
o
o
(1:2-1 :64)
*Not done in three patients. tTransient in two patients and not done in one patient.
Table V. Systemic treatments administered Clinical diagnosis (No.)
Chronic bullous disease of childhood: 25 Childhood cicatricial pemphigoid: 4 Linear IgA disease of adults: 25
Dapsone
14: 20-200 mg 3: 100-400 mg 23: 50-600 mg
Systemic treatment: No. treated and dosage range Sulfapyridine Sulfamethoxypyriduine Steroids
15: 500 mg-2 gm 3: 250 mg-3 gm 4: 3 gm
that for the children (64%). The age of onset shows a bimodal distribution, with one peak in childhood and the other in old age; the disease is most common in the nonreproductive years. As in some previously reported series,3,7,8,13 a high proportion of female patients was seen in all groups. The majority of patients complained of intense pruritus or burning or were seen to scratch, although a few patients did not experience these symptoms. A prolonged prodrome of pruritus was unusual and less common than in bullous pemphigoid. Although there were differences in distribution between the patients with chronic bullous disease of childhood and those with adult linear IgA disease, they were not absolute. The trunk and limbs were affected in over 96% of adults and children. The majority of patients with chronic bullous disease of childhood had involvement of the classic sites of the face and perineum, whereas only
2: 500 rng-I gm
a 3: 500 mg-l gm
8: prednisone <10 mg 2: prednisone <15 mg 7: prednisone 5-100 mg
Other
1: arsenic 3: azathioprine 1: colchicine
40% of those with adult linear IgA disease had facial involvement and only 32% had perineal involvement. Younger children tended to have the classic distribution, and the eruption was more like bullous pemphigoid, with widespread large bullae in older children. The lesions were identical in all groups. The annular lesions emphasized previously in adult linear IgA diseases" 13 were seen in all groups, but they were more common in adult linear IgA disease (32%) than in chronic bullous disease of childhood (16%), Large blisters were equally common in chronic bullous disease of childhood and linear IgA disease. Papulovesicles were seen in a minority of persons in both groups. The patient who had no cutaneous involvement resembled the patient reported by Kumar et at.18 Mucous membrane involvement was prominent in all groups and was present in 64% of chronic bul-
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 803
lous disease of childhood cases, 100% of childhood cicatricial pemphigoid cases, and 80% of adult linear IgA disease cases. Ocular involvement was more common in adult linear IgA disease (72%) than in chronic bullous disease of childhood (40%), and it became the dominant feature in all cases of childhood cicatricial pemphigoid and two cases of adult linear IgA disease. Scarring was observed in both children and adults, and the frequency may have been underestimated inasmuch as fewer than half the patients were examined by an ophthalmologist. Ocular scarring had not been previously reported in chronic bullous disease of childhood and was associated with long-standing disease. Oral involvement was similar in both chronic bullous disease of childhood and adult linear IgA disease and was very troublesome in one case of childhood cicatricial pemphigoid and three of adult linear IgA disease. Genital involvement was more common in the children, and nasal problems were limited to the adults. Mucous membrane involvement, with or without ocular scarring, was thus not a basis for distinguishing the groups. Although there were no histologic distinctions between chronic bullous disease of childhood and adult linear IgA disease, findings like bullous pemphigoid were more common in adult linear IgA disease. Dermatitis herpetiformis-like findings were seen equally in both groups. Immunopathologic findings showed IgA at the dermoepidermal junction in all patients. IgM was also present in 20% of patients with chronic bullous disease of childhood, but in only one case of childhood cicatricial pemphigoid and one of adult linear IgA disease in which there were also IgG and C3 present. IgG alone or with C3, which occurred in 15% of cases, was mainly confined to patients with adult linear IgA disease. The significance of these additional immunoreactants is obscure, although they have been observed previously. 1:3-7 IgG and C3 did seem to be associated with mucosal involvement and a poorer prognosis, but there were many exceptions. The patients with this finding bear some resemblance to those with cicatricial pemphigoid, but they have much more prominent cutaneous disease and their disease cannot be clearly distinguished from linear IgA disease by any other criterion. We did not observe a shift from IgG
to 19A with time, as has been described." The circulating IgA antibasement membrane zone antibody was common in children (chronic bullous disease of childhood, 72%; childhood cicatricial pemphigoid, 75%) and rare in adults, in whom it was detected in 20%. The adult titers were lower than the children's, which may reflect the lower incidence of HLA B8 that is associated with high immune responsiveness." These antibodies can persist in both skin and blood for years after remission, but in the majority of patients they disappear in remission, and this was observed within 6 months, suggesting that persistence of IgA is not due to failure to clear it from the skin. Serum IgA was normal in most patients. There was an increased incidence of autoantibodies in the children and adults. This finding had been previously observed in adults.' HLA B8 was increased in the children in an incidence similar to that of previous series.v 3, 7 Occurrence of B8 may predispose the individual to the earlier appearance of the disease and to higher titers of antibodies. 21 All patients treated with dapsone or sulfonamides responded rapidly, including those patients with IgG, IgM, and C3 in addition to IgA. The additional benefit of low- or high-dose steroids was impossible to assess. No cases were controlled with less than 30 mg prednisone alone; however, topical steroids gave symptomatic relief. We concur with Leonard et al.' and Marsden et a1.7, 12 in believing dapsone or sulfonamides to be the treatment of choice. Control of mucous membrane lesions was often difficult; topical steroids alleviated the eye symptoms. Ophthalmologic monitoring of all such patients is mandatory. The evidence from this study suggests that there is no sound clinical or immunopathologic basis for distinguishing chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease from each other. The antigen(s) involved in this disease are as yet uncharacterized. Ultrastructural studies on the site of the antigen with the use of normal skin split through the lamina lucida by suction or by incubation with 1 M NaCF2 have demonstrated both a lamina lucida and possibly a sublamina densa component. 23-25 Immunoelectron microscopic studies have demonstrated the antigen in both the lamina
