Open access peer-reviewed chapter

Bullous Pemphigoid

Written By

Derya Yayla, Pelin Hizli and Yeşim Yayla

Submitted: May 15th, 2017 Reviewed: January 5th, 2018 Published: January 29th, 2018

DOI: 10.5772/intechopen.73543

Chapter metrics overview

1,166 Chapter Downloads

View Full Metrics

Abstract

Bullous pemphigoid (BP) is a chronic, acquired, autoimmune bullous disease characterized by subepidermal bullae. It is usually seen in the elderly but, rarely, may also be seen in children. Autoantibodies against hemidesmosomal proteins BP230 (BPAG1) and BP180 (BPAG2 or type XVII collagen) are blamed for the pathogenesis. Clinically, it is characterized by large, tense blisters. Blisters can occur on normal skin or erythematous base with a predilection of flexural aspects of the limbs, abdomen, groin and axillae. Mucous membrane involvement is seen in about 10–35% of the patients. For treatment, general maintenance of BP patients is the first step. Systemic steroids are the common treatment agents. But localized disease can be treated successfully with topical corticosteroids. The common immunosuppressive agents are azathioprine, mycophenolate mofetil, methotrexate, chlorambucil and less often cyclophosphamide. In a minority of resistant cases, intravenous immunoglobulins, plasma exchange, anti-CD20 immunotherapy (rituximab), leflunomide, chlorambucil and methotrexate may be effective.

Keywords

  • blistering diseases
  • tense bullae
  • BP230
  • BP180
  • gestational pemphigoid

1. Introduction

Bullous pemphigoid (BP) is a chronic, acquired, autoimmune bullous disease characterized by subepidermal bullae [14]. It is the most common bullous disease, and its incidence has been gradually increasing [2, 5]. It is usually seen in the elderly, but rarely may also be seen in children [2, 6, 7]. In general, the clinical manifestations are tense bullae, urticarial lesions and intense pruritus [3, 5, 7]. Although mucosal findings are not common, oral findings are observed in 10–25% of cases [4, 5]. Autoantibodies against hemidesmosomal proteins BP230 (BPAG1) and BP180 (BPAG2 or type XVII collagen) are blamed for the pathogenesis [2].

Advertisement

2. History

In 1953, Walter Lever, M.D. was the first who described that BP was a distinct disease from pemphigus [8, 9]. In 1967, Jordon, Beutner et al. demonstrated the circulating autoantibodies against the epidermal basal membrane zone (BMZ) in patients with bullous pemphigoid using the immunofluorescence method [9].

Advertisement

3. Epidemiology

The annual incidence is approximately 6–7 new cases per million [8]. While the incidence in Europe ranges from 7 to 43 per million [10], this rate is 2.6 per million in Basra and 14 per million in the North East Scotland [2]. It is often seen in the elderly population (particularly in over 65 years of age) and more frequent in men [5, 11]; however, it has been cited in many studies that it is seen with equal frequency in both genders [4]. Patients older than 90 years have also a relative risk 300 times higher than those younger than 60 years [5]. Although it is rare in children, its incidence has been increasing [7]. In addition, there are no geographical or ethnic differences [4, 8].

Advertisement

4. Etiology

4.1. Genetic factors

No strong association was found with any of the HLA class I and II DR antigens [12]. Nevertheless, in some studies, HLA class II alleles were found to be more frequent in BP patients than in the general population [11]. A significant association with DQB1*0301 alleles was also found in Caucasians, while there was an association with DRB1*04, DRB1*1101 and DQB1*0302 alleles in Japanese patients [11]. In some studies, residual essential amino acids were detected in positions 71–77 of the DQB1 gene in patients with BP [5].

4.2. Environmental factors

It has been shown that furosemide, psoralen, ibuprofen, galantamine, hydrobromide, ACEi, spironolactone, penicillin, levofloxacin, metronidazole may lead to BP [13]. Adalimumab and etanercept (TNF-alpha blockers) associated BP cases have also been reported [5]. Another cause blamed in the etiology is vaccinations. BP may develop after 1 day–4 weeks of vaccination. In particular, most infantile BP cases have been described after the first dose [14]. In addition, trauma, radiotherapy and UVB exposure may cause bullous lesions by uncovering BP antigens [5]. In contrast to pemphigus vulgaris, no relationship between any dietary factor and BP has been found yet [5].

Advertisement

5. Accompanying diseases

The incidence of malignancy is increased in BP cases (stomach cancer, lung cancer, etc.) [8, 15, 16]. There is also an increase in the incidence of psoriasis [8]. Although the immunogenetic and immunopathological mechanisms are not clear, it is considered that treatments for psoriasis (such as UVA-UVB) may play a trigger role for BP [8]. Another association is autoimmune diseases. BP is accompanied by some diseases such as rheumatoid arthritis, Hashimoto’s thyroiditis, dermatomyositis and autoimmune thrombocytopenia [8]. In addition, multiple sclerosis, dementia, stroke, epilepsy, Parkinson’s disease, Shy-Drager syndrome and ALS are the most common neurological diseases in BP patients [10]. Although the mechanism is not clearly understood, BP1 and BP2 antigens are considered to play a role as autoreactive antigens in brain and skin [10].

