Intercellular IgA dermatosis

ARTICLE

To date, more than 40 cases with vesiculopustular and vesiculobullous eruptions characterized by intercellular IgA deposition on direct immunofluorescence of perilesional skin have been reported [1-40] (Table I).

A wide array of synonyms have been used in the literature since the first case was reported [1]: "intra-epidermal IgA pustulosis" [44], "IgA-pemphigus" [14, 17, 21], "intercellular IgA dermatosis" [22], "intraepidermal neutrophilic IgA dermatosis" [7, 10, 15, 18, 23] and recently "intercellular IgA vesiculopustular dermatosis (IAVPD)" [45] but no consensus has been reached to denominate this disorder.

We propose the name "intercellular IgA dermatosis" (IAD) for the disease entity comprising a spectrum ranging from IgA pemphigus to intercellular IgA vesiculopustular dermatosis. On clinical and histological grounds a distinction can be made between the two ends of the spectrum: IgA pemphigus (clinically and histologically pemphigus) and intercellular IgA vesiculopustular dermatosis. In between we observe cases combining clinical features and histological characteristics of both ends of the spectrum. Historically, the term IgA pemphigus (foliaceus) has been used for patients who do not show both the clinical and histological features of pemphigus [17, 21].

Within the entity "IAD", IgA pemphigus could be considered part of the pemphigus spectrum mediated by IgA [14]. The term should be reserved to those cases with clinical and histological characteristics of pemphigus [14, 21, 31]. Moreover IgA antibodies were shown to be directed against antigens closely related to the pemphigus foliaceus antigen in one case [21].

On the other hand a lot of cases within the spectrum of IAD are different from classic pemphigus in many aspects [17] :

1. Clinically: a vesiculopustular disease with absence of Nikolsky's sign and relatively benign course.

2. Histologically: scanty acantholysis with abundance of neutrophils.

3. Immunologically: rare intercellular deposition of C₃ and lower levels of circulating antibodies.

4. Therapeutically: responsiveness to dapsone in many cases.

Immunoblot analysis in these cases demonstrated that IgA auto-antibodies recognize different epidermal antigens from either pemphigus or other IgA related dermatoses [46] but also classic pemphigus vulgaris [23, 28, 42] and foliaceus [30, 35] antigens.

These findings reflect the heterogeneity within the spectrum of IAD.

We report three cases of IAD and review the literature.

Case report 1

A 74-year-old man with no previous medical history was referred to our clinic for evaluation of a vesiculobullous eruption which had been present for one month. Initially located on the scalp, the pruritic pustular lesions progressively extended to the back, the groins and the oral mucosa. Nikolsky's sign was not elicited. This clinical picture was first diagnosed as dermatitis herpetiformis.

On examination we noted a large erythematous macular area in the middle of the back. The periphery was seeded with confluent pustules and well demarcated erosions whereas the center tended to heal (Fig. 1). The groin displayed coalescent pustules in an annular pattern on a background of erythema (Fig. 2). Adherent crusts on an erythematous base were observed on the scalp. Several small erosions and two tense bullae were present on the oral mucosa.

General physical examination revealed no particularities except for a left-sided eye prosthesis. The patient was on no medication.

Investigations

Laboratory investigations showed a slight increase of sedimentation rate: 22/29 mm/h (normal value: < 7/15 mm/h) and CRP 1.14 mg/dl (normal value: 0-0.5 mg/dl). Urinalysis was normal. Protein electrophoresis on blood and urine revealed no abnormalities, more specifically no monoclonal IgA gammopathy was detected. Immunoelectrophoresis and immunofixation were not performed. Microbiology of pustule content remained negative.

Blister smear cytology mainly demonstrated inflammatory cells and a few round shaped keratinocytes indicating an acantholytic process. Tests for autoantibodies detected a strongly nucleolar ANF and the presence of anticytoplasmic Ro-antibodies: anti-ENA: SSA. The Shirmer test was bilaterally abnormal. The diagnosis of Sjögren's syndrome was made.