Journal of the American Academy of Dermatology
804 Wojnarowska et al.
lucida and sublamina densa.2, 26-33 Many of the patients in this study have been examined by both direct and indirect immunoelectron microscopy, and the in vivo deposition of both the antibody and the antigen has been demonstrated in the sublamina densa." Tissue and species distribution studies of the antigen in both adult linear IgA disease and chronic bullous disease of childhood suggest that the antigen is neither the bullous pemphigoid nor the epidermolysisbullosa acquisita antigen." This belief has been confirmed by preliminary immunoblotting studies" and by the lack of cross-reactivity with bullous pemphigoid antigen.20 The relationship of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease to cicatricial pemphigoid remains to be defined. This study supports previous findings1·8. 16 that the three diseases are not a variant of dermatitis herpetiformis because of the lack of association with gluten-sensitive enteropathy, the high incidence of mucosal involvement, and clinical and immunopathologic remission. It is unusual for an autoimmune disease to be associated with an IgA autoantibody, although this does occur in dermatitis herpetiformis, IgA nephropathy, and Henoch-Schonlein purpura. The reason for an IgA response to a normal basement membrane antigen is unclear. The raised titers of IgA, but not IgG antigliadin antibody, suggest that the patients may have an IgA-producing diathesis, although we have been unable to demonstrate abnormal IgA production by peripheral blood lymphocytes." Alternatively, the class of antibody may reflect a mucosal route of entry of a crossreacting antigen, either dietary or infectious. The finding of a gluten-sensitive enteropathy and other gut disease in association with adult linear IgA disease, even in only a few patients," 3 may be relevant, as may the preceding upper respiratory tract infection and other infections in many of the children with this disease.v-" The raised incidence of HLA B8 suggests that this group contains hyperimmune responders," which may explain the increased incidence of anti-basement membrane zone and other autoantibodies. A number of questions remain unanswered. The exact relationship of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and
adult linear IgA disease to each other and to the other subepidermal blistering diseases, as well as the nature and localization of the antigen, currently are being investigated. Finally, the reasons for mounting an IgA response to a normal component of the basement membrane zone and the high frequency of clinical and immunopathological remission require further investigation. We thank Professor R. H. McMinn and Dr. P. Ciclitira for performing the intraepitheLial lymphocyte counts; Dr. P. Ciclitira and Mr. D. Unsworth for estimating the antigliadin antibodies; Dr. Peggy Frith and Mr. P. Wright for the ophthalmologic assessments; and Dr. Philip McKee for classifying the histologic findings.
REFERENCES I. Jablonska S, Chorzelski TP, Beutner EH, Maciejowska E, Rzesa G. Dermatitis herpetiformis and bullous pemphigoid. Arch Dermatol 1976;112:45-8. 2. Lawley rr, Strober W, Yaoita H, Katz SI. Small intestinal biopsies and HLA types in dermatitis herpetiformis patients withgranular and linearIgA skindepostis. J Invest Dermatol 1980;74:9-12. 3. Leonard IN, Haffenden GP, Ring NP, et al. Linear IgA disease in adults. Br J Dermatol 1982;107:301-16. 4. Mobacken H, Kastrup W, Ljunghall K, et al. Linear IgA dermatosis: a study of ten adult patients. Acta Derm Venereol (Stockh) 1983;63:123-8. 5. Wilson BD, Bcutner EH, Kumar V, Chorleski TP, Jablonska S. Linear IgA bullous dermatitis. An immunologically defined disease. Int J Dermatol 1985;24:56974. 6. Chorzelski TP, Jablonska S. IgA linear dermatosis of childhood (chronic bullous disease of childhood). Br J Dcrmatol 1979;101:535-42. 7. Marsden RA, McKee PH, Bhogal B, BlackMM, Kennedy LA. A study of benign chronic bullous dermatosis of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood. Clin Exp DermatoI1980;5:159-72. 8. Wojnarowska F, Marsden RA, Bhogal B, Black MM. Childhood cicatricial pemphigoid with linear IgA deposits. Clin Exp Dermatol 1984;9:407-15. 9. Langeland T. Childhood cicatricial pemphigoid with linear IgA deposits. Acta Derm Venerol (Stockh) 1985; 65:354-5. 10. Leonard JN, Wright P, Williams DM, et aJ. The relationship between linear IgA disease and benign mucous membrane pemphigoid. Br J Dermatol 1984; 110:307-14. II. Grant PW. Juvenile dermatitis herpetiformis. Trans St John's Hosp Dermatol Soc 1968;54:128-36. 12. Marsden RA. The treatment of benign chronic bullous dermatosis of childhood, and dermatitisherpetiforrnis and bullous pemphigoid beginning in childhood. Clin Exp Dermatol 1982;7:653-63. 13. Wojnarowska F, Marsden RA, Bhogal B, Black MM. The spectrum of linear IgA dermatoses. In: McDonald
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14.
15.
16.
17.
18.
19. 20. 21.
22.
23.
24.
25. 26.
Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 80S
DM ed. Immunodermatology . London: Butterworth, 1985:245-9. Unsworth DJ, Leonard IN, McMinn RMH, Swain AF. Holborow EJ, Fry L. Anti-gliadin antibodies and small intestinal mucosal damage in dermatitis herpetiformis. Br J Dermatol 1981;105:653-8. Ciclitira PJ, Ellis HL, Venning VA, et al. Circulating antibodies to gliadin subfractions in dermatitis herpetiformis and linear IgA dermatosis of adults and children. Clin Exp Dermatol 1986;11 :502-9. Kim R, Winkelmann RK. Dermatitis herpetiformis in children-relationship to bullous pemphigoid. Arch Dermatol 1961;83:49-56. Jordan RE, Bean SF, Triftshauser cr, Winkelmann RK. Childhood bullous dermatitis herpetiformis-s-negative immunofluorescent tests. Arch Dermatol 1970; 101:62934. Kumar V, Rogozinski T. Yarbrough C, Beumer EH, Chorzelski TP. A case of cicatricial pemphigoid or cicatricial linear IgA bullous dermatosis. J AM ACAD DERMATOL 1980;2:327-31. Fine JD, Neises GR, Katz SI. Immunofluorescence and immunoelectron microscopic studies in cicatricial pemphigoid. J Invest Dermatol 1984;82:39-43. Petersen MJ, Gammon WR . Briggarnan RA. A case of linear IgA disease presenting initially with IgG immune deposits. JAM ACAD DERMATOL 1986;14:1014-9. Ambinder JM, Chiorazzi N, Gibofsky A, Fotino M. Kunkel HG. Special characteristics of cellular immune function in normal individuals of the HLA-DR3 type. Clin Immunol Immunopath 1982;23:269-74. Woodley D. Sauder D, Talley MJ, Silver M, Grotendorst G, Qwarnstrom E. Localization of basement membrane components after dermal-epidermal junction separation. J Invest Dermatol 1983;81:149-53. Aboobaker J, Bhogal B, Wojnarowska F, Black MM, McKee P. The localization of circulating IgA antibodies in linear IgA disease, chronic bullous disease of childhood and childhood cicatricial pemphigoid using suction blisters as substrate. Br J Dermatol 1987;116:293-03. Wojnarowska F. Pothupitiya GM, Bhogal BS, Black MM, McKee PH: Comparison of the antigen in linear IgA bullous dermatosis with the antigens in epidermolysis bullosa acquisita and bullous pemphigoid suggests it is a unique antigen. In: Caputo R, ed. Immunodermatology. Rome: Cicedizioni Internazionali 1987:237-40. Roberts LJ, Sontheimer RD. Chronic bullous dermatosis of childhood: immunopathologic studies. Paediatr Dermatol 1987;4:6-10. Yaoita H, Hertz KC, Katz SI. Dermatitis herpetiformis:
