**3. Bullous phemphigoid**

Bullous phemphigoid is the most common autoimmune blistering disease which affects the elderly, particularly in patients older than 70 years. The median age for bullous pemphigoid is 80 years. The incidence of the disease has increased significantly in last years due to the increased life expectancy of the aging population [18, 19]. BP has a significantly increased fatality, with 1-year mortality rates ranging from 6 to 41% in literature [17]. Infections are most important cause of death. Risk factors for mortality are advanced age, non-white ancestry, low health insurance accessibility, and the presence of neurological comorbidity and functional impairment at presentation [17, 20].

In the previous decades, neurological conditions including Parkinson's disease, dementia, stroke, epilepsy, and multiple sclerosis have been identified to be highly associated with BP patients. This association may be explained by the cross-reactivity between the neuronal (BP230) and epithelial isoforms of BP Ag1 which are both encoded by dystonin gene. Recently, psychiatric comorbidities, such as schizophrenia and bipolar disorder, as well as personality disorders have been reported in BP

patients [17, 21]. A significant association with hematological malignancies between BP was revealed in the pooled analysis of cross-sectional studies while no association between BP and overall cancer was found in any of the study designs in the results of a meta-analysis [17]. Additionally, in BP risk of developing a thromboembolic disease is 15-fold higher [22].

A geographic or ethnic predilection of the disease is defined recently. Certain HLA class II alleles are more prevalent in patients with BP than in the general population. In Caucasians, a significant association with DQB1\*0301 and in the Japanese population DRB1\*04, DRB1\*1101, and DQB1\*0302 alleles have been found [17, 23].

It is associated with a humoral and cellular immune response directed against the components of the skin BM zone (BMZ). There are two self-antigens that are components of the hemidesmosomes: BP230 and BP180 [24]. *In vitro* studies have shown that human BP180 antibodies play a key role in the pathogenesis of the disease and are responsible for dermal-epidermal separation and subsequent subepidermal blister formation in patients with BP [18, 25]. In DIF, IgG-type antibodies are observed in 90–95% of cases and C3 accumulation is observed in 100% of cases, and this is a critical test for diagnosis. In a smaller group of patients, accumulation of IgE, IgA, and IgM can also be detected [26]. Those that are associated with pathogenesis are IgG and IgEtype antibodies. In particular, IgG1-type antibodies through complement activation, and IgE-type antibodies through mast cell degradation; cause neutrophil and eosinophil chemotaxis. Proteolytic enzymes released from these cells also cause separation at the dermo-epidermal junction. IgG4-type antibodies can also cause degradation by complement-independent antibody-dependent pathways. IgE-type antibodies are responsible for pruritic urticarial plaques, especially in the prebullous stage [27, 28].

The disease usually first presents with pruritus accompanied by localized or generalized excoriated lesions, eczematous, papular, and or urticarial lesions [29]. Blisters may accompany the first lesions or occur a few weeks up to months after the development of the first cutaneous signs [22]. Tense bullae can arise on an erythematous base or normal skin [29]. Blisters most commonly disperse symmetrically and predilection sites are the lower abdomen, flexor surfaces of the limbs, groin, and axilla [30]. The disease heals without scarring, but postinflammatory hypo-hyperpigmentation and milia can be seen [18]. Oral mucosal involvement is seen in 10–20% of affected patients [31–33].

The disease has a non-bullous phase in which typical clinical signs have not yet appeared. Classical bullous lesions are not seen in 20% of patients diagnosed with BP at the time of diagnosis [22, 30]. In this prodromal phase, patients may have only mild to severe pruritus. In an elderly patient who had especially neurological disorders, excoriations accompanied by severe pruritus should cause BP suspect. While eczematous patches can persist for months to years before the development of bullae progression from urticarial pemphigoid to bullous form is seen more quickly in approximately 6 weeks [22]. Another presentation form of BP are Prurigo nodularis-like lesions. Most Pemphigoid nodularis patients develop bullae within years but it is not necessary [22].

