1.2.6 Pemphigoid group

Bullous pemphigoid (BP) is the most common. Typically presents in older adults (>60 -70 years). The clinical presentation can be polymorphic, especially in the early stages. The annual incidence has been estimated to be at least 6-30 new cases per million population. The relative estimated risk in patients over 80 years of age is about 300-fold higher than in 60 years old patients. M = F.

BP is an immune-mediated disease associated with a humoral and cellular response directed against two hemidesmosomal adhesion proteins of the cutaneous basement membrane, BP antigen 180 (BP180) and BP230. High levels of several cytokines including CCL-2, CCL-17, IL-5, IL-6, IL-8 and IL-17 are found with increased blister fluid levels of CCL11, eotaxin, and TNF-α. Autoantibodies in BP react with two structural components of the dermal-epidermal junction (DEJ): type XVII collagen (COL17, also called BP180 or BPAG2) and BP230 (also called dystonin or BPAG1) In some cases, drugs like gliptins and diuretics may be a trigger to the development of BP.

• BP: initially erythematous and urticarial patches and plaques and severe pruritus, followed by vesicles and tense blisters on a normal or erythematous skin. The blisters measure 0.5-4 cm in diameter, with a clear fluid inside, hesitating in ulcerate lesions and then in crusted lesions. Sometimes the fluid inside can become haemorrhagic. The lesions are usually symmetric in the distribution and are located in the flexural areas of extremities and in the abdomen and lower trunk. The residual lesions show hyper- and hypopigmentation. Mucosal involvement is uncommon, with less than 10% of patients manifesting blister and erosions in the oral cavity.

• In mucous membrane pemphigoid lesions are almost exclusively on the mucosae, most frequently on the oral mucosa, and less frequently genital mucosae and conjunctiva.

• Linear IgA disease is most common in childhood, and manifests with with bullous lesions on erythematous skin frequently forming rosette-like configuration. It can be drug-induced

• Pemphigoid gestationis: is a bullous pemphigoid-like clinical picture but occurring in 2nd-3rd trimesters. Disease usually starts around the umbilicus and heals spontaneously after delivery.

• Epidermolysis bullosa acquisita is subepidermal bullous dermatosis occurring in adulthood due to an immune reaction against collagen VII of the upper dermal anchoring fibrils. It may manifest with the classic mechano-bullous form or with an inflammatory type, bullous pemphigoid-like form. Blisters tend to be localized on the areas subjected to trauma, and erythematous atrophic scars as well as milia are present at sites of previous bullous lesions.

The diagnosis of BP is based on the clinical presentation, histopathology, and especially on positive direct immunofluorescence (DIF). Direct and indirect (IIF) immunofluorescence: demonstration of antibodies directed against basement membrane zone (linear deposits of C3 and IgG). DIF microscopy of perilesional skin demonstrates the presence of fine, linear, continuous deposits of C3 and/ or IgG (IgG4 and IgG1) along the basement membrane. Regarding IIF, in 60-80% of patients the circulating anti-basement membrane autoantibodies of IgG, less frequently IgA and IgE, are detectable. Hypereosinophilia is common, ELISA for the detection of BP180 and BP230 specific auto-antibodies in serum. Diagnosis of Epidermolysis bullosa acquisita is based on the detection of serum anti-collagen VII auto-antibodies.

Subepidermal blister with dermal infiltrate of eosinophils in bullous pemphogoid. Neutrophils prevail in epidermolysis bullosa acquisita.

Chronic and progressive, with spontaneous exacerbations. The majority of cases are not associated with a trigger. In some cases, drugs cause the lesions in bullous pemphigoid, such as diuretics (captopril, furosemide, spironolactone), anticonvulsants, psychotropics, analgesics, and gliptins (dipeptil-peptidase IV inhibitors, agents to treat type 2 diabetes mellitus). Linear IgA disease can be triggered by antibiotics (vancomicin, penicillin). Other agents linked to the exacerbations of pemphigoid are UV light, radiation, and infections (human herpes virus).

Skin-related sepsis, fluid and protein loss. Mortality among elderly patients. Permanent mucosal scars in mucous membrane pemphigoid.

Tzanck test negative. Histology (subepidermal blister formation, tissue eosinophilia). Direct immnunofluorescence: linear deposits of C3 and IgG along the dermoepidermal junction. Linear IgA dermatosis is characterised by linear deposits of IgA rather than IgG along the basement membrane zone. Indirect inmmunofluorescence: circulating IgG which binds to the dermo-epidermal junction of normal skin and to the roof of human sodium chloride split skin. ELISA for the detection of BP180 and BP230, or colleagen VII specific auto-antibodies in serum.

The treatment can be different according of the severity of the disease and the co-morbidities. For the extensive form, defined by a number of lesions major of 10 new blisters/day or an involvement of a large body surface area, the first line treatment is systemic corticosteroids (0.5-1 mg/kg/day) for 1-2 weeks, then progressively tapered in the several months. Doxycycline may act as a steroid sparing agent. In severe, refractory cases: azathioprine, mycophenolate mofetil, methotrexate, dapsone, or cyclophosphamide; some cases may respond to rituximab or high dose intravenous immunoglobulins. Dupilumab targeting the interleukin-4 receptor has demonstrated promising efficacy in treating refractory BP patients. Drugs targeting IL-5 are also under investigation. For localized forms, potent topical corticosteroids may be sufficient.