27. 28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
immunoelectron microscopic and ultrastructural studies of a patient with linear deposition of IgA . J Invest DermatoI1976;67:69i-5. Yaoita H, Katz SI. Circulating IgA anti-basement membrane zone antibodies in dermatitis herpetiformis, J Invest Dermatol 1977;69:558-60. Pehamberger H, Konrad K, Holubar K. Circulating 19A anti-basement membrane antibodies in linear dermatitis herpetiformis (Duhring) : immunofluorescence and immunoelectron microscopic studies. J Invest Dermatol 1977; 69:490-3. Dabrowski J, Chorzelski T, Jablonska S, Krainska T, Jarzabek-Chorzelska M . Immunoelectron microscopic studies in IgA linear dermatosis . Arch Dermatol Res 1979;265:289-98. Dabrowski J, Chorzelski TP, Jablonska S, Krainska T, Jarzabek-Chorzelska M. The ultrastructural localization of 19A deposits in chron ic bullous disease of chiidhood (CBDC). J Invest Dermatol 1979;72:291-5. Yamasaki Y. Hashimoto T, N ishikawa T. Dermatitis herpetiformis with linear 19A deposition: ultrastructural localization of in vivo bound IgA . Acta Derm Venereal (Stockh) 1982;62:401-5. Fry L. ImrnunoHaffenden GF, Ring Np, Leonard electron microscopical studies in patients with linear IgA deposits [abstract] . J Invest Dermatol 198~;80:J63. Horiguchi Y, Toda xr, Okamoto H. Imamura S: Immunoelectron microscopic observations in a case of linear 19A bullous dermatosis of childhood. JAM ACAD DERMATOL 1986;14:593-9. Bhogal B, Wajnarowska F, Marsden RA, Das A, Black MM, McKee PH. Linear 19A bullous dermatosis of adults and children. An irnmunoelectron microscopic study. Br J Dermatol 1987;117:289-96. Pothupitiya GM, WojI}arowska F, Ilhogal BS, Black MM. The tissue distribution and phylogenetic distribution of the antigen in adult linear IgA disease · a,nd chronic bullous dermatosis of childhood suGG6Sl§ that it is a single and unique antigen. Br J Dermatol 1988;1l~: 175-83. Wojnarowska F, Whitehead p. Bhogal B. Plack MM. Leigh 1M. Characterisation of the antigen in chronic. bullous dermatosis of childhood and adult linear IgA disease [abstract] . Br J Dermatol 1988;118:268. Wojnarowska F, Perl S. Normal IgA ·production by peripheral blood lymphocytes in dermatitis herpetiforrnis and linear IgA dermatosis . Arch Dermatol Res ' (in
m,
press). 38. Berlin C. Dermatitis herpetiformis in children, Br J Dermatol 1982;64:281-90.
From the Department of Dermatology.s The Slade Hospital, Oxford, the,Department of Dermatology, ...... S1. George's Hospital, London, and the Institute of Dermatology.wv St. John's Hospital for Diseases of the Skin, London. The data in this article have been presented as Poster Exhibits at the American Academy of Dermatology meetings in 1983, 1984, and 1986; awarded Gold Awards in 1983 (Teaching Value) and 1986 {Original Investigation). Accepted for publication Feb. 8, 1988. Reprint requests to: Dr. Fenella Wojnarowska, Department of Dermatology, The Slade Hospital, Oxford OX3 7 JH, England.
792
Linear IgA deposition at the dermoepidermal junction is found in three characteristic clinical syndromes: linear IgA diseaseof adults (synonyms: linear IgA bullous dermatosis and linear dermatitis herpetiformis),'? chronic bullous disease of childhood (synonyms: benign chronic bullous dermatosis of childhood and juvenile dermatitis herpetiformis)6,7 and childhood cicatricial pemphigoid.8.9 Linear IgA disease of adults, chronic bullous
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 793
I
6
1
2
1
4
5
•
7
•
•
Pr...pub.rtal Post ..pub.rtal
10 15 20 25 10 15 4D 45 50 55
eo
15 70 75 10 15
Age (years)
Fig. 1. Age of onset of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease.
disease of childhood, and childhood cicatricial pemphigoid have been regarded as separate entities. 3• 6, B Adult linear IgA disease, which is distinguished by frequent mucosal involvement, persists indefinitely.vv'? Chronic bullous disease of childhood has previously been regarded as being limited to the skin and remitting before puberty, 11, 12 and childhood cicatricial pemphigoid initially resembles chronic bullous disease of childhood but later progresses to ocular scarring. All, however, are subepidermal bullous diseases that are responsive to dapsone and sulfonamides. A long-term study of 54 patients with linear IgA dermatoses was therefore undertaken to determine the prognosis of this condition and whether the marked differences among the groups previously described': 1, 8 were maintained. PATIENTS AND METHODS
Patients The study consisted of 54 patients with acquired bullous diseases, with linear IgA at the basement membrane zone in clinically uninvolved skin. In 42 patients IgA was the sole immunoreactant, and in 12 IgG, IgM, or C3 was present in addition to IgA. In none were there circulating IgG or C3 antibasement zone antibodies alone. The cases of all patients were studied by one of us, and the patients were followed up for at least 2 years. Although reports of some of these cases have been previously published.' 7, 8, II, 13 additional data are now available. Eleven children and 18 adults were assessed by an ophthalmologist.
Investigations Biopsy specimens of a blister or other skin lesion from 46 patients were used for diagnosis, and the results of histologic findings were classified as similar to or combining features of dermatitis herpetiformis or bullous pemphigoid.' A biopsy specimen was taken from clinically uninvolved or perilesional skin in each case, and standard immunofluorescence techniques were used to detect deposition of IgA, IgG, IgM, C3, and fibrin. Indirect immunofluorescence examination for IgG, IgA, and complement-fixing antibodies was performed with the use of normal human skin and rabbit esophagus as substrate. Typing for human leukocyte antigen (HLA) was determined for 46 patients. Autoantibody screens for both organ- and non-organ-specific antibodies were performed in 40 patients, and serum immunoglobulin levels were estimated in 27 patients. Gluten-sensitive enteropathy. Evidence for glutensensitive enteropathy was sought by clinical history, measurement of serum folate (37 patients) and of IgG and IgA antigliadin antibodies (31 patientsj.lv" and screening for antireticulin antibody (39 patients). Jejunal biopsies were performed in 28 patients, with intraepithelial lymphocyte counts determined in 24 patients.
RESULTS
Clinical features Clinical classification of the 54 cases showed 25 cases of chronic bullous disease of childhood, 4 of childhood cicatricial pemphigoid (onset before puberty), and 25 of adult linear 19A disease (onset
Journal of the American Academy of Dermatology
794 Wojnarowska et al.
Table I. Patients with linear IgA disease of adults, chronic bullous disease of childhood, and childhood cicatricial pemphigoid: clinical and immunologic data Clinical features
Patient No.
