Linear IgA dermatosis L13.8

Chorzelski and Jablonska

Rare, chronic, autoimmunologic, blistering dermatosis with linear IgA and C3 deposition at the dermo-epidermal junction zone, which belongs to the pemphigoid group. A basic distinction is made between:

IgA-linear dermatosis (LAD) in adulthood:

• idiopathic IgA-linear dermatosis
• IgA-linear dermatosis triggered by medication (e.g. At1 receptor blockers)

IgA linear dermatosis in children = benign chronic bullous dermatosis in children

Incidence (for Germany and France): Approximately 0.02-0.05/100,000 population/year. In larger contingents of blistering diseases, less than 1% of patients with linear IgA dermatosis are found. The disease appears to be more common in China and some regions of Africa.

In children, the disease is the most common blistering autoimmune disease!

Basically, from an etiopathogenetic point of view, a distinction must be made between 2 forms of LAD in adulthood.

• Idiopathic LAD: In this variant, associations with other autoimmune diseases and malignant tumors have been described.
• Drug-induced LAD: The following drugs have been described as triggers: vancomycin (over 50% of drug-induced cases in adults are due to vancomycin ), diclofenac, glibenclamide, iodine, penicillin, cephalosporins, non-steroidal anti-inflammatory drugs, piperacillin, interferon gamma, sulbactam, cytostatics (Lammer J et al. 2019), atezolizumab, COVID-19 vaccination (Zouh H et al. 2023); romiplostim (thrombopoietin receptor agonist/Heser S et al. 2023). Apparently, the triggering drugs can cross-react with the target epitope, change the conformation of the epitopes or make previously hidden antigens accessible to the immune system (Paul C et al. 1997).

A high percentage of IgA antibodies (60% of cases), a lower percentage of IgG antibodies (30%) and less frequently both types of antibodies (20%) against autoantigens were detected.

Target autoantigens are the 120 kDa protein LAD-1 (produced by proteolysis at the NH2 terminus of the extracellular domain of BP 180 = bullous pemphigoid antigen = type XVII collagen - see also under COL17A1 gene).

IgA antibodies against BP230 (see dystonin below) are rarer. There are no differences in the occurrence of antibodies between adults and children(chronic bullous dermatosis of childhood).

Ultrastructurally, the antigens can be detected on the anchoring fibrils of the lamina lucida and on the lamina densa.

Several HLAs, including HLA-B8, HLA-DR3, HLA-DQ2 and HLA-cw7, have been associated with the occurrence of linear IgA dermatosis.

Most common blistering disease of childhood, usually appearing for the first time at the age of 2-4 years (average 2.7 years). Boys are more frequently affected in childhood (m:w= 1.78:1.0).

Onset in adulthood usually between 20-40 LY and after the 6th decade (in larger contingents, the average in adults was around 60 years). In adulthood w:m= 2:1

Frequent is the affection of the face (especially perioral and ears) and / or the capillitium.

Trunk, here without special predilection sites, possibly with emphasis on the sacral region, groin and anogenital region. This (classic large blistered form) is indistinguishable from bullous pemphigoid by its distribution pattern.

Variants with clinical analogy to dermatitis herpetiformis (small vesicles) show an emphasis on the extensor side (elbow, sacral region) of small vesicles grouped herpetiformly or "jewel-like".

Variants with clinical analogy to the scarring mucous membrane pemphigoid show mucosal involvement of oral mucosa, pharynx, nose, eyes.

Moderately to intensely pruritic, urticarial plaques with marginal vesicular or bullous lesions, often herpetiform or rosette-like, but also anular or garland-like. The rosette form is caused by the episodic appearance of ring-shaped vesicular neoplasms around older blisters that have not yet healed.

In individual cases, the picture of bullous dermatosis may be complemented by IgA purpura (Schönlein-Henoch purpura).

Remark: The clinical pictures correspond on the one hand to dermatitis herpetiformis, on the other hand also to bullous pemphigoid. In rare cases there are also extensive skin manifestations reminiscent of erythema exsudativum multiforme, also under the clinical findings of Stevens-Johnson syndrome.

Mucosal changes are found in 50%-80% of patients, especially in the oral mucosa and conjunctiva. Ocular involvement may result in scarring and even blindness.

Less commonly associated are:

• ulcerative colitis
• M. Crohn's
• IgA nephropathy
• Eosinophilic pneumonia.