Advertisement

6. Pathogenesis

BP is a subepidermal bullous disease with autoantibodies against hemidesmosomal proteins, BP 180 and 230 [17]. Hemidesmosomes are cellular adhesion proteins that bind basal keratinocytes to the extracellular matrix of the epidermis [5]. BP180 is a type 2 transmembrane protein kinase, also known as collagen XVII, while BP230 is a cytoplasmic protein [5]. The main target in BP is the noncollagenous region of BP180 (NC16A). Both IgG- and IgE-type autoantibodies against this structure are developed [3].

The role of BP230 is not clearly known in pathogenesis [18]. Many studies support that anti-BP230 antibodies play an important role in the onset of clinical symptoms and in the bulla formation [19]. Only anti-BP230 antibodies are detected in the serum of a few patients, while both anti-BP180 and anti-BP230 antibodies are present in all BP patients [18].

Anti-BP180 autoantibody titers were found to correlate with disease activity, itch intensity, peripheral blood eosinophil count and disease duration [17, 18, 20]. This correlation could not be obtained with anti-BP230 autoantibody titers [18].

In addition, a significant increase in total serum IgE levels was observed in 75–77% of patients with BP [3, 20]. IgE autoantibodies are against the NC16A region of BP180, as in IgG [3]. These autoantibodies were injected into mice, and urticarial lesions were detected [3, 21].

In patients with BP, an autoreactive T-cell response against BP180 and BP230 develops, which stimulates B cells to produce pathogenic autoantibodies [11]. These T lymphocytes are in the CD4+ phenotype and produce both Th1 (e.g., INF-gamma) and Th2 cytokines (such as IL-4, IL-5 and IL-13), and their major epitopes are located on NC16 domain [11]. Th2 cytokines are especially important in the pathogenesis of the disease and with their release, IgG4-type autoantibodies against BP180 are developed [11].

Unlike the pemphigus group of diseases, the autoantibodies deposited in the BMZ are not sufficient to cause disease emergence [22]. After antigen–antibody reaction, complement deposition and activation of both classical and alternative pathways are necessary for subepidermal bulla development [23]. IgG and IgE autoantibodies against BP180 activate the complement system, which triggers the onset of inflammatory events [1, 5]. Therefore, mast cell degranulation and the release of TNF alpha, PAF and other cytokines, matrix metalloproteinase 9 and leukotrienes occur [1, 5, 11]. Proteolytic enzymes released from eosinophils and neutrophil elastase breakdown various extracellular matrix proteins and BP180 [9, 11]. Proinflammatory mediators such as protease, IL-5 and eotaxin are released from infiltrating eosinophils, contributing to tissue damage [11]. In conclusion, BP180 autoantibodies directly stimulate keratinocytes to express various cytokines (such as IL-6, IL-8) and enhance inflammatory response [11].

A variant of BP, namely pemphigoid gestationis (PG) is one of the rare, pregnancy-specific bullous dermatoses, also known as herpes gestationis [24, 25]. Usually occurring in the second or third trimester of pregnancy, it is characterized by vesiculobullous rashes [24]. The disease can be seen in any trimester of the pregnancy as well as postpartum [26]. The incidence ranges from 1/50.000 to 1/1700 [24, 27]. The triggering factors are not known [27]. Graves’ disease is the most commonly detected secondary autoimmune disease [24]. Rarely, it may also be associated with hydatidiform mole and chorionic epithelioma [24].

John Laws Milton first described the disease in 1872, as herpes gestationis [24]. Although the pathophysiology of PG has not been clearly explained, it is considered that MHCII antigens present in the placenta lead to an immunological response with a cross-reaction to the maternal skin [24]. HLA DR3 and HLA DR4 antigens were more frequently detected in these patients [25, 26].

The pathogenesis is similar to BP, and there are autoantibodies against the NC16A domain of BP2 antigen [25, 26]. In 10% of patients, autoantibodies against BP1 antigen are present [26]. Following this antigen-antibody interaction, complement activation takes place, and eosinophil chemotaxis occurs in the BMZ, where the antigen-antibody complex is present [25]. Eosinophil degranulation also leads to damage in the dermoepidermal region and bulla formation [25].

Advertisement

7. Clinical features

BP shows a clinical polymorphism [28]. Clinically, it is characterized by large, tense blisters. Blisters can occur on normal skin or erythematous base with a predilection of flexural aspects of the limbs, abdomen, groin and axillae [29]. The most common initial clinical presentations are pruritic eczema or urticarial-like erythema without blisters and it is called nonbullous phase [30, 31]. Itching of various degrees may be seen in the course of the disease. However, significant pruritus is more frequent, and therefore, it may be the only manifestation of the disease, especially in older patients [30, 32].

BP commonly starts with pruritus and nonspecific skin lesions. Pruritus may persist for many months before the eruption [30, 33]. Therefore, physicians should consider BP in differential diagnosis of elderly patients with long-term persisting pruritus and nonspecific eczema-like or urticarial lesions [31]. Blisters frequently occur after 1–3 weeks of nonbullous phase. Nonbullous urticarial lesions may stay several months before the blisters occur [33].

In bullous stage, vesicles and bullae appear on normal or erythematous skin together with urticarial and infiltrated papules with an annular or figurate pattern [34]. Blisters are tense, filled with serous fluid, sometimes hemorrhagic, and Nikolsky sign is negative (Figure 1) [29, 34, 35].

