Linear IgA disease associated with lymphocytic colitis

A 66-year-old woman presented with a bullous skin eruption and chronic diarrhoea. Lesional skin showed subepidermal blistering, and direct immunofluorescence of perilesional skin revealed linear deposits of IgA at the dermoepidermal junction, establishing a diagnosis of linear IgA disease (LAD). Chronic watery diarrhoea complicated by substantial loss of body weight preceded the skin eruption for several months. On endoscopy, the colon appeared macroscopically normal. On histology, the colon mucosa showed increased numbers of intraepithelial lymphocytes and infiltrates of mononuclear cells in the lamina propria, indicative of lymphocytic colitis. Treatment with methylprednisolone and dapsone led to complete clearing of the bullous skin eruption and marked improvement of the patient's diarrhoea. Gastrointestinal disorders such as lymphocytic colitis have rarely been reported in patients with LAD. Whether the simultaneous occurrence of these two diseases is coincidental or due to related pathogenetic mechanisms remains to be seen.     

IgA multiple myeloma presenting as an acquired bullous disorder

A 63-year-old man presented with an intensely pruritic vesiculo-bullous eruption on the limbs and was subsequently found to have an IgA kappa multiple myeloma. The eruption clinically and histologically was suggestive of linear IgA disease (LAD), dermatitis herpetiformis (DH), epidermolysis bullosa acquisita (EBA), or bullous lupus erythematosus (LE), with the skin biopsy revealing subepidermal bullae and dermal papillary micro-abscesses. However, direct immunofluorescence showed a unique pattern of diffuse dermal IgA staining. Although chemotherapy produced a dramatic resolution of the lesions, which paralleled the fall in serum IgA paraprotein level, the myeloma later became progressive and the resulting paraprotein increase was accompanied by recurrence of the eruption. We propose that this patient's rash was the presenting manifestation of his multiple myeloma, and was a consequence of transudation of IgA paraprotein into the dermis.     

Drug-associated linear IgA disease mimicking toxic epidermal necrolysis

Linear IgA disease (LAD) is an uncommon, acquired, autoimmune blistering disorder with a characteristic linear IgA deposition along the basement membrane zone. LAD can be idiopathic or drug-induced. Drug-related LAD most commonly occurs after exposure to vancomycin, but phenytoin and other medications have been implicated. A small number of cases of drug-induced LAD clinically resembling TEN have been reported. We report a case of phenytoin-associated LAD clinically mimicking TEN in a 57-year-old woman. This case shows the necessity of investigating TEN patients for autoimmune bullous diseases, using immunofluorescence studies.     

Vancomycin-induced linear IgA disease with autoantibodies to BP180 and LAD285

Linear IgA disease (LAD) is an acquired autoimmune subepidermal bullous disease characterized by the linear deposition of IgA at the basement membrane zone. A minority of cases are induced by drugs, of which the most frequently implicated is vancomycin. The target antigens in idiopathic LAD are heterogeneous, but have not previously been reported in vancomycin-induced LAD. We report three cases, and in two of these we investigated the target antigens. In both we identified IgA antibodies to LAD285 and IgA and IgG antibodies (dual response) to BP180.     

Linear IgA bullous dermatosis associated with rheumatoid arthritis.

A case of linear IgA bullous dermatosis associated with rheumatoid arthritis is described. The eruption consisted of multiple irregular erythematous plaques and small numbers of tense vesicles mainly on the trunk. An immunofluorescence study showed linear IgA and IgG deposition along the basement membrane zone, whereas C3 deposition was not found. IgA or IgG anti-basement membrane zone antibody was not detected in the serum. Treatment with dapsone resulted in good control of the eruption. Coexistence of linear IgA bullous dermatosis and rheumatoid arthritis has not been reported previously.     

Chronic Bullous Disease of Childhood with IgG Predominance: What is the Locus Standi?