Histology of lesional skin showed an intra-epidermal pustule lined by 1 or 2 layers of keratinocytes on the bottom. The pustule mainly contained polymorphonuclear eosinophils with a small number of neutrophils and a only few acantholytic cells (Fig. 3a, b).

Direct immunofluorescence of perilesional skin detected deposition of C₃ along the basal membrane and intercellular deposition of IgA throughout the epidermis (Fig. 4).

Standard indirect immunofluorescence technique on monkey esophagus detected no circulating IgA antibodies.

Immunoblot analysis on human skin extract detected a 130 kD antigen for IgA and IgG.

Treatment and progress

The patient was initially treated with 75 mg/d prednisolone and 100 mg Azathioprine. Within 1 month the lesions were healed but when the doses were lowered the symptoms recurred. Prednisolone 50 mg/d was then associated with 100 mg dapsone and the lesions cleared in two weeks. Dapsone was not tried on its own before the association with prednisolone. After 1 month the doses of both drugs could be progressively lowered to 10 mg/d prednisolone and 50 mg/d dapsone. No new lesions appeared for 6 months. When the patient developed small pustules on an erythematous base on the trunk, dapsone was increased to 100 mg/d and prednisolone to 15 mg/d. Indirect immunofluorescence on monkey esophagus detected circulating IgA and IgG autoantibodies (titer 1:60) in the intercellular spaces at time of recurrence (Fig. 5). Peripheral blood count was regularly controlled and revealed a non-progressive slight anemia with normal methemoglobinemia. Indirect immunofluorescence technique was negative after two months of increased drug doses. After 3 more months circulating IgA (titer 1:30) and IgG (titer 1:60) autoantibodies were detected (intercellular staining pattern). No immunoblot studies were performed at the time of positive indirect immunofluorescence. Meanwhile the patient kept on having small recurrent lesions at each visit, while both drug doses were progressively tapered. At the time of writing the patient continues to have small erosions and crusts on the scalp while taking 7.5 mg prednisolone a day and alternatively 50 and 100 mg dapsone a day.

Case report 2

A 56-year-old woman presented with a generalized pustular pruritic eruption present for 6 months. Initially located on the left lower leg the lesions gradually spread to the anterior aspects of the trunk and the thighs and to the abdomen (Fig. 6). The extremities were also involved. Mucous membranes were intact. The individual lesions consisted of vesiculopustules on an erythematous base. After rupturing, a central excoriation appeared, sometimes covered with fibrinous debris or a crusta while new vesicles with a herpetiform aspect appeared in the surrounding area (Fig. 7). The clinical differential diagnoses were: subcorneal pustular dermatosis, IAVPD or linear IgA dermatosis.

The patient was otherwise healthy. Physical examination was essentially normal except for edema at the left ankle. She was on the following chronic medication: propanololhydrochloride (Inderal^®) 40 mg/d, paroxetine (Seroxat^®)
20 mg/d, estriol (Aacefemine^®) 2 mg/d and lormetazepam (Loramet^®) 2 mg/d.

Investigations

Laboratory investigations showed a slight increase of sedimentation 37/62 (normal value: < 7/15 mm/h) and CRP 1.19 mg/dl (normal value: 0-0.5 mg/dl). A macrocytic anemia (RBC: 3.54 10⁶/ul (nl 4.7-6.1 10⁶/ul)), hematocrit 35.5% (nl 41-53%), MCV 100 fl (nl 80-94) with normal folic acid and vitamin B12 values was present. Total protein was low: 6 g/l (normal value 6.7-7.9 g/l), gamma GT high: 108 U/l (normal value: 11-49) and uric acid high: 10.5 mg/dl (normal value 3.4-7.3).

Urinalysis was normal. Protein electrophoresis on blood and urine showed a normal pattern. Immunoelectrophoresis and immunofixation were not performed. Microbiology of pustule content remained negative. Immunologic studies including ANA and rheumatoid factor latex fixation were negative.

A first biopsy of lesional skin showed an intraepidermal pustule filled with polynuclear neutrophils, some eosinophils and a few acantholytic cells. Direct and indirect immunofluorescence studies were negative. A second biopsy of a newly formed pustule showed subcorneal pustule formation with mainly polynuclear neutrophils and only a few eosinophils. Subepidermal edema infiltrated with polynuclear cells was present.