Figure 1.

Nikolsky negative blisters and erythematous plaques on upper extremity and shoulders.

Blisters usually appear in symmetric distribution. A central resolution commonly occurs, and postinflammatory hyperpigmentation and milia may be seen. Additionally, persistent erythema may occur and remain for many weeks at the site of the prior blisters [29, 33, 36].

Mucous membrane involvement is seen in about 10–35% of the patients. Most affected mucous membrane is buccal mucosa [29]. In buccal mucosa, mucosal erosions are common, while intact blisters are rare [37]. Involvement of other mucosal sites like nose, esophagus, pharynx or anogenital system is relatively rare [34].

Unusual clinical variants of BP previously described depending on different clinical presentations are as follows: dyshidrosiform BP, intertrigo-like BP, prurigo-nodularis-like BP, vesicular BP, papular BP, eczematous BP, erythrodermic BP, lymphomatoid papulosis-like BP, lichen planus pemphigoides and BP with TEN-like lesions.

Several different localized forms are pretibial BP, peristomal BP, umbilical BP, vulvar BP, stump pemphigoid (distal end of amputated limbs), BP on paralyzed limbs, BP on body sites of radiotherapy [34, 35, 38]. The most common localized form is pretibial BP. Another localized form is vulvar BP and is seen in young girls presenting with vulvar erosions, blisters and ulcers. Localized forms either may not progress for years or generalization may occur [29, 37].

Pemphigoid nodularis is a rare clinical type of BP commonly seen in elderly women. It may present with prurigo-nodularis-like intensely itchy nodules, papules and BP-like blisters together [39, 40].

In childhood BP, there are some clinical differences. Commonly, the disease first appears acrally in infants and then may generalize. The face, palms and soles are frequently affected. Genital involvement is seen in older children [41]. In most children, the disease lasts less than 1 year [37].

PG is a special clinical variant of BP seen especially during late pregnancy, but it may occur at any time of pregnancy or immediately after delivery. In general, it starts from the abdomen, especially from periumbilical region as urticarial erythema. Then, herpetiform vesicles may occur at the periphery of the erythema. Tense bullae on erythematous base may also be present [35, 42]. Rapidly, it may progress to a pemphigoid-like eruption involving entire body (Figure 2). Generally, face, scalp and oral mucosa are not affected.

Figure 2.

Targetoid lesions and erythematous eruptions involving upper and lower extremities.

After delivery, flare of the disease is seen in 75% of patients, and in some patients, explosive onset of blistering occurs within hours. Usually, PG disappears spontaneously within 3 months after delivery [34, 37]. Recurrences may be associated with menstruation and oral contraceptive usage. In subsequent pregnancies, recurrence with early onset and a more severe disease are common [37].

Ten percent of newborns develop skin lesions due to the maternal antibodies [34]. But the eruption is self-limited and does not need treatment [29].

Advertisement

8. Histology

The most valuable diagnostic biopsy for BP is that taken from early small blisters [29]. The histopathologic findings of BP under light microscopy are subepidermal bullae without acantholysis and eosinophil-rich superficial dermal infiltrate.

The amount of superficial dermal infiltrate varies, as does the cellular content. Hence, the biopsies may be categorized as granulocyte-rich and granulocyte-poor, depending on whether the biopsy was taken form inflamed or noninflamed region. Eosinophils are usually the predominant inflammatory cells of the infiltrate, whereas some biopsies may show neutrophil predominance [37, 43].

In urticarial lesions at the prodromal stage, the histopathologic findings may not be specific. There may be only a superficial dermal infiltrate of lymphocytes, histiocytes and abundant eosinophils with papillary dermal edema and eosinophilic spongiosis occasionally [44].

Advertisement

9. Special tests

In 23% of BP patients, biopsies were not used in the diagnosis of BP; at that point, direct immunofluorescence (DIF), indirect immunofluorescence (IIF) and ELISA are critical for correct diagnosis [37].

In almost all patients, direct IF of perilesional healthy skin shows thin, linear (tubular or toothpaste pattern) and continuous deposition of IgG and/or C3 along the BMZ [4549]. Predominantly, the deposition of IgG1 and IgG4 has been shown; also, all IgG subclasses and IgE have been reported. False-negative results are more common on lower extremities. Close analysis of the pattern of immune deposition may be helpful for us to differentiate autoimmune blistering diseases. For example, there is an n-serrated pattern in BP and linear IgA bullous dermatosis and u-serrated pattern in epidermolysis bullosa acquisita EBA [50].

There are circulating anti-basement membrane zone IgG and IgE autoantibodies in 60–80% (approximately 70%) of the BP patients [4749, 5156]. These autoantibodies typically bind to epidermal side of 1 M NaCl-split human skin substrate or less often binds to both dermal and epidermal sides. Even if not routinely used, computer-aided fluorescence overlay antigen mapping (FOAM) shows the exact localization of the immune deposition [56]. For IIF, 1 M NaCl-split human skin is rather preferred than intact human skin or monkey esophagus. By incubating the human skin with 1 M NaCl, the epidermis will be separated from the dermis at lamina lucida. Using 1 M NaCl-split skin substrate has another advantage, and it can be used to differentiate BP from EBA. EBA autoantibodies bind to the base or the floor of the split skin (i.e., dermal side), but BP autoantibodies bind to the roof of it (i.e., epidermal side).