Linear IgA disease (LAD) is an acquired, autoimmune, subepidermal, blistering disease, characterized by linear deposition of IgA along the dermoepidermal junction on immunofluorescence. Some cases known as 'mixed immunobullous disease' show weak staining with other immune reactants like IgG, IgM or C3. We report a rare case of a child having typical manifestations of LAD (chronic bullous disease of childhood), but with IgG predominance rather than IgA. Obviously it is improper to term this as linear IgA disease. Such cases are reported in literature as variants of LAD, with a multitude of terms like mixed immune bullous disease, linear IgG / IgA disease, linear IgA / IgG disease, and so on. In view of the tremendous confusion that these multiple terms cause in the absence of any practical benefit, we propose that the broad term 'chronic bullous disease of childhood' be applied to all childhood cases, irrespective of the nature of the immune deposits.     

Linear IgA dermatosis in association with angioimmunoblastic T-cell lymphoma infiltrating the skin: A case report with literature review

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive form of peripheral T-cell lymphoma, characterized by systemic symptoms, diffuse lymphadenopathy, hepatosplenomegaly and immunodysregulation. Half of AITL is associated with cutaneous symptoms, but only few cases with bullous eruption have been described. Association with a linear IgA dermatosis is extremely rare. Linear IgA dermatosis can be idiopathic, or linked with drug intake or neoplastic disorders. Some cases of linear IgA dermatosis presenting as toxic epidermal necrolysis (TEN) have been described, most of them being drug induced. We here present the case of a 72-year-old man recently diagnosed with AITL who developed a bullous eruption, presenting as TEN. Histopathology showed deep cutaneous involvement of the lymphoma with a sub-epidermal blistering and direct immunofluorescence revealed a heavy IgA linear deposit on the dermal-epidermal junction. A diagnosis of linear IgA dermatosis associated with cutaneous involvement of an angioimmunoblastic T-cell lymphoma was made. Chemotherapy and corticosteroids allowed cutaneous improvement but the patient died of his lymphoma shortly after.     

IgA bullous pemphigoid: a distinct blistering disorder

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

Linear IgA bullous dermatosis of adults and children: an immunoelectron microscopic study

The ultrastructural localization of the IgA deposits in the skin of 15 patients with linear IgA bullous dermatosis of adults (LAD), 13 with chronic bullous dermatosis of childhood (CBDC) and three with childhood cicatricial pemphigoid (CCP) were studied. The site of the antigen was determined using sera from two LAD, 13 CBDC and two CCP patients. In all 31 patients the IgA was located predominantly below the lamina lucida (sublamina densa). Similarly, the indirect immunoelectron microscopic studies demonstrated the antigen to be present at the same site, below the lamina densa. This suggests that in linear IgA bullous dermatosis the antibody reacts with the antigen in the sublamina densa region of the basement membrane zone.     

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

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

Drug-induced linear IgA bullous disease following antibiotics

A 69-year-old woman presented with pneumonia and subacute bacterial endocarditis. Nine days after intravenous vancomycin and ciprofloxacin were commenced, the patient developed a bullous mucocutaneous eruption. Clinical presentation and histopathology were consistent with drug-induced linear IgA bullous disease (LABD). The patient's lesions resolved with cessation of antibiotics. A review of the features of drug-induced LABD and the drugs that have been implicated are presented.     

An Analysis of 24 Patients with IgA Deposition at the BMZ

A study of 24 patients with IgA deposition at the BMZ of the skin showed that five conditions could be recognized: 1) linear IgA bullous dermatosis in adults (LAD, 7 cases); 2) linear IgA and IgG bullous dermatosis in adults (LAGD, 10 cases); 3) chronic bullous disease of childhood (CBDC, 3 cases); 4) dermatitis herpetiformis (DH, 1 case), and 5) systemic lupus erythematosus (SLE, 3 cases). Histopathologically, 5 of 7 patients with LAD were similar to the DH group, but 7 of 10 patients with LAGD were similar to the BP group. Half the patients with LAD and LAGD had oral lesions, and most of them had excellent responses to dapsone and Tripterygium Wilfordii, but the patients with CBDC did not respond to these treatments. In the patients with LAD and LAGD, the positivity rates of IgA anti-BMZ antibodies examined by indirect immunofluorescence (IIF) on intact skin and NaCl split skin were 41% and 64%, respectively. The heterogeneity of the histopathologic pictures of LAD and LAGD, the incidence of DH, and the value of using NaCl split skin for IIF are discussed.     