Direct immunofluorescence of perilesional skin detected intercellular IgA deposition throughout the whole epidermis.

Standard indirect immunofluorescence technique on monkey esophagus remained negative.

Immunoblot was not performed.

Treatment and progress

The patient was treated with dapsone 100 mg daily and all lesions cleared within two weeks. During further follow-up small scattered pustules occasionally appeared. The dapsone dose was lowered to 50 mg/d after three months as the patient developed a slight hemolytic anemia. After normalization of hematological values an alternate dose of 50/70 mg/d was required for four months to control the lesions. The patient remains currently on 50 mg dapsone daily and has developed no new lesions.

Case report 3

A 59 year-old woman presented with a two month history of pruritic bullous dermatosis subsequently involving the trunk, upper extremities, axillae and forehead (Fig. 8). The eruption was characterized by intact and flaccid bullae rapidly evolving to crusty lesions on a base of erythema.

The clinical differential diagnosis was pemphigus and impetigo.

General physical examination was normal and the patient was on Emcoretic^® (combination of bisoprolol 10 mg and hydrochlorothiazide 25 mg).

Laboratory investigations revealed no abnormalities. Protein electrophoresis on blood was normal. Immunoelectrophoresis and immunofixation were not performed. Microbiology of pustule content remained negative.

Histology of lesional skin showed suprabasal acantholysis with formation of intra-epidermal bullae. Infiltrating eosinophils and neutrophils were sparse in the cavity of the bullae. A perivascular lymphocytic infiltration was present (Fig. 9).

Direct immunofluorescence on perilesional skin detected intercellular IgA throughout the epidermis.

Indirect immunofluorescence detected no circulating antibodies.

Immunoblot was not performed.

Treatment and progress

The patient was treated with 100 mg dapsone and 32 mg methylprednisolon. Dapsone was not tried on its own before association with steroids. All the lesions cleared within a few weeks and methylprednisolon was progressively tapered to 16 mg without relapse of the disease at time of writing.

Discussion

We add three patients to the published cases of intercellular IgA mediated dermatoses (Table I). From our point of view they all three belong to the spectrum of intercellular IgA dermatosis which is characterized by clinical, histological and immunological heterogeneity. The first two cases could be diagnosed in the spectrum part of IAVPD. This is based on the clinical and histological picture. The immunoblot findings in case 1 (130 kD antigen) are not those typically described for IAVPD which may suggest the diagnosis of pemphigus. However we think that the histological picture is not compatible with this diagnosis.

The third case is different in two main aspects: it has the clinical and histological picture of classic pemphigus. We therefore name it IgA pemphigus.

Demography

The age at onset of the disease ranges between 5 and 92 years [8, 22]. Women are more affected than men (27 women: 21 men). It mostly concerns adults. The disease often starts after the fourth decade. However children can also be affected (5 cases < 11 years) [25].

Clinical features

In the majority of cases of IAD (IAVPD end of the spectrum), the patients display a refractory, often pruritic, vesiculopustular eruption. The predilection sites are: the trunk, the extremities and the intertriginous regions such as the axillae and groins [18, 44, 45]. The face and the scalp may also be involved. The eruption consists of clear vesicles or small bullae on an erythematous base. They rapidly evolve from flaccid pustules to erosions and crusty or scaly erythematous macules. The vesicles may become confluent and display a circinate or annular configuration. A centrifugal evolution is observed: while the center of the plaque tends to heal, new vesicles develop peripherally. Lesions in different stages are observed in the various affected areas. Nikolsky's sign is not elicited [18, 44, 45].

The clinical presentation of IAD may typically resemble pemphigus foliaceus, pemphigus herpetiformis [5, 10, 14, 19, 21, 31] or pemphigus vegetans [43]. In one case Nikolsky's sign could be elicited [31].

The oral mucosa is often spared in IAD. Borradori described one case in association with Crohn's disease where the oral cavity was the only affected area [27].