This is not the only histological difference between EBA and BP. C3 deposition is sometimes absent in EBA but is nearly always present in BP, and type-4 collagen stains the roof of the blister in EBA, whereas it stains the base in BP. In more than 70% of patients, there are circulating anti-BMZ autoantibodies [57, 58]. Unlike pemphigus, in BP, circulating IIF autoantibody levels do not show the disease activity or the extent of the disease [59].

ELISA has been found to be fairly specific (90%), especially ELISA that is using recombinant proteins, which bind to specific regions of the BP antigens like the NC16A part of BP180 and the C-terminus of BP180 or BP230 [60, 61]. ELISA has also proven to be sensitive for detecting the circulating antigen-specific IgG and IgE autoantibodies, so for that reason, ELISA is useful in both research and clinical settings. ELISA tests are commercially available with sensitivity of 89% and specificity of 98% [62].

Almost three out of four patients have antigen-specific IgE detectable by IF and ELISA [20, 54, 6367]. Patients with antigen-specific IgE antibody may develop more severe form of disease. IgE plays a role in attracting eosinophils to skin lesions, so patients with antigen-specific IgE antibody may develop instant urticarial-like lesions [21, 65, 66].

Sometimes, elderly patients with pruritic cutaneous eruptions or healthy subjects have low titer false-positive results. Approximately 7% of the normal population has anti-BP180 antibodies detectable by ELISA but shows no clinical or histological features of the disease; therefore, ELISA must be used in appropriate conditions not as a screening method [68].

Similar to BP, the main diagnostic marker of PG is the linear deposition of C3 along BMZ of perilesional healthy skin. The linear deposition of C3 is observed in 100%, but linear IgG deposition is only seen in 30% of PG patients. On conventional IIF testing, nearly 30% of PG patients have a circulating IgG anti-basement zone antibody. But when complement-enhanced IIF testing is used, nearly 75% of patients show PG factor (a complement-fixing anti-BMZ IgG1 autoantibody) [34].

Advertisement

10. Treatment

General maintenance of the patient is the first step in the treatment of BP patients. It is important to drain the large blisters because the serous fluid inside the blisters makes an essential environment for infections. If there is any local pain, infection possibility should be kept in mind and after taking wound culture, a proper antibiotic has to be started.

Treatment of BP depends on the extent of disease and mostly on clinical experience rather than controlled clinical trials [6979].

Systemic steroids are the common treatment agents. But localized disease can be treated successfully with topical corticosteroids [48, 49, 80]. In recent studies, clobetasol propionate cream 0.5% was applied twice daily to the entire surface of the body so the patients received a daily dose of 40 g [72]. This amount of high-potency topical corticosteroid may result in high systemic absorption and can cause local and systemic side effects [81]. This kind of topical treatment is very difficult and expensive to apply, and these controlled studies did not emphasize the patients’ ability to reach complete disease-free period as with systemic corticosteroids. Nevertheless, potent topical corticosteroids can control even generalized BP and may be safer than oral corticosteroids [7779, 81]. Topical tacrolimus can also be a useful agent in some cases of localized pemphigoid [80, 8285].

Patients with generalized disease are usually treated with oral prednisone [80, 86, 87]. For more extensive disease, a regimen of oral prednisone at a dose of 0.5–1 mg/kg/day can control the disease within 1–2 weeks. Afterwards, the dose can be tapered over a period of 6–9 months. On some occasions, pulse methyl prednisolone therapy may be required for rapid controlling of active blister formation [88]. Systemic corticosteroids are always associated with serious side effects (like osteoporosis, diabetes and immunosuppression) and in elderly patients, these side effects may be even more severe [89].

In order to minimize the side effects of oral glucocorticosteroids, immunosuppressive drugs can be used in conjunction with prednisone [80, 87, 9096]. However, there are very few controlled trials for this common approach. The use of immunosuppressive drugs is controversial. They can also be used as second-line therapy if corticosteroids are contraindicated or fail to control the disease. The common immunosuppressive agents are azathioprine, mycophenolate mofetil (1.5–3 g/day), methotrexate, chlorambucil (0.1 mg/kg/day, frequently 4–6 mg/day), and less often cyclophosphamide (1–3 mg/kg/day). The dosage of azathioprine (0.5–2.5 mg/kg/day) is adjusted by thiopurine methyltransferase level, with this adjustment, the efficacy of azathioprine will increase and side effects will be decreased. Choosing an immunosuppressive agent primarily depends on side effect profile, patients’ general status and doctors’ experience.

When corticosteroids are contraindicated, few reports have described successful treatment of some patients with the combination of nicotinamide (500–2000 mg/day) and minocycline or tetracycline or erythromycin; or tetracycline alone [97, 98]. Sulfones can be used to treat some patients. If there is no glucose-6-phosphate dehydrogenase deficiency, dapsone and sulfapyridine have been reported to control the disease activity in 15–44% of BP patients [87, 99101]. In a minority of resistant cases, intravenous immunoglobulins (IVIg) [102104], plasma exchange [73], anti-CD20 immunotherapy (rituximab) [105107], leflunomide [108], chlorambucil [109] and methotrexate [92, 94, 110] may be effective.