There is currently no standardized classification of BP. However, it is possible to recognize distinct variants of the disease according to the age of onset, clinical presentation, location of the lesions, and triggering factors [34]. The presence of concomitant lichen planus with BP is defined as lichen planus pemphigoid. Bullae that demonstrate classic immunopathologic findings of BP develop both on lichen planus lesions and on normal skin [22]. Pemphigoid vegetans is a form of BP in which clinical findings are similar to pemphigus vegetans but histopathology and immunofluorescence findings are identic with BP. BP rarely may manifest as exfoliative erythroderma characterized by generalized erythema and desquamation [34]. Another type is seborrheic pemphigoid involved seborrheic area and resembles pemphigus erythematosus. Also, BP may show ecthyma gangrenosum-like, erosive, toxic epidermal necrolysis-like presentations, and several localized forms. These localized forms that have better prognosis are dyshidrosiform pemphigoid characterized by pompholyx-like palmoplantar lesions, stomal pemphigoid sited stomal region, radiation aggravated pemphigoid limited to the site of radiation therapy, hemiplegic pemphigoid limited to the area of neurologic deficit, stump pemphigoid arised in a stump, pretibial umbilical and vulvar pemphigoid [22].

Pediatric BP is rare and has a more favorable prognosis than adults. Two peaks of incidence, one with an average age of 4 months in infantile BP and another with an age of 8 years in childhood BP were characterized [34]. Infantile BP significantly presents with face and acral involvement [22, 34]. Childhood BP may present localized lesions with genital involvement. Pediatric BP may be related to vaccination [34].

Drug-induced BP has been defined in the literature and several drugs, such as inhibitors of dipeptidyl peptidase-IV (especially vildagliptin and linagliptin, sitagliptin, anagliptin, alogliptin, teneligliptin, and saxagliptin) diuretics (furosemide and spironolactone), ACE inhibitors (captopril, enalopril, and lisinopril), β-blockers, NSAID's, TNF-a inhibitors, antipsychotics, calcium channel blockers and checkpoint inhibitors (Pembrolizumab, Nivolumab, and Durvalumab) are blamed for BP [21, 29, 34, 35].

Histopathology demonstrates subepidermal blister with a moderate to dense inflammatory infiltrate. Inflammatory cell infiltrates usually contain eosinophils and which are often seen in the blister cavity and basement membrane [18, 30]. These infiltrates may also contain neutrophils and lymphocytes [26, 36]. Direct immunofluorescence (DIF) examination shows linear immunoglobulin G (IgG) and/or C3 deposition along the basement membrane [25, 30]. The diagnosis is based on the combination of clinical features, histopathological and immunofluorescence findings.

Salt split DIF is useful in differentiating BP from other pemphigoid group diseases, such as epidermolysis bullosa acquisita, mucous membrane pemphigoid, and anti-p200 pemphigoid. The immune deposits are detected with salt-split DIF on the epidermal side of the skin in BP [18, 29].

Topical and systemic treatments can be used in the treatment of BP, depending on the severity of the disease, age, general health, medical history, and any contra-indications of the use of systemic medications for each patient. Topical clobetasol propionate should be the first choice in patients with < 5–10 new blisters per day. Clobetasol propionate cream can be applied only to the affected areas or to the whole body, sparing the face. If > 10 new blisters are present, systemic treatments can be used together with topical treatments. Oral corticosteroids are preferred first in systemic treatment to get the disease under control quickly. Azathioprine 1–3 mg/day, mycophenolate mofetil 2 g/day, oxytetracycline 2 g/day or doxycycline 200 mg/day with or without nicotinamide 2 g/day, methotrexate 15 mg/week, dapsone 1–5 mg/kg/day, chlorambucil 2–4 mg/day, cyclophosphamide 50 mg/day, anti-CD20 and anti-IgE monoclonal antibodies, intravenous immunoglobulin (IVIG), plasmaphereses and can be used to keep the disease under control and avoid steroid side effects in long-term treatment [37–39].