Other differential diagnoses are subcorneal pustular dermatosis [14, 17, case 2], dermatitis herpetiformis [14, case 1] or impetigo [9, 25, case 3].

The course of the disease is chronic and benign, with self-limiting lesions [3, 17]. Twenty-two patients consulted more than 1 year after the onset of the eruption. However in our three patients, the disease started quite acutely.

Histology

One side of the IAD-spectrum (IAVPD end) is histologically characterized by the infiltration of polymorphonuclear cells in the epidermis with formation of pustules, bullae or blisters at various levels. The infiltrating cells are mainly neutrophils with few lymphocytes, histiocytes or eosinophils. Occasionally, as in our first case, eosinophils can be the dominating cell type [8, 9, 15]. The absence of a distinct neutrophilic infiltrate either in the dermis or epidermis was reported by Neumann but histologically his case resembles pemphigus foliaceus [31].

Iwatsuki distinguished two types according to the level of pustule formation (and IgA deposition). The subcorneal pustular dermatosis type (SPD, subcorneal pustule formation) and the intraepidermal neutrophilic type (IEN, intra-epidermal pustule formation) [45]. However, pustules were described at other levels: subepidermally [11], suprabasally [27] and neutrophilic microabcesses in the epidermis [10, 43] were also observed. In addition, as exemplified in our second patient, pustules may be found at different levels in one patient, which might depend on the age of the lesion [35, case 2]. These observations point to the arbitrary character of subdividing the disease in different types [11, 16, 17, 20, 29, 35, 37] based on the level of pustule formation.

Acantholytic cells are often sparse or absent which is reflected in the absence of Nikolsky's sign [17]. But acantholysis can be occasionally pronounced [4, 10, 13, 26, 30, 34].

The histological findings at the other end of the spectrum [17, 21] are identical to classic pemphigus vulgaris, showing cleavage with acantholytic cells and very occasional neutrophils and lymphocytes in the cavity [case 3, 17, 21]. In other cases the histological diagnosis was pemphigus foliaceus [14, 31].

Immunofluorescence (direct)

The major hallmark of IAD is the intercellular IgA deposition which can be found at many different epidermal levels or throughout the epidermis.

According to the level of IgA deposition an intraepidermal neutrophilic type (deposition throughout the epidermis) and a subcorneal pustular dermatosis type (deposition in upper epidermal layers : at the "subcorneal level" [26], in the horny layer [16] or in the "upper epidermis" [5, 12, 20, 25, 28, 32, 33]) are proposed [45]. Again this might be arbitrary as other locations of IgA deposition have been described: at the suprabasal level [7, 15, 27] in the stratum spinosum [8] or in the lower to midepidermis [23]. In three cases a linear subcorneal IgA deposition is observed [1, 3, 11] and Sneddon describes IgA deposition inside the pustule [2].

In our patient with IgA pemphigus, IgA deposition was present throughout the epidermis. Cases of IgA pemphigus foliaceus (clinical and histological pemphigus foliaceus) are reported with IgA deposition in the upper stratum spinosum [14, 31]. Similarly a case of IgA pemphigus vegetans displayed intercellular IgA in the lower epidermis [43].

Iwatsuki stated that intercellular IgA alone is the major characteristic of the disease because IgA deposition can sometimes co-exist in patients with classic pemphigus [45]. However, occasionally concomitant deposition of other immunoreactants is present in the reviewed series: ex. IgM [5, 26, 38], Clq [5, 38] or C4 [2]. Only in a few cases C₃ deposition can be found in the basal membrane zone [case 1, 6, 24, 27] or in the intercellular spaces [5, 26, 28, 30, 31, 35, 38]. Intercellular IgG [5, 26-28, 30, 32, 35, 38] is the most frequently observed. Immunoblot studies detected classic pemphigus antigens as a target of these IgG immunoglobulins in some cases. This could suggest a simultaneous occurrence of intercellular IgA vesiculopustular dermatosis and pemphigus vulgaris [28] or pemphigus foliaceus [30, 35].

In one patient with IAD limited to the oral cavity, uninvolved buttock skin showed a similar staining pattern of IgA in the epidermis on direct immunofluorescence [27].