The localization of the binding site of circulating IgA antibodies in linear IgA disease of adults, chronic bullous disease ofchildhood and childhood cicatricial pemphigoid

Biopsies from suction blisters raised in three normal volunteers were used as substrate in the indirect immunofluorescence technique to determine the binding site of circulating IgA antibodies in serum from three patients with adult linear IgA disease (LAD), nine with chronic bullous disease of childhood (CBDC), three with childhood cicatricial pemphigoid (CCP), and four with bullous pemphigoid (BP). Direct immunofluorescence was done using suction blisters raised in two patients with LAD and one with CCP. The circulating IgA antibodies in LAD and CBDC bound mainly to the roof of the blister but also to the base, and in CCP they bound only to the base of the blister. The circulating IgG antibodies in BP bound to the roof and base of the blister. These results demonstrate that the antigens in the various linear IgA dermatoses are heterogenous and are localized at different sites. The LAD and CBDC antigens are present in the lamina lucida, and the antigen in CCP is associated with the basal lamina.     

Ultrastructural immunogold studies in two cases of linear IgA dermatosis. Are there two distinct types of this disease?

It has been suggested that patients with homogeneous linear IgA deposits at the basement membrane zone constitute a distinct bullous disorder called linear IgA dermatosis (LAD) of adults or children. The results of the present ultrastructural immunogold study in two patients with LAD suggest that LAD is not a single disease entity. LAD in a 10-year-old girl was found to be ultrastructurally similar to an IgA-type pemphigoid. IgA was detected in the uppermost lamina lucida underlying the basal cell plasma membrane. In a second patient, an 86-year-old man, IgA deposits were present within the lamina densa and the anchoring plaques. The distribution of IgA in this patient was ultrastructurally identical with that of IgG in epidermolysis bullosa acquisita skin and with that of the non-collagenous globular terminus of collagen VII within the basement membrane zone of normal skin. By using the immunogold technique, we could distinguish two distinct types of LAD according to the IgA binding sites in the diseased skin. We suggest that different labelling patterns may correspond to different clinical pictures.     

Mapping of epitopes on the BP180 ectodomain targeted by IgA and IgG autoantibodies in patients with the lamina lucida-type of linear IgA disease

Abstract Linear IgA disease (LAD) is an autoimmune subepidermal blistering skin disease characterized by the linear deposition of IgA at the dermoepidermal junction. Serum from patients with LAD most commonly contains autoantibodies that are directed against the hemidesmosomal transmembrane glycoprotein BP180 (type XVII collagen). Various antigenic sites on the extracellular domain of this anchoring filament protein have been shown to be targeted by autoantibodies in different autoimmune bullous skin diseases, including bullous pemphigoid and cicatricial pemphigoid (CP). However, little is known about epitopes on BP180 recognized by autoantibodies in LAD. In this study, we used three recombinant GST fusion proteins, together roughly covering the entire BP180 ectodomain, to characterize the autoimmune response in serum from patients with LAD. Interestingly, we found both IgA and IgG reactivity to all three portions of the BP180 ectodomain. The strongest reactivity was observed with the C-terminal portion of BP180. This is also the major region recognized by autoantibodies in patients with CP. This finding correlates with the observation that there may be significant overlap of the clinical and immunopathological findings in LAD and CP. Received: 21 August 2000 / Revised: 8 November 2000 / Accepted: 13 December 2000     