Sex
Age at onset
Cutaneous eruption
Chronic bullous disease oj childhood 1 M 2 2 M 6 2Jh 3 F IJh 4 F F 5 5 6 F 10 7 M Y2 7Y2 8 F 9 M 1 10 F 3 11 lY2 M 12 6 M 13 F 2 14 M 3 15 F 6 16 F 3V2 17 M 3Y2 18 M 3 19 F 9 20 F 7 21 M 8
22 23 24 25
5
F F F
8 3V2
M
3Y2
Mucosal involvement
+ + + + +
+
+
+
+ + + + + + + + + + + + + + + + +
after puberty). The clinical features are shown in Table I. Age of onset. The age of onset is shown in Fig. 1 and Table I; there were two peaks, one at 0 to 5 years and one at 60 to 65 years. Chronic bullous disease of childhood commenced at ages ranging from 6 months to 10 years, with a mean of 41h years. There was a similar age of onset with childhood cicatricial pemphigoid from 21h years to 101h years, with a mean of 5 years. There was a wide range of age of onset in adult linear IgA disease, from 14 to 83 years, with a mean of 52 years. Sex distribution. Female patients were more commonly affected than were male patients (1.6: 1) in all groups.
+ + + + + + + + +
+
NK NK
+
+ + + + +
Response to dapsone or sulfonamidcs
+ + + + + + + + + + + + +
+ + + + + + + + + + + +
Duration (yr)
1 6 6 16 7 V2 V2
Remission
+ + + +
7
2 9
10 4 2 3
1 12 6 3
4 5 lh
2 14 2 1
+ +
+
NK + + + + + +
+
+ +
Prodromal events. Many patients reported a preceding illness or ingestion of drugs shortly before the onset of their disease. Thirty-eight percent of the children and 26% of adults had a preceding infection that ranged in severity from an upper respiratory tract infection to typhoid, brucella, and tetanus. Thirty-one percent of patients had taken nonsteroidal anti-inflammatory drugs or antibiotics before onset of the eruption. Some patients noted transient pruritus before their eruption. Three adult patients had a prolonged period of prodromal itching, which in one patient lasted 1 year. Distribution of the eruption. Distribution of the eruption in the three groups is shown in Table II. Chronic bullous disease of childhood. The
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 795
Immunopathology
IgA
+ + + + + + + + + + + + + + + + + + + + + + + + +
C3
+ + +
+
Indirect: Antibasement membrane zone antibodies (titer)
+IgA +IgA +IgA +IgA
(1:4) (1:8) (1:4) (l :64)
+IgA +IgA +IgA +IgA +IgA
(1:4) (1 :8) (1 :8) (1: 16) (l :8)
ND +IgA +IgA +IgA
ND
+IgA (l :32) +IgA (1 :32) +IgA (1: 16)
ND +IgA (1 :8) +
+
+ +IgA (1:32) +IgA (l :8)
majority of patients had involvement of the perineum (84%) (Fig. 2) and the perioral area (60%). This distribution was seen particularly in children under 5 years. The face were involved in 72%, and the ears in 34%. Involvement of the trunk (Fig. 3) and limbs was most common (96%), and many (80%) had involvement of the hands and feet. Older children had a more widespread bullous pemphigoid-like disease (Fig. 3). Childhood cicatricial pemphigoid. Three cases began with a generalized eruption that involved the face, trunk, limbs, hands, and feet; the fourth was typical of chronic bullous disease of childhood. In two long-standing cases that were reviewed in adult life, lesions were restricted to the face and upper body after puberty.
Fig. 2. Chronic bullous disease of childhood: involve-
ment of the perineum with annular vesicular lesions. (From Marsden RA. Clin Exp Dermatol 1982;7:65363.)
Adult linear IgA disease. The trunk (96%) (Figs. 4 and 5) and limbs (88%) were the most commonly affected areas. Dermatitis herpetiformis-like involvement of the limbs, restricted to the extensor surfaces of the knees and elbows, was noted in only two patients. The hands and feet were affected in half the patients, but only three had pompholyx-like involvement. Involvement of the perineum (32%), the face (40%), perioral area (36%), and ears (16%) were less frequent than in the children. Skin lesions. The eruption was usually symptomatic and was described as pruritic or burning. The lesions were variable and changed with time. The earliest lesions were urticated lesions (24%) or annular, polycyclic, or target lesions (30%) (Figs. 3 and 4). These were equally common in adults (32%) and children (32%) (100% of those with childhood cicatricial pemphigoid and 16% of those with chronic bullous disease of childhood); they were so striking in four adults that the initial diagnosis was erythema multiforme. Large bullae, occasionally hemorrhagic, were the most common lesions and occurred in 72% of children and of adults. In the children they were often grouped in the classical "cluster of jewels" sign (Fig. 2). Patients whose eruption was incompletely suppressed by therapy often had urticarial lesions. In both adults and children blisters and vesicles were observed at the edge of annular lesions, creating the "string of beads" sign. Small vesicles
Journal of the American Academy of Dermatology
796 Wojnarowska et al.
Table I. Cont'd Clinical features
Patient No.
Sex
Age at onset
Childhood cicatricial pemphigoid 26 F 2\6 27 F 10\6 28 F 5 29 F 4 Linear IgA disease oj adults 30 F 27 F 31 45 32 M 29 33 F 67 34 F 72 35 M 59 36 M 58 37 62 F 38 57 M 39 F 63 40 F 14 41 F 18 42 F 46 43 F 61 44 M 50 45 M 64
46 47 48 49 50 51 52 53 54
M F F F
F M M F M
28 65 30 69 45 83 79 33 67
Cutaneous eruption
Mucosal involvement
+ +
+ +
+
+
+
+ + + + + + + + +
+ +
+ + + +
+ + + + + + + +
+
+
+
+ + + +
+ + + + + +
+ +
+ + + +
+ + +
Response to dapsone or sulfonamides
+
+ + +
+ + + + + + + + (+) + + + + + + + + + + + + + NT NT
+
Duration (yr)
Remission
3 2 17 33 \6 l,h
\6 2 2 2
<10 2 2 2
+ + + + +
+
+ +
10 40 34 3 3 2
+
10
<\6
+
2
2 5
1
+
+
+, Positive; -, negative; NK, not known; ND, not done; NT, not tested.
or papulovesicles (Fig. 5) were more common in adults (44%) than children (28%). The initial diagnosis in two children and five adults was dermatitis herpetiformis. Six children, as they grew older, had a shift from large bullae to papulovesides, which often were confined to the head and upper trunk. Milia were noted in four patients. Mucous membrane involvement. Mucous membrane involvement occurred in 74% patients (Tables I and III). It was ahnost equally common in those with chronic bullous disease of childhood
(64%) as in those with adult linear IgA disease (80%). Chronic bullous disease of childhood. On direct questioning 40% of the children had ocular symptoms, that is, pain, grittiness, discharge, and redness. They had had disease for 5 to 16 years, and two (of seven examined by an ophthahnologist) had unequivocal signs of fine scarring; 48% had oral involvement with recurrent and troublesome mouth ulcers. One child reported nasal symptoms. The perineal area and external genitalia were
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease
797
Immunopathology
C3
IgA
+ + + +
Indirect: Antibasement membrane zone antibodies (titer)
+IgA (l :8) +
(+)
+ +IgA (neat) +lgA (1:4)
+ + + + + + +
+ + +
+ +
+
+ +
+
+IgA (1:2)
+
+
+
+IgA (l :8) +IgA (1:40) +IgA (1 :2) +C3 (1 :2)
+
+ + + + + +
+ Fig. 3. Chronic bullous disease of childhood: widespread annular bullous eruption that resembles bullous pemphigoid and demonstrates the "string of pearls" sign.