In some cases IgA deposits consisted only of one chain of immunoglobulin: the IgA lambda [31] or IgA kappa [3, 26, 33] chain and the same IgA chain could be found on indirect immunofluorescence [2, 33]. A monoclonal IgA chain gammopathy was often found in these cases [4, 26, 33] and an association with myeloma may be observed [3, 26].

Immunofluorescence (indirect)

Circulating IgA anti-intercellular autoantibodies are detected with standard indirect immunofluorescence technique using normal skin, monkey esophagus or rat tongue and esophagus substrate. They are found in low titers ranging from 1:10 to 1:80 (occasionally 1:2560 [31]) and in a pattern comparable with the distribution on direct immunofluorescence [45].

Recently a skin explant culture technique was introduced as a more sensitive way to detect IgA autoantibodies if standard methods failed to do so [47]. We used normal human skin and monkey esophagus and first detected circulating IgA in a low titer (1:60) in our first patient when the lesions recurred 8 months after diagnosis. Higher titers of circulating IgG antibodies can be found in patients with IgG deposits in perilesional skin [30, 32, 35]. However, in our first patient we detected circulating IgG antibodies without positive direct immunofluorescence.

The titer of IgA immunoglobulins may decrease upon successful therapy and increase when the disease relapses [31]. In our first patient, IgA titers became negative during an uncontrolled relapse of the disease. They may also remain positive during periods of remission [17, 35]. IgA titer does not seem to be a reliable reflection of the disease activity.

Whole serum containing IgA autoantibodies is able to induce intraepidermal acantholysis in skin explant cultures. Circulating IgA anti-cell surface antibodies may play a complement-independent role in this process of acantholysis [47]. Cutaneous IgA deposits (in linear IgA bullous dermatosis and dermatitis herpetiformis) can be ligands for neutrophils and play a role in the localization of inflammation in these conditions but also in certain vesiculobullous diseases affecting the epidermis [48]. IgA has been associated with leucocyte chemotaxis [49] and IgA receptors were detected on polymorphonuclear leucocytes [50]. Neutrophil IgA-mediated phagocytosis may lead directly to the formation of epidermal lesions [51]. As Neumann suggested in his case without neutrophilic infiltration, other IgA mediated processes may contribute to epidermal damage [31]: IgA dependent cellular cytoxicity [52], regulation of B [53] and T cells [54] and activation of complement by the alternative pathway [55].

Immunoblot studies

Immunoblot studies characterizing the target antigens for IgA antibodies were thought to clarify the relation between IAD and other autoimmune diseases. However, available immunoblot results are inconsistent.

The serum of three patients with "SPD type IAVPD" reacted with a doublet of 105 and 115 kD proteins in a bovine desmosome sample, corresponding with desmocollin I and II, desmosomal core proteins [5, 12, 45]. In one case both IgA and IgG detected this doublet of antigens [32]. The significance of these findings was unclear because no reaction was found with human desmocollins. Hashimoto reported that the IgA autoantibodies in 6 patients with the "SPD type of IAVPD" reacted with transfected cells expressing recombinant human desmocollin I [56]. A 120 kD protein in normal human skin and bovine desmosome sample (possibly desmocollin H, higher molecular weight desmocollin [57]) was detected by IgA antibodies in 1 patient with "IAVPD of the IEN type" [22, 46]. These target antigens were different from those detected by IgG related pemphigus diseases: IgG in pemphigus foliaceus recognizes a 160 kD protein, desmoglein I (DsgI) (Dsg = desmosomal glycoprotein) [58-60]; IgG in pemphigus vulgaris detects a 130 kD protein, desmoglein III (DsgIII) [59].

Chorzelski demonstrated by immunoblocking studies, that IgA antibodies from a patient with IgA pemphigus foliaceus are directed either to the same antigen as the IgG pemphigus foliaceus antigen or to one that is close enough to give steric hindrance [21].