In rare cases, associations with angioimmunoblastic T-cell lymphoma (AITL), an aggressive form of peripheral T-cell lymphoma, have been described (Colmant C et al 2020).

The histology of LAD is not diagnostic!

Both subepidermal blistering with infiltrate of lymphocytes and numerous neutrophil granulocytes, few eosinophil granulocytes and occasionally intrapapillary microabscesses (see DD for dermatitis herpetiformis) and subepidermal blistering with perivascular and interstitial lymphocytic infiltrate are found.

There are cases in which eosinophilic granulocytes dominate (differentiation from bullous pemphigoid is then difficult).

Immunoelectron microscopy can distinguish 2 types, the more common lamina lucida type and the sublamina densa type.

The DIF shows linear IgA deposits at the dermoepidermal junction zone (100%), further but weaker C3 (50%) and IgG (30%).

In slit examinations (preparation is pretreated in 1 M NaCl solution), the deposits are found on the dermal or epidermal side; rarely on both sides.

Immunoelectron microscopy reveals deposits on the lamina lucida and the sublamina densa.

Clinical:

• Bullous pemphigoid
• Pemphigoid, scarring (mucous membrane pemphigoid)
• Dermatitis herpetiformis Duhring
• Epidermolysis bullosa acquisita
• bullous impetigo
• bullous drug exanthema
• Erythema multiforme.

Histologic:

• Dermatitis herpetiformis Duhring
• Inflammatory epidermolysis bullosa acquisita
• Bullous pemphigoid
• Bullous drug exanthema

Associated diseases have mostly been described in single case reports:

• Crohn's disease
• Gluten-sensitive enteropathy (0-24%); Note: this constellation is questioned by some authors!
• ulcerative colitis
• Systemic lupus erythematosus
• Dermatomyositis
• Malignancies (B-cell lymphoma, myeloid leukemia)

If the conjunctiva are affected, scarring and blindness may occur.

Antipruriginous and anti-inflammatory treatment e.g. with 3-5% polidocanol lotio(e.g. Optiderm, R200) alternating with weak to medium-strong glucocorticoids such as 1% hydrocortisone cream(e.g.hydrogals, R119 ), 0.1% hydrocortisone-17-butyrate cream (e.g. Laticort), 0.1% methylprednisolone cream (e.g. Advantan), 0.1% mometasone fat cream(e.g. Ecural). Treatment with synthetic tanning agents, e.g. Tannosynt, Tannolact, has also proven to be effective.

The first choice is DADPS (e.g. Dapson-Fatol). Gradual dosage, initially 50-75 mg/day, after 2 weeks full dose from 100-150 mg/day to max. 300 mg/day. Maintenance dose according to clinic (wide range of variation). Initially adjuvant prednisone (e.g. Decortin) 20-40 mg/day p.o. If the results improve, continue dapsone as monotherapy, if the results deteriorate, temporary adjuvant administration of prednisolone. At the earliest after 6 months of freedom from symptoms.

If the clinical success is unsatisfactory, the use of azathioprine (e.g. Imurek) 1-2 mg/kg bw/day in combination with systemic corticoids may be considered. Further treatment options are cyclophosphamide, mycophenolate mofetil, colchicine, methotrexate and ciclosporin A.

To reduce itching, additional systemic administration of antihistamines such as desloratadine (e.g. Aerius) 5 mg/day p.o. or levocetirizine (e.g. Xusal) 10 mg/day p.o. may be necessary.

Dietetic measures are largely ineffective in IgA linear dermatosis.

In idiopathic LAD, a course lasting for years must be expected.

In the case of drug-induced LAD, healing can be expected within a few weeks/months after discontinuation of the triggering medication.

While the skin lesions heal without scarring, ocular involvement can lead to scarring and, in extreme cases, blindness.

The prognosis of the disease also depends on the organ involvement: ulcerative colitis, Crohn's disease, IgA nephropathy, gluten-sensitive enteropathy.

Linear IgA dermatosis, bullous pemphigoid, pemphigoid gestationis and mucous membrane pemphigoid have the identical target antigen (BP 180/type VIII collagen). In contrast to these, however, the autoantibody of linear IgA dermatosis belongs to the IgA class.

The role of ulcerative colitis as rare concomitant disease of IgA linear dermatosis remains unclear so far. It can precede the LAD by years.

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