ND + +
+ + +
+ +
+IgA (1:8) +
involved in 72%, but only one child had urinary symptoms. Childhood cicatricial pemphigoid. All four children had ocular scarring, which manifested as symblepharon in three (Fig. 6), with entropion in one and such severe corneal scarring in one that she was registered as blind by the age of 12 years (Fig. 7). Oral ulceration occurred in all four, and in one it was continuous and caused scarring of the lower lip. One had episodes of hoarseness, probably a result of involvement of the larynx, and one
Fig. 4. Adult linear IgA disease: annular lesions on the trunk. (Courtesy H. R. Vickers, Oxford, England.)
Journal of the American Academy of Dermatology
798 Wojnarowska et a/.
Table II. Distribution of cutaneous lesions Clinical diagnosis and number of patients
Chronic bullous disease of childhood: 25 Childhood cicatricial pemphigoid: 4 Linear IgA of disease of adults: 25 Total
Face
Perioral
18
15 (60) 3 (75) 9 (36) 27 (50)
(72) 4 (100) 10 (40) 32 (60)
Hands
24 (96) 4 (100) 24 (96)
2L (96)
21 (84)
1 (25) 8 (32) 30 (56)
24 (96) 4 (l00) 22 (88) ~ (93)
20 (80) 4 (100) 13 (52)
.n. (69)
Table III. Mucous membrane involvement in patients with linear IgA disease of adults, chronic bullous disease of children, and childhood cicatricial pemphigoid No. of patients, with site ,of involvement Clinical diagnosis and number of patients
Ocular (scarring)
Chronic bullous disease of children: 25 Childhood cicatricial pemphigoid: 4 Linear 19A disease of adults: 25 Total
10 (2) 4 (4) 18 (10)
32
Genital
Nasal"
Total· excluding genitals
12
18
16
4
2
4
16
10
5
20
32
30
7
40
(16) • Ascertained in 19 patients.
reported nasal symptoms. Two had involvement of the vulval area, and one also had dysuria. Adult linear IgA disease. Of the 72% of patients with ocular involvement, 60% had symptoms and 40% had definite scarring with symblepharon; an additional 20% had minor scarring. Four patients with scarring had no eye symptoms. In one patient the eye symptoms became the dominant part of his disease. Oral symptoms were noted by 64% patients and in three were very troublesome, with persistent painful ulceration (Fig. 8). Two had symptoms despite suppression of the skin eruption, and the third never had clinical skip involvement (patient No. 53). One patient had severe gingivitis that cleared with dapsone. Two patients had episodes of hoarseness; 20% of patients had nasal symptoms of stuffiness, crusting, and bleeding. In 40% of patients the genitals were involved with erosions and blisters. Associated diseases. Many patients had other
diseases. Five had atopic symptoms and three had autoimmune diseases. There were no marked disease associations. Two adults had carcinomas, one a lymphoma, and one a myeloma. Investigations Histopathology. Biopsy specimens from 46 patients were reviewed, of which only 37 showed a subepidermal blister. Chronic bullous disease oj childhood. Fourteen biopsy specimens showed a subepidermal blister. Eight had. a dermatitis herpetiformis-like appearance (with neutrophils predominating), one was bullous pemphigoid-like (predominantly eosinophils), two showed mixed results, and three findings were unhelpful Childhood cicatricial pemphigoid. One biopsy specimen was dermatitis herpetiforrnis-like and two bullous pemphigoid-like. Adult linear IgA disease. Histologic findings for
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 799
Fig. 5. Adult linear IgA disease: papulovesicular plaque on the trunk.
Fig. 6. Childhood cicatricial pemphigoid: conjunctivitis and symblepharon formation.
six patients showed a dermatitis herpetifonnis-like appearance. More patients showed bullous pemphigoid (eight) or mixed histology (four) than did those with chronic bullous disease of childhood. Two studies were unhelpful. Immunopathology. Immunopathology findings are summarized in Tables I and IV. Linear IgA deposition at the basement membrane zone was present in all patients; in 78% it was the sole immunoreactant. Chronic bullous disease of childhood. IgM was found in five patients, one of whom showed IgM, IgG, and C3 (this pattern was constant for 5
years). Of the patients tested 72% had a circulating IgA antibody in titers ranging from 1: 4 to 1: 64. Childhood cicatricial pemphigoid. One patient showed IgM, IgG, and C3. Three had circulating IgA antibodies present in low titers (neat-l :4). Adult linear IgA disease. IgG and C3 were found together in three patients, one of whom also showed IgM; three patients showed IgG, and 20% of patients had circulating IgA antibody. In two patients the antibodies were transient and related to clinical exacerbation. The titers were low (1 : 2~ 1: 64). One patient had serum that bound C3 at the dermoepidermal junction, without IgG or C3 all
800
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Wojnarowska et ai.
Fig. 7. Childhood cicatricial pemphigoid: end-stage cicatrizing conjunctivitis and symblepharon. (Courtesy P. Wright, London, England.)
direct immunofluorescence. The presence of IgM in addition to IgA did not correlate with mucous membrane involvement, prognosis, or duration of disease. Serum immunoglobulins. Serum IgA was normal in all but four patients. There were minor transient abnormalities in three, and one showed low IgA in association with an IgM paraproteinemia and lymphoma. In all other patients there were only minor abnormalities of IgG and IgM. Autoantibodies. Organ-specific antibodies, mainly thyroid, were present in 23% of patients. They were more common in patients with adult linear IgA disease (27%) than those with chronic bullous disease of childhood (14%) «15% in the normal population). Antinuclear antibodies were present in low titers (1 : 10-1 :40) in 20% of patients with chronic bullous disease of childhood and adult linear IgA disease (similar to our normal population). Immunogenetics. There was a striking difference between the incidence of HLA B8 in chronic bullous disease of childhood, in which the incidence was 76% (16/21) of patients (four of whom were homozygous), in childhood cicatricial pemphigoid, in which it was absent, and in adult linear IgA disease, in which the incidence was 28% (6/21) (20% of the normal population of the United Kingdom have HLA B8). HLA B 12 was present in 16% of those with chronic bullous disease of
childhood, in 25% of those with childhood cicatricial pemphigoid, and in 25% of those with adult linear IgA disease (HLA B12 in the normal population of the United Kingdom, 30%). Gluten-sensitive enteropathy. There was no evidence to support a close association between the linear IgA dermatoses and gluten-sensitive enteropathy. Four patients (three children) had gastrointestinal symptoms, and three patients had raised intraepithelial lymphocyte counts. Two adults had antireticulin antibodies, four raised IgA antigliadin antibodies, and three had transient low folates. Treatment The treatments that were given are shown in Tables I and V. Most patients were maintained on regimens of dapsone, sulfapyridine, or sulfamethoxypyridazine. They responded within 72 hours but relapsed on stopping the drug. Seventeen patients also received steroids. In five the initial diagnosis was bullous pemphigoid, and prednisolone controlled the eruption at doses above 30 mg daily. The value of the addition of low-dose steroids to the therapy of patients whose disease was partially controlled was difficult to assess, inasmuch as the effect was neither rapid nor dramatic. Two patients never received systemic therapy. The mucous membranes responded less well to dapsone and sulfonamides. It was common for
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 801
mucosal activity to persist despite control of the skin lesions. Seven patients adhered to a gluten-free diet for up to 2 years without benefit.