In 3 patients IgA anti-intercellular antibodies recognized a 150(-160) kD protein, identical to the pemphigus foliaceus antigen [29, 30, 35]. Prost detected a 210 kD antigenic molecule, possibly the pemphigus vulgaris antigen, for IgA autoantibodies in a case of intraepidermal neutrophilic IgA dermatosis [23]. This 210 kD protein consists of the known 130 kD pemphigus vulgaris antigen bound with a disulfide bond to a 80 kD protein. Both IgG and IgA antibodies, in the case of Gengoux [28], detected the 130 kD pemphigus vulgaris antigen. In our first case, immunoblot detected a strong band at ± 130 kD for IgA and IgG. This band could also be identical to the 130 kD pemphigus vulgaris antigen Dsg III. Wang et al. recently identified desmoglein III as the target antigen in a case of IEN IgA dermatosis: the patient's IgA autoantibodies labeled a recombinant desmosomal protein desmoglein III (DsgIII) (extracellular domain of 66 kD) on immunoblotting and immunolabeling of epithelial cell surfaces was eliminated by preabsorbtion with Dsg III [42]. In two cases [30, 35] both IgA and IgG detected 150 kD antigen on bovine desmosome sample and in one of these patients [35] only IgG detected a 140 kD antigen on human epidermal extracts ­ the nature of which is unclear but possibly a new isoform of the desmoglein family.

A discrepancy between the results with bovine desmosome and human epidermal extracts is observed. The reason for a higher sensitivity in a bovine desmosome preparation is unknown [35].

In one patient with pemphigus foliaceus who had high titers of IgG pemphigus antibodies, IgA anti-intercellular antibodies reacted with antigenic molecules not detected by IgA antibodies from a patient with the "SPD type of IAVPD" [61].

Anti-intercellular IgA antibodies seem to recognize a variety of known and newly discovered antigens. This reflects the heterogeneity of IgA antibodies within the spectrum of IAD but does not elucidate the problem of classification of the disease versus other immunoglobulin mediated diseases. As immunoblot findings are not available in all reviewed cases it is difficult to position the diseases within the spectrum of IAD according to detected target antigens. However with the given results we could characterize the ends of the spectrum: IgA of IAVPD recognizes 105-115-120 kD antigens (Desmocollins) [5, 12, 22, 32]; IgA of IgA pemphigus recognizes a classic pemphigus antigen [21]. Cases with combined features of both ends could be positioned in between these two ends [case 1, 23, 28-30, 35, 36, 42]. Further research is required to characterize the nature of the autoantigens in order to resolve these issues.

Dmochowski [62] published three intriguing cases of bullous dermatosis with circulating IgA anti-intercellular and anti-basement membrane zone antibodies. Also IgG anti-intercellular and anti-basement membrane zone antibodies were observed on direct and indirect immunofluorescence. The patients had IgG immunoblot features of bullous pemphigoid or pemphigus foliaceus. Immunoblot studies detected antigens of 170 kD (minor bullous pemphigoid antigen) and 97 kD (antigen of linear IgA disease) for the IgA antibodies. It is not clear whether these cases represent mixed or co-existent bullous diseases. The production of anti IC antibodies might be a secondary phenomenon in certain cases with subepidermal blistering skin diseases leading to the exposure of "hidden" antigenic epitopes in the intercellular space, a phenomenon called "epitope spreading" [63]. These cases certainly illustrate the difficulty of classifying bullous dermatoses as well as the heterogeneity of IgA auto antibodies. We include the second patient in our series because of the clinical and the histological picture (vesiculopustular eruption and neutrophilic blisters in the entire epidermis) [36].

The belief is growing that autoimmune bullous diseases may all be the expression of an underlying disregulation of the immune system [64]. This could explain how cases are interpreted as combinations of different bullous diseases [28, 30, 35]. The presence of ANF and anti-RO antibodies in our first case could fit in this same thought. Another case of IAD in association with Sjögren's disease has been reported [38] and one case was published with the diagnosis of Sjögren's disease and pemphigus [65]. In two other cases a positive ANF was detected [17, 39].

Immunoelectron microscopy

Immunoelectron microscopy has been used in an attempt to locate the antigen in IgA pemphigus. Prost [23] and Kim [37] observe a uniform IgA deposition along the keratinocyte cell membrane in both desmosomal and nondesmosomal areas. IgA deposition on the cell surface of cytoplasmic projections without association with desmosome-like structures has been demonstrated on cultured keratinocytes [66]. Intercellular accumulation of IgA deposits in the region of desmosomes has also been reported [16].