Even if the duration of treatment has not been clear yet, BP patients generally need to be treated for about 12–18 months. This period of time includes both active disease treatment and also a maintenance phase after cessation of active disease. This maintenance phase lasts for about 3–6 months, and during this phase, low-dose oral prednisone (<10 mg/day) or topical clobetasol propionate (10 g/week) is used [111]. As previously mentioned, initial doses of prednisone of 0.5–1.0 mg/kg/day or even less can control the disease. After new blister formation has stopped and erythema has disappeared—this usually has happened within 1–2 weeks—progressive tapering of prednisone over a 6–9-month period or rarely longer is recommended. Lowering the dose of 5 mg for every week until reaching 30 mg is commonly used. The patients’ clinical response should be monitored carefully, and lowering of the prednisone dose should be done according to this response. Because of the side effects of glucocorticoids, it is important to minimize the total dose and duration of the treatment. It is important to eliminate the complications of glucocorticoids by using osteoporosis prophylaxis and gastric protection, monitoring the cardiovascular function and infection risk [35].

BULLOUS PEMPHIGOID TREATMENT STEPS
General maintenance
Drainage of blisters
Prevention of local infections
Localized disease
Super potent topical corticosteroids (e.g., clobetasol propionate)
Topical immunomodulators (e.g., tacrolimus)
Nicotinamide in association with minocycline, doxycycline or tetracycline
Erythromycin
Dapsone, sulfonamides
Extensive or refractory disease
Oral corticosteroids
Azathioprine
Mycophenolate mofetil
Methotrexate
Chlorambucil
Cyclophosphamide
IVIg
Plasma exchange
Rituximab

The treatment of PG is similar to that of BP. But teratogenic side effects of some therapeutical agents for BP limit their usage during pregnancy. Mild cases of PG can be successfully treated with topical corticosteroids. But halogenated corticosteroids can cross the placenta, so class 6 and 7 corticosteroids are the safest (e.g., mometasone furoate, prednicarbate, methylprednisolone aceponate). For systemic treatment, prednisolone is the main choice because it is largely inactivated in the placenta (mother:fetus = 10:1). During the first trimester, especially between 8 and 11 weeks, there is a slightly increased risk of cleft lip/cleft palate. Nevertheless, if dosages are <10–15 mg/day, it appears to be safe. But for long-term use, risk of adrenal insufficiency in the newborn should be kept in mind, and fetal growth should also be monitored [112]. A few refractory cases may be treated with dapsone, doxycycline or minocycline ± nicotinamide, pyridoxine, cyclosporine, methotrexate, cyclophosphamide, gold and IVIg. But all these agents with the exception of cyclosporine and IVIg should be avoided during pregnancy period. Plasmapheresis may be a rather safe treatment option during pregnancy if corticosteroid is contraindicated or fails to control the disease [34].