Prognosis Remission, defined as absence of cutaneous lesions or mucous membrane symptoms without treatment, occurred in 52% patients. The duration of the disease varied from a few weeks to 40 years. Chronic bullous disease of childhood. In 64% (16) of patients remission occurred, in most cases within 2 years. Three female patients with active disease are now postpubertal at ages 14, 17, and 22 years. Childhood cicatricial pemphigoid. The skin cleared completely in two patients, but mucous membrane activity continued. Two patients, now 23 and 38 years of age, have active skin disease and severe and cumulative ocular scarring. Adult linear IgA disease. In 48% (12) of patients remission occurred, all except two within 2 years (40% within 1 year); in two the disease was present for only a few weeks. In those cases in which remission did not occur, the mean duration of disease was 7 years (range, 2-40 years). Immunopathologic findings during remission. In both chronic bullous disease of childhood and adult linear IgA disease, the majority of patients lost their immunoreactants from both skin (12/17) and serum (5/9, initially positive). This loss occurred within 6 months in one patient; however, circulating antibody persisted for 4 years after remission in one patient with chronic bullous disease of childhood. DISCUSSION
The relationship of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease is unclear. The diseases have a common immunopathology, differing only in frequency of circulating IgA antibasement zone antibodies. There have been considered to be very marked clinical differences, not only in age of onset but also in extent of mucosal involvement and prognosis. Chronic bullous disease of childhood has been regarded as benign, that is, without any long-term sequelae of mucosal scarring and with an
Fig. 8. Adult linear IgA disease: persistent painful erosion on the tongue.
excellent prognosis, with rermssion occurring before puberty.7.I1,12,16.17 Adult linear IgA disease is characterized by mucosal involvement, 10,13, 18 and remission has been regarded as rare-"; however, IgA deposition also is seen in cicatricial pemphigoid." Contrary to previous reports, this study has shown substantial clinical overlap between chronic bullous disease of childhood and adult linear IgA disease. The high incidence of mucosal involvement and ocular scarring in adult linear IgA disease'? has been confirmed but also has been demonstrated in chronic bullous disease of childhood, which suggests that childhood cicatricial pemphigoid is a severe form of chronic bullous disease of childhood. Remission before puberty has been shown not to be universal in chronic bullous disease of childhood and was more common in patients with adult linear IgA disease than previously reported. The remission rate of the adults (48%), however is less than
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802 Wojnarowska et al.
Table IV. Immunopathologic findings in patients with linear IgA disease of adults, chronic bullous disease of children, and childhood cicatricial pemphigoid No, of patients with linear deposition at dermoepidermal junction
I
Direct
Clinical diagnosis and number of patients
IgA
Chronic bullous disease of childhood: 25 Childhood cicatricial pemphigoid: 4 Linear IgA disease of adults: 25
j
IgG
I
C3
I
IgM
25
5
4
1
25
6
1
3
I
Indirect IgA
18* (1:4-1 :64) 3 (neat-I:4)
5t
I
IgG
I
o o o
C3
o
o
(1:2-1 :64)
*Not done in three patients. tTransient in two patients and not done in one patient.
Table V. Systemic treatments administered Clinical diagnosis (No.)
Chronic bullous disease of childhood: 25 Childhood cicatricial pemphigoid: 4 Linear IgA disease of adults: 25
Dapsone
14: 20-200 mg 3: 100-400 mg 23: 50-600 mg
Systemic treatment: No. treated and dosage range Sulfapyridine Sulfamethoxypyriduine Steroids
15: 500 mg-2 gm 3: 250 mg-3 gm 4: 3 gm
that for the children (64%). The age of onset shows a bimodal distribution, with one peak in childhood and the other in old age; the disease is most common in the nonreproductive years. As in some previously reported series,3,7,8,13 a high proportion of female patients was seen in all groups. The majority of patients complained of intense pruritus or burning or were seen to scratch, although a few patients did not experience these symptoms. A prolonged prodrome of pruritus was unusual and less common than in bullous pemphigoid. Although there were differences in distribution between the patients with chronic bullous disease of childhood and those with adult linear IgA disease, they were not absolute. The trunk and limbs were affected in over 96% of adults and children. The majority of patients with chronic bullous disease of childhood had involvement of the classic sites of the face and perineum, whereas only
2: 500 rng-I gm
a 3: 500 mg-l gm
8: prednisone <10 mg 2: prednisone <15 mg 7: prednisone 5-100 mg
Other
1: arsenic 3: azathioprine 1: colchicine
40% of those with adult linear IgA disease had facial involvement and only 32% had perineal involvement. Younger children tended to have the classic distribution, and the eruption was more like bullous pemphigoid, with widespread large bullae in older children. The lesions were identical in all groups. The annular lesions emphasized previously in adult linear IgA diseases" 13 were seen in all groups, but they were more common in adult linear IgA disease (32%) than in chronic bullous disease of childhood (16%), Large blisters were equally common in chronic bullous disease of childhood and linear IgA disease. Papulovesicles were seen in a minority of persons in both groups. The patient who had no cutaneous involvement resembled the patient reported by Kumar et at.18 Mucous membrane involvement was prominent in all groups and was present in 64% of chronic bul-
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Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 803
lous disease of childhood cases, 100% of childhood cicatricial pemphigoid cases, and 80% of adult linear IgA disease cases. Ocular involvement was more common in adult linear IgA disease (72%) than in chronic bullous disease of childhood (40%), and it became the dominant feature in all cases of childhood cicatricial pemphigoid and two cases of adult linear IgA disease. Scarring was observed in both children and adults, and the frequency may have been underestimated inasmuch as fewer than half the patients were examined by an ophthalmologist. Ocular scarring had not been previously reported in chronic bullous disease of childhood and was associated with long-standing disease. Oral involvement was similar in both chronic bullous disease of childhood and adult linear IgA disease and was very troublesome in one case of childhood cicatricial pemphigoid and three of adult linear IgA disease. Genital involvement was more common in the children, and nasal problems were limited to the adults. Mucous membrane involvement, with or without ocular scarring, was thus not a basis for distinguishing the groups. Although there were no histologic distinctions between chronic bullous disease of childhood and adult linear IgA disease, findings like bullous pemphigoid were more common in adult linear IgA disease. Dermatitis herpetiformis-like findings were seen equally in both groups. Immunopathologic findings showed IgA at the dermoepidermal junction in all patients. IgM was also present in 20% of patients with chronic bullous disease of childhood, but in only one case of childhood cicatricial pemphigoid and one of adult linear IgA disease in which there were also IgG and C3 present. IgG alone or with C3, which occurred in 15% of cases, was mainly confined to patients with adult linear IgA disease. The significance of these additional immunoreactants is obscure, although they have been observed previously. 1:3-7 IgG and C3 did seem to be associated with mucosal involvement and a poorer prognosis, but there were many exceptions. The patients with this finding bear some resemblance to those with cicatricial pemphigoid, but they have much more prominent cutaneous disease and their disease cannot be clearly distinguished from linear IgA disease by any other criterion. We did not observe a shift from IgG
to 19A with time, as has been described." The circulating IgA antibasement membrane zone antibody was common in children (chronic bullous disease of childhood, 72%; childhood cicatricial pemphigoid, 75%) and rare in adults, in whom it was detected in 20%. The adult titers were lower than the children's, which may reflect the lower incidence of HLA B8 that is associated with high immune responsiveness." These antibodies can persist in both skin and blood for years after remission, but in the majority of patients they disappear in remission, and this was observed within 6 months, suggesting that persistence of IgA is not due to failure to clear it from the skin. Serum IgA was normal in most patients. There was an increased incidence of autoantibodies in the children and adults. This finding had been previously observed in adults.' HLA B8 was increased in the children in an incidence similar to that of previous series.v 3, 7 Occurrence of B8 may predispose the individual to the earlier appearance of the disease and to higher titers of antibodies. 21 All patients treated with dapsone or sulfonamides responded rapidly, including those patients with IgG, IgM, and C3 in addition to IgA. The additional benefit of low- or high-dose steroids was impossible to assess. No cases were controlled with less than 30 mg prednisone alone; however, topical steroids gave symptomatic relief. We concur with Leonard et al.' and Marsden et a1.7, 12 in believing dapsone or sulfonamides to be the treatment of choice. Control of mucous membrane lesions was often difficult; topical steroids alleviated the eye symptoms. Ophthalmologic monitoring of all such patients is mandatory. The evidence from this study suggests that there is no sound clinical or immunopathologic basis for distinguishing chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease from each other. The antigen(s) involved in this disease are as yet uncharacterized. Ultrastructural studies on the site of the antigen with the use of normal skin split through the lamina lucida by suction or by incubation with 1 M NaCF2 have demonstrated both a lamina lucida and possibly a sublamina densa component. 23-25 Immunoelectron microscopic studies have demonstrated the antigen in both the lamina
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804 Wojnarowska et al.
lucida and sublamina densa.2, 26-33 Many of the patients in this study have been examined by both direct and indirect immunoelectron microscopy, and the in vivo deposition of both the antibody and the antigen has been demonstrated in the sublamina densa." Tissue and species distribution studies of the antigen in both adult linear IgA disease and chronic bullous disease of childhood suggest that the antigen is neither the bullous pemphigoid nor the epidermolysisbullosa acquisita antigen." This belief has been confirmed by preliminary immunoblotting studies" and by the lack of cross-reactivity with bullous pemphigoid antigen.20 The relationship of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and adult linear IgA disease to cicatricial pemphigoid remains to be defined. This study supports previous findings1·8. 16 that the three diseases are not a variant of dermatitis herpetiformis because of the lack of association with gluten-sensitive enteropathy, the high incidence of mucosal involvement, and clinical and immunopathologic remission. It is unusual for an autoimmune disease to be associated with an IgA autoantibody, although this does occur in dermatitis herpetiformis, IgA nephropathy, and Henoch-Schonlein purpura. The reason for an IgA response to a normal basement membrane antigen is unclear. The raised titers of IgA, but not IgG antigliadin antibody, suggest that the patients may have an IgA-producing diathesis, although we have been unable to demonstrate abnormal IgA production by peripheral blood lymphocytes." Alternatively, the class of antibody may reflect a mucosal route of entry of a crossreacting antigen, either dietary or infectious. The finding of a gluten-sensitive enteropathy and other gut disease in association with adult linear IgA disease, even in only a few patients," 3 may be relevant, as may the preceding upper respiratory tract infection and other infections in many of the children with this disease.v-" The raised incidence of HLA B8 suggests that this group contains hyperimmune responders," which may explain the increased incidence of anti-basement membrane zone and other autoantibodies. A number of questions remain unanswered. The exact relationship of chronic bullous disease of childhood, childhood cicatricial pemphigoid, and
adult linear IgA disease to each other and to the other subepidermal blistering diseases, as well as the nature and localization of the antigen, currently are being investigated. Finally, the reasons for mounting an IgA response to a normal component of the basement membrane zone and the high frequency of clinical and immunopathological remission require further investigation. We thank Professor R. H. McMinn and Dr. P. Ciclitira for performing the intraepitheLial lymphocyte counts; Dr. P. Ciclitira and Mr. D. Unsworth for estimating the antigliadin antibodies; Dr. Peggy Frith and Mr. P. Wright for the ophthalmologic assessments; and Dr. Philip McKee for classifying the histologic findings.
REFERENCES I. Jablonska S, Chorzelski TP, Beutner EH, Maciejowska E, Rzesa G. Dermatitis herpetiformis and bullous pemphigoid. Arch Dermatol 1976;112:45-8. 2. Lawley rr, Strober W, Yaoita H, Katz SI. Small intestinal biopsies and HLA types in dermatitis herpetiformis patients withgranular and linearIgA skindepostis. J Invest Dermatol 1980;74:9-12. 3. Leonard IN, Haffenden GP, Ring NP, et al. Linear IgA disease in adults. Br J Dermatol 1982;107:301-16. 4. Mobacken H, Kastrup W, Ljunghall K, et al. Linear IgA dermatosis: a study of ten adult patients. Acta Derm Venereol (Stockh) 1983;63:123-8. 5. Wilson BD, Bcutner EH, Kumar V, Chorleski TP, Jablonska S. Linear IgA bullous dermatitis. An immunologically defined disease. Int J Dermatol 1985;24:56974. 6. Chorzelski TP, Jablonska S. IgA linear dermatosis of childhood (chronic bullous disease of childhood). Br J Dcrmatol 1979;101:535-42. 7. Marsden RA, McKee PH, Bhogal B, BlackMM, Kennedy LA. A study of benign chronic bullous dermatosis of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood. Clin Exp DermatoI1980;5:159-72. 8. Wojnarowska F, Marsden RA, Bhogal B, Black MM. Childhood cicatricial pemphigoid with linear IgA deposits. Clin Exp Dermatol 1984;9:407-15. 9. Langeland T. Childhood cicatricial pemphigoid with linear IgA deposits. Acta Derm Venerol (Stockh) 1985; 65:354-5. 10. Leonard JN, Wright P, Williams DM, et aJ. The relationship between linear IgA disease and benign mucous membrane pemphigoid. Br J Dermatol 1984; 110:307-14. II. Grant PW. Juvenile dermatitis herpetiformis. Trans St John's Hosp Dermatol Soc 1968;54:128-36. 12. Marsden RA. The treatment of benign chronic bullous dermatosis of childhood, and dermatitisherpetiforrnis and bullous pemphigoid beginning in childhood. Clin Exp Dermatol 1982;7:653-63. 13. Wojnarowska F, Marsden RA, Bhogal B, Black MM. The spectrum of linear IgA dermatoses. In: McDonald
Volume 19 Number 5, Part 1 November 1988
14.