Associated findings

Some pathological conditions are repeatedly or occasionally found in association with intercellular IgA dermatosis. Monoclonal IgA gammopathy is the most frequent associated finding (11 cases): 7 with IgA kappa gammopathy [3, 4, 6, 20, 24, 26, 33] and three with IgA lambda gammopathy [30, 35, 41]. With the available data, these numbers cannot be compared to the number of cases where such a finding could be definitely excluded (not only routine electrophoresis but also immunoelectrophoresis or immunofixation). In three cases this was associated with myeloma [20, 26, 33], 1 patient had a B cell lymphoma [4] and 1 patient was HIV infected [41]. The monoclonal IgA gammopathy can precede [20] the cutaneous manifestations or can be diagnosed several years after onset of the skin lesions [5, 24, 33].

Malaise and fever are occasionally mentioned [11, 23]. Other associated conditions were: lung cancer [32], Sjögren's syndrome [case 1, 38], Crohn's disease [27], gluten-sensitive enteropathy [1], acute polyarthritis [11] and rheumatoid arthritis [38].

HIV infection results in both immunodeficiency and immune disregulation with polyclonal B-cell activation, which has been associated with autoantibody formation and the development of autoimmune disease. Of the three reported cases, two had a polyclonal gammopathy or IgA lambda paraproteinemia [34, 40, 41]. One patient presented skin lesions in association with colitis and IgA deposits in the large bowel epithelium were detected [15]. Presence of ulcerative colitis for 8 years prior to skin lesions is also reported [36].

Treatment

Dapsone (50-100 mg/d) appears to be the drug of choice in most cases of intercellular IgA dermatosis, inducing a marked resolution of the eruption [15, 17, 45]. It probably reduces the neutrophil's cytotoxicity to adjacent cells by interfering with their myeloperoxidase-hydrogen peroxide cytotoxic system [14]. Twenty-five patients out of 33 who received the drug showed considerable improvement or clearance of the skin lesions, 6 patients showed no response. The drug should be discontinued or the dose lowered if side effects occur (e.g. hemolytic anemia case 2). Testing of glucose-6-phosphate dehydrogenase values is recommended in black people, Asians and people of Mediterranean origin. Dapsone is given in monotherapy or can be combined with oral steroids (case 1) or nicotinamide [38].

Effective therapeutic alternatives in some cases include: etretinate [5, 12, 24, 29], systemic steroids [9, 13, 17, 29, 30, 31, 37], immunosuppressive agents (azathioprine (case 1), cyclophosphamide [21]), PUVA [14, 21], colchicine [28, 37], plasmapheresis [21] and different combinations of these. Treatment of an associated myeloma by combination chemotherapy can induce dramatic improvement of the skin lesions [33]. Topical steroids were effective in two cases [41, 42].

CONCLUSION

We view IAD as a group of vesiculopustular or vesiculobullous diseases with wide heterogeneity in clinical and histological features mediated by intercellular IgA deposition at various levels of the epidermis.

Clinically, the picture varies from classic pemphigus (and variants) to what has been named "IAVPD" in the recent literature. The classic histological features of pemphigus can be encountered but also neutrophilic infiltration resulting in pustule formation at various levels of the epidermis with sparse or no acantholysis is seen as described in IAVPD. We suggest only using the term "pemphigus" when histological and clinical criteria are present. A lot of cases of IAD can be positioned on clinical and histological grounds between these two ends of the spectrum. Additionally, cases with various combinations of these clinical and histological aspects are described. This observed heterogeneity cannot be reflected if IAD is divided in arbitrary subtypes (according to level of IgA deposition or pustule-bulla formation). We would rather consider IAD as a spectrum of diseases with IgA pemphigus and IAVPD at each end. Characterization of various target antigens (although not available for all cases) for the IgA autoantibodies also reflects the heterogeneity of the disorder and supports this hypothesis. *

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