References

  1. 1. Qiao P, Dang E, Cao T, Fang H, Zhang J, Qiao H, Wang G. Dysregulation of mCD46 and sCD46 contribute to the pathogenesis of bullous pemphigoid. Scientific Reports. 2017;7(1):145. DOI: 10.1038/s41598-017-00235-3
  2. 2. Leuci S, Gürcan HM, Ahmed AR. Serological studies in bullous pemphigoid: A literature review of antibody titers at presentation and in clinical remission. Acta Dermato-Venereologica. 2010;90(2):115-121. DOI: 10.2340/00015555-0819
  3. 3. Kalowska M, Ciepiela O, Kowalewski C, Demkow U, Schwartz RA, Wozniak K. Enzyme-linked immunoassay index for anti-NC16a IgG and IgE auto-antibodies correlates with severity and activity of bullous pemphigoid. Acta Dermato-Venereologica. 2016;96(2):191-196. DOI: 10.2340/00015555-2101
  4. 4. Patrício P, Ferreira C, Gomes MM, Filipe P. Autoimmune Bullous dermatoses: A review. Annals of the New York Academy of Sciences. 2009;1173:203-210. DOI: 10.1111/j.1749-6632.2009.04737
  5. 5. Patel F, Wilken R, Patel FB, Sultani H, Bustos I, Duong C, Zone JJ, Raychaudhuri SP, Maverakis E. Pathophysiology of autoimmune bullous diseases: Nature versus nurture. Indian Journal of Dermatology. 2017;62(3):262-267. DOI: 10.4103/0019-5154.159620
  6. 6. Osawa M, Ueda-Hayakawa I, Isei T, Yoshimura K, Fukuda S, Hashimoto T, Okamoto H. A case of childhood bullous pemphigoid with IgG and IgA autoantibodies to various domains of BP180. Journal of the American Academy of Dermatology. 2014;70(6):e129-e131. DOI: 10.1016/j.jaad.2013.06.006
  7. 7. Schwieger-Briel A, Moellmann C, Mattulat B, Schauer F, Kiritsi D, Schmidt E, Sitaru C, Ott H, Kern JS. Bullous pemphigoid in infants: Characteristics, diagnosis and treatment. Orphanet Journal of Rare Diseases. 2014;10(9):185. DOI: 10.1186/s13023-014-0185-6
  8. 8. Stoica LE, Patrascu V, Dascalu RC, Ciurea ME. Bullous pemphigoid associated with psoriasis, breast cancer and Parkinson’s disease. Current Health Science Journal. 2014;40(1):62-66. DOI: 10.12865/CHSJ.40.01.12
  9. 9. Kasperkiewicz M, Zillikens D. The pathophysiology of bullous pemphigoid. Clinical Reviews in Allergy and Immunology. 2007;33(1–2):67-77
  10. 10. Tarazona MJ, Mota AN, Gripp AC, Unterstell N, Bressan AL. Bullous pemphigoid and neurological disease: Statistics from a dermatology service. Anais Brasileiros de Dermatologia. 2015;90(2):280-282. DOI: 10.1590/abd1806-4841.20153334
  11. 11. Bolognia JL, Jorizzo JL, Rapini RP. Dermatoloji. Elsevier Limited. 2012:431-438
  12. 12. Taylor G, Venning V, Wojnarowska F, Welch K. Bullous pemphigoid and autoimmunity. Journal of the American Academy of Dermatology. 1993;29(2 Pt 1):181-184
  13. 13. Moitra S, Sen S, Banerjee I, Sikder A, Das P. Metronidazole-induced bullous pemphigoid: A case report. Journal of Clinical and Diagnostic Research. 2015;9(12):FD01-FD03. DOI: 10.7860/JCDR/2015/14669.6972
  14. 14. Bisherwal K, Pandhi D, Singal A, Sharma S. Infantile bullous Pemphigoid following vaccination. Indian Pediatrics. 2016;53(5):425-426
  15. 15. Schulze F, Neumann K, Recke A, Zillikens D, Linder R, Schmidt E. Malignancies in pemphigus and pemphigoid diseases. The Journal of Investigative Dermatology. 2015;135(5):1445-1447. DOI: 10.1038/jid.2014.547
  16. 16. Ogawa H, Sakuma M, Morioka S, Kitamura K, Sasai Y, Imamura S, Inaba Y. The incidence of internal malignancies in pemphigus and bullous pemphigoid in Japan. Journal of Dermatological Science. 1995;9(2):136-141
  17. 17. Cai SC, Lim YL, Li W, Allen JC, Chua SH, Tan SH, Tang MB. Anti-BP180 NC16A IgG Titres as an indicator of disease activity and outcome in Asian patients with bullous pemphigoid. Annals of the Academy of Medicine, Singapore. 2015;44(4):119-126
  18. 18. Patsatsi A, Kyriakou A, Pavlitou-Tsiontsi A, Giannakou A, Sotiriadis D. Association of autoantibodies to BP180 with disease activity in Greek patients with bullous pemphigoid. Clinical & Developmental Immunology. 2012;854795. DOI: 10.1155/2012/854795
  19. 19. Mueller S, Klaus-Kovtun V, Stanley JR. A 230-kD basic protein is the major bullous pemphigoid antigen. The Journal of Investigative Dermatology. 1989;92(1):33-38
  20. 20. Messingham KA, Noe MH, Chapman MA, Giudice GJ, Fairley JA. A novel ELISA reveals high frequencies of BP180-specific IgE production in bullous pemphigoid. Journal of Immunology Methods. 2009 July 31;346(1–2):18-25. DOI: 10.1016/j.jim.2009.04.013
  21. 21. Fairley JA, Burnett CT, Fu CL, Larson DL, Fleming MG, Giudice GJ. A pathogenic role for IgE in autoimmunity: Bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice. The Journal of Investigative Dermatology. 2007;127(11):2605-2611
  22. 22. Liu Z, Giudice GJ, Zhou X, Swartz SJ, Troy JL, Fairley JA, Till GO, Diaz LA. A major role for neutrophils in experimental bullous pemphigoid. The Journal of Clinical Investigation. 1997;100(5):1256-1263
  23. 23. Nelson KC, Zhao M, Schroeder PR, Li N, Wetsel RA, Diaz LA, Liu Z. Role of different pathways of the complement cascade in experimental bullous pemphigoid. The Journal of Clinical Investigation. 2006;116(11):2892-2900