Identification of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults

Disease-associated autoantibodies to basement membrane proteins have been used to characterize structural components of the epidermal basement membrane such as bullous pemphigoid (BP) antigen and epidermolysis bullosa acquisita (EBA) antigen (type VII collagen). The autoimmune bullous diseases characterized by IgA autoantibodies to the basement membrane zone (BMZ), i.e. linear IgA disease of adults (LAD) and chronic bullous disease of childhood (CBDC) may have circulating antibodies. Previous studies of tissue distribution and ultrastructural binding have suggested that the LAD and CBDC antigens are similar, if not identical, and differ from the target antigens of the other bullous diseases. We present the molecular characterization of the LAD/CBDC antigens by Western blotting of a large series of antisera. Seven of 33 sera (21%) were positive on immunoblotting and bound to the same antigen which has a molecular weight (MW) of 285 kDa. Using both defined polyclonal antisera to BP and LH 7.2 monoclonal antibody to type VII collagen (carboxy terminal) we have shown that the LAD and CBDC antisera both bind to an identical molecular weight protein which clearly differs from both the BP and EBA (type VII collagen) antigens. Although detectable in dermal tissue extracts like EBA, the MW of 285 kDa is heavier than type VII collagen (250 kDa, in our system, using non-collagenous standards). This study confirms the identity of LAD and CBDC antigens to be the same and to differ from previously described basement membrane proteins.     

Ibuprofen-induced bullous leukocytoclastic vasculitis

A dramatic case of ibuprofen-induced bullous leukocytoclastic vasculitis (LCV) is described in a patient with a history of prior sensitization to ibuprofen, a common household nonsteroidal anti-inflammatory drug (NSAID) that has few reported adverse skin reactions. Bullous LCV is a relatively rare clinical presentation of LCV, which requires differentiation from other blistering diseases, including bullous erythema multiforme, bullous fixed drug eruption, linear IgA bullous dermatosis, and bullous pemphigoid. The distinctive histopathologic changes of leukocytoclastic vasculitis readily distinguish this bullous eruption from the others.     

Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype

BACKGROUND: Autoantibodies in linear immunoglobulin A (IgA) disease (LAD) are reported to be of IgA class and directed against a 97-120 kDa epidermal antigen. METHODS: We report a 39-year-old woman with clinical features of LAD and with circulating IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180). RESULTS: Histopathology of lesional skin revealed a subepidermal blister with mixed inflammatory cell infiltrate. Direct immunofluorescence of perilesional skin showed linear deposits of IgA along the dermal-epidermal junction. The antigen specificity of the patient's circulating antibodies was determined by Western blotting and enzyme-linked immunoabsorbent assay (ELISA) using various antigen sources, including cultured human keratinocytes, dermal protein lysates, and purified laminin-5, as well as proteins corresponding to BP180, the 230 kDa bullous pemphigoid antigen (BP230), laminin-5 subunits, and collagen IV alpha1-alpha6 chains. IgA and IgG antibodies in the patient's serum were directed against BP180, and no IgA or IgG reactivity was found against the other skin antigens. CONCLUSIONS: These data provide evidence for the presence of a subtype of LAD with dual IgA and IgG autoimmune response to BP180.     

A comparative study of benign chronic bullous dermatosis of childhood and linear IgA dermatosis of adults

Benign chronic bullous dermatosis of childhood (BCBDC) is an apparently self-limiting vesiculo-bullous disease showing linear IgA deposits in the basement membrane zone and which seems to occur exclusively in children. Its relationship to linear IgA dermatosis of adults (LAD) is uncertain and for this reason we studied 28 patients with BCBDC (onset before puberty) and compared them with 18 patients with LAD (onset after puberty).
No significant clinical, HLA, histological or immunopathological differences were found between the two disorders. Surprisingly, nine patients in each group had conjunctival scarring which in some produced a cicatricial pemphigoid-like appearance and in one case of BCBDC resulted in blindness. Remissions with loss of IgA from the skin occurred in patients from both groups. However, the disease duration varied considerably (BCBDC 2–28 and LAD 1–40 years) with six BCBDC patients having had their disease for over 10 years and five of them passing puberty.
All patients (six BCBDC, eight LAD) studied by immuno-electronmicroscopy showed localization of IgA beneath the basal lamina. Direct and indirect immunofluorescence studies using suction blisters also gave similar results in both groups.
As a result of this study many of our former views on BCBDC have been revised and we now believe that both BCBDC and LAD are manifestations of the same disease.     

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

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