15.
16.
17.
18.
19. 20. 21.
22.
23.
24.
25. 26.
Bullous disease of childhood, childhood pemphigoid, and linear IgA disease 80S
DM ed. Immunodermatology . London: Butterworth, 1985:245-9. Unsworth DJ, Leonard IN, McMinn RMH, Swain AF. Holborow EJ, Fry L. Anti-gliadin antibodies and small intestinal mucosal damage in dermatitis herpetiformis. Br J Dermatol 1981;105:653-8. Ciclitira PJ, Ellis HL, Venning VA, et al. Circulating antibodies to gliadin subfractions in dermatitis herpetiformis and linear IgA dermatosis of adults and children. Clin Exp Dermatol 1986;11 :502-9. Kim R, Winkelmann RK. Dermatitis herpetiformis in children-relationship to bullous pemphigoid. Arch Dermatol 1961;83:49-56. Jordan RE, Bean SF, Triftshauser cr, Winkelmann RK. Childhood bullous dermatitis herpetiformis-s-negative immunofluorescent tests. Arch Dermatol 1970; 101:62934. Kumar V, Rogozinski T. Yarbrough C, Beumer EH, Chorzelski TP. A case of cicatricial pemphigoid or cicatricial linear IgA bullous dermatosis. J AM ACAD DERMATOL 1980;2:327-31. Fine JD, Neises GR, Katz SI. Immunofluorescence and immunoelectron microscopic studies in cicatricial pemphigoid. J Invest Dermatol 1984;82:39-43. Petersen MJ, Gammon WR . Briggarnan RA. A case of linear IgA disease presenting initially with IgG immune deposits. JAM ACAD DERMATOL 1986;14:1014-9. Ambinder JM, Chiorazzi N, Gibofsky A, Fotino M. Kunkel HG. Special characteristics of cellular immune function in normal individuals of the HLA-DR3 type. Clin Immunol Immunopath 1982;23:269-74. Woodley D. Sauder D, Talley MJ, Silver M, Grotendorst G, Qwarnstrom E. Localization of basement membrane components after dermal-epidermal junction separation. J Invest Dermatol 1983;81:149-53. Aboobaker J, Bhogal B, Wojnarowska F, Black MM, McKee P. The localization of circulating IgA antibodies in linear IgA disease, chronic bullous disease of childhood and childhood cicatricial pemphigoid using suction blisters as substrate. Br J Dermatol 1987;116:293-03. Wojnarowska F. Pothupitiya GM, Bhogal BS, Black MM, McKee PH: Comparison of the antigen in linear IgA bullous dermatosis with the antigens in epidermolysis bullosa acquisita and bullous pemphigoid suggests it is a unique antigen. In: Caputo R, ed. Immunodermatology. Rome: Cicedizioni Internazionali 1987:237-40. Roberts LJ, Sontheimer RD. Chronic bullous dermatosis of childhood: immunopathologic studies. Paediatr Dermatol 1987;4:6-10. Yaoita H, Hertz KC, Katz SI. Dermatitis herpetiformis:
27. 28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
immunoelectron microscopic and ultrastructural studies of a patient with linear deposition of IgA . J Invest DermatoI1976;67:69i-5. Yaoita H, Katz SI. Circulating IgA anti-basement membrane zone antibodies in dermatitis herpetiformis, J Invest Dermatol 1977;69:558-60. Pehamberger H, Konrad K, Holubar K. Circulating 19A anti-basement membrane antibodies in linear dermatitis herpetiformis (Duhring) : immunofluorescence and immunoelectron microscopic studies. J Invest Dermatol 1977; 69:490-3. Dabrowski J, Chorzelski T, Jablonska S, Krainska T, Jarzabek-Chorzelska M . Immunoelectron microscopic studies in IgA linear dermatosis . Arch Dermatol Res 1979;265:289-98. Dabrowski J, Chorzelski TP, Jablonska S, Krainska T, Jarzabek-Chorzelska M. The ultrastructural localization of 19A deposits in chron ic bullous disease of chiidhood (CBDC). J Invest Dermatol 1979;72:291-5. Yamasaki Y. Hashimoto T, N ishikawa T. Dermatitis herpetiformis with linear 19A deposition: ultrastructural localization of in vivo bound IgA . Acta Derm Venereal (Stockh) 1982;62:401-5. Fry L. ImrnunoHaffenden GF, Ring Np, Leonard electron microscopical studies in patients with linear IgA deposits [abstract] . J Invest Dermatol 198~;80:J63. Horiguchi Y, Toda xr, Okamoto H. Imamura S: Immunoelectron microscopic observations in a case of linear 19A bullous dermatosis of childhood. JAM ACAD DERMATOL 1986;14:593-9. Bhogal B, Wajnarowska F, Marsden RA, Das A, Black MM, McKee PH. Linear 19A bullous dermatosis of adults and children. An irnmunoelectron microscopic study. Br J Dermatol 1987;117:289-96. Pothupitiya GM, WojI}arowska F, Ilhogal BS, Black MM. The tissue distribution and phylogenetic distribution of the antigen in adult linear IgA disease · a,nd chronic bullous dermatosis of childhood suGG6Sl§ that it is a single and unique antigen. Br J Dermatol 1988;1l~: 175-83. Wojnarowska F, Whitehead p. Bhogal B. Plack MM. Leigh 1M. Characterisation of the antigen in chronic. bullous dermatosis of childhood and adult linear IgA disease [abstract] . Br J Dermatol 1988;118:268. Wojnarowska F, Perl S. Normal IgA ·production by peripheral blood lymphocytes in dermatitis herpetiforrnis and linear IgA dermatosis . Arch Dermatol Res ' (in
m,
press). 38. Berlin C. Dermatitis herpetiformis in children, Br J Dermatol 1982;64:281-90.