  24. 24. Stevenson ML, Marmon S, Tsou H, Boyd KP, Robinson MR, Meehan SA, Pomerantz R. Pemphigoid gestationis. Dermatology Online Journal. 2013;19(12):20715
  25. 25. Cobo MF, Santi CG, Maruta CW, Aoki V. Pemphigoid gestationis: Clinical and laboratory evaluation. Clinics (São Paulo, Brazil). 2009;64(11):1043-1047. DOI: 10.1590/S1807-59322009001100002
  26. 26. Huilaja L, Mäkikallio K, Tasanen K. Gestational pemphigoid. Orphanet Journal of Rare Diseases. 2014;9:136. DOI: 10.1186/s13023-014-0136-2
  27. 27. Singla A, Shree S, Mehta S. Pregnancy with pemphigoid gestationis: A rare entity. Journal of Clinical and Diagnostic Research. 2016;10(7):QD06-QD07. DOI: 10.7860/JCDR/2016/19491.8215
  28. 28. Di Zenzo G, Della Torre R, Zambruno G, Borradori L. Bullous pemphigoid: From the clinic to the bench. Clinics in Dermatology. 2012;30(1):3-16
  29. 29. Stanley J: Bullous pemphigoid. In: Fitzpatrick’s dermatology in general medicine. Volume 1, 7th edition. Edited by Fitzpatrick TB, Wolff K. New York: McGraw-Hill Medical; 2008:475-480
  30. 30. Baum S, Sakka N, Artsi O, Trau H, Barzilai A. Diagnosis and classification of autoimmune blistering diseases. Autoimmunity Reviews. 2014;13(4–5):482-489
  31. 31. Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. Journal der Deutschen Dermatologischen Gesellschaft. 2011;9(10):844-856; quiz 857
  32. 32. Bakker CV, Terra JB, Pas HH, Jonkman MF. Bullous pemphigoid as pruritus in the elderly: A common presentation. JAMA Dermatology. 2013;149(8):950-953
  33. 33. Wojnarowska F, Venning V. Immunobullous diseases. In: Burns TF, Rook A, editors. Rook’s Textbook of Dermatology. 8th ed. Oxford: Wiley-Blackwell; 2010. pp. 1895-1956
  34. 34. Borradori L BP: Vesiculobullous diseases. In: Jean L. Bolognia, Joseph L. Jorizzo, Ronald P. Rapini; associate and artwork editor, Julie V. Schaffer. Dermatology (Basel, Switzerland). Volume 1, 2nd ed.St. Louis, Mo.; London: Mosby Elsevier; 2008:431-445
  35. 35. Schmidt E, della Torre R, Borradori L. Clinical features and practical diagnosis of bullous pemphigoid. Immunology and Allergy Clinics of North America. 2012;32(2):217-232
  36. 36. Amber KT, Murrell DF, Schmidt E, Joly P, Borradori L. Autoimmune subepidermal bullous diseases of the skin and mucosae: Clinical features, diagnosis, and management. Clinical Reviews in Allergy and Immunology. 2017
  37. 37. James WD, Elston DM, Berger TG. Andrews’ Diseases of the Skin: Clinical Dermatology, 10th Edn. London: Saunders Elsevier; 2006
  38. 38. Liu HN, Su WP, Rogers RS 3rd. Clinical variants of pemphigoid. International Journal of Dermatology. 1986;25(1):17-27
  39. 39. Kwong HL, Lim SP. Pemphigoid nodularis mimicking nodular prurigo in an immune-suppressed patient with rheumatoid arthritis. Acta dermato-venereologica. 2015;95(2):237-238
  40. 40. Powell AM, Albert S, Gratian MJ, Bittencourt R, Bhogal BS, Black MM. Pemphigoid nodularis (non-bullous): A clinicopathological study of five cases. The British Journal of Dermatology. 2002;147(2):343-349
  41. 41. Waisbourd-Zinman O, Ben-Amitai D, Cohen AD, Feinmesser M, Mimouni D, Adir-Shani A, Zlotkin M, Zvulunov A. Bullous pemphigoid in infancy: Clinical and epidemiologic characteristics. Journal of the American Academy of Dermatology. 2008;58(1):41-48
  42. 42. Lipozencic J, Ljubojevic S, Bukvic-Mokos Z. Pemphigoid gestationis. Clinics in Dermatology. 2012;30(1):51-55
  43. 43. Yancey KB. The pathophysiology of autoimmune blistering diseases. The Journal of Clinical Investigation. 2005;115(4):825-828
  44. 44. Murrell D. Blistering Diseases: Clinical Features, Pathogenesis, Treatment. Berlin: Springer; 2015
  45. 45. Beutner EH et al. Autoantibodies in pemphigus vulgaris: Response to an intercellular substance of epidermis. Journal of the American Medical Association. 1965;192:682
  46. 46. Jordon RE et al. Basement zone antibodies in bullous pemphigoid. Journal of the American Medical Association. 1967;200(9):751
  47. 47. Person JR, Rogers RS 3rd. Bullous and cicatricial pemphigoid. Clinical, histopathologic, and immunopathologic correlations. Mayo Clinic Proceedings. 1977;52(1):54
  48. 48. Hadi SM et al. Clinical, histological and immunological studies in 50 patients with bullous pemphigoid. Dermatologica. 1988;176(1):6
  49. 49. Ahmed AR, Maize JC, Provost TT. Bullous pemphigoid. Clinical and immunologic follow-up after successful therapy. Archives of Dermatology. 1977;113(8):1043
  50. 50. Vodegel RM, Jonkman MF, Pas HH, de Jong MC. U-serrated immunodeposition pattern differentiates type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases. The British Journal of Dermatology. 2004;151:112-118
  51. 51. Dimson OG et al. Identifiation of a potential effector function for IgE autoantibodies in the organ-specifi autoimmune disease bullous pemphigoid. The Journal of Investigative Dermatology. 2003;120(5):784
  52. 52. Bushkell LL, Jordon RE. Bullous pemphigoid: A cause of peripheral blood eosinophilia. Journal of the American Academy of Dermatology. 1983;8(5):648
  53. 53. Beutner EH, Jordon RE, Chorzelski TP. The immunopathology of pemphigus and bullous pemphigoid. The Journal of Investigative Dermatology. 1968;51(2):63
  54. 54. Fairley JA, Fu CL, Giudice GJ. Mapping the binding sites of anti-BP180 immunoglobulin E autoantibodies in bullous pemphigoid. The Journal of Investigative Dermatology. 2005;125(3):467
  55. 55. Parodi A, Rebora A. Serum IgE antibodies bind to the epidermal side of the basement membrane zone splits in bullous pemphigoid. The British Journal of Dermatology. 1992;126(5):526
  56. 56. De Jong MC, Bruins S, Heeres K, et al. Bullous pemphigoid and epidermolysis bullosa acquisita. Differentiation by fluorescence overlay antigen mapping. Archives of Dermatology. 1996;132:151-157
  57. 57. Gammon WR et al. Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunoflorescence on 1.0 M sodium chloride-separated skin. The Journal of Investigative Dermatology. 1984;82(2):139
  58. 58. Kelly SE, Wojnarowska F. The use of chemically split tissue in the detection of circulating antibasement membrane zone antibodies in bullous pemphigoid and cicatricial pemphigoid. The British Journal of Dermatology. 1988;118(1):31
  59. 59. Sams WM Jr, Jordon RE. Correlation of pemphigoid and pemphigus antibody titres with activity of disease. The British Journal of Dermatology. 1971;84(1):7
  60. 60. Zillikens D, Rose PA, Balding SD, et al. Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies. The Journal of Investigative Dermatology. 1997;109:573-579
  61. 61. Di Zenzo G, Marazza G, Borradori L. Bullous pemphigoid: Physiopathology, clinical features and management. Advances in Dermatology. 2007;23:257-288
  62. 62. Sakuma-Oyama Y et al. Evaluation of a BP180-NC16a enzyme-linked immunosorbent assay in the initial diagnosis of bullous pemphigoid. The British Journal of Dermatology. 2004;151(1):126
  63. 63. Christophoridis S et al. IgG, IgA and IgE autoantibodies against the ectodomain of BP180 in patients with bullous and cicatricial pemphigoid and linear IgA bullous dermatosis. The British Journal of Dermatology. 2000;143(2):349
  64. 64. Dopp R et al. IgG4 and IgE are the major immunoglobulins targeting the NC16A domain of BP180 in bullous pemphigoid: Serum levels of these immunoglobulins reflect disease activity. Journal of the American Academy of Dermatology. 2000;42(4):577
  65. 65. Ishiura N et al. Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. Journal of Dermatological Science. 2008;49(2):153
  66. 66. Iwata Y et al. Correlation of IgE autoantibody to BP180 with a severe form of bullous pemphigoid. Archives of Dermatology. 2008;144(1):41
  67. 67. Woodley DT. The role of IgE anti-basement membrane zone autoantibodies in bullous pemphigoid. Archives of Dermatology. 2007;143(2):249
  68. 68. Wieland CN et al. Anti-bullous pemphigoid 180 and 230 antibodies in a sample of [1] unaffected subjects. Archives of Dermatology. 2010;146(1):21
  69. 69. Korman NJ. Bullous pemphigoid. Journal of the American Academy of Dermatology. 1987;16:907-924
  70. 70. Joly P, Benichou J, Lok C, et al.: Prediction of survival for patients with bullous pemphigoid: A prospective study. Archives of Dermatology 2005;141:691-698
  71. 71. Korman NJ. New and emerging therapies in the treatment of blistering diseases. Dermatologic Clinics. 2000;18:127-137
  72. 72. Joly P et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. The New England Journal of Medicine. 2002;346:321-327
  73. 73. Roujeau JC et al. Plasma exchange in bullous pemphigoid. Lancet. 1984;2:486-488
  74. 74. Morel P, Guillaume JC. Treatment of bullous pemphigoid with prednisolone only: 0.75mg/kg/day versus 1.25mg/kg/day. A multicenter randomized study. Annales de Dermatologie et de Vénéréologie. 1984;111:925-928
  75. 75. Guillot B, Donadio D, Guilhou JJ, et al. Long term plasma exchange therapy in bullous pemphigoid. Acta Dermato-Venereologica. 1986;66:73-75
  76. 76. Dreno B, Sassolas B, Lacour P, et al. Methylprednisolone versus prednisolone methylsulfobenzoate in pemphigoid: A comparative multicenter study. Annales de Dermatologie et de Vénéréologie. 1993;120:518-521
  77. 77. Guillaume JC, Vaillant L, Bernard P, et al. Controlled trial of azathioprine and plasma exchange in addition to prednisolone in the treatment of bullous pemphigoid. Archives of Dermatology. 1993;129:49-53
  78. 78. Fivenson DP, Breneman DL, Rosen GB, et al. Nicotinamide and tetracycline therapy of bullous pemphigoid. Archives of Dermatology. 1994;130:753-758
  79. 79. Chan LS et al. Immune-mediated subepithelial blistering diseases of mucous membranes. Pure ocular cicatricial pemphigoid is a unique clinical and immunopathological entity distinct from bullous pemphigoid and other subsets identified by antigenic specificity of autoantibodies. Archives of Dermatology. 1993;129:448-455
  80. 80. Fine JD. Management of acquired bullous skin diseases. The New England Journal of Medicine. 1995;333(22):1475
  81. 81. Bystryn JC, Wainwright BD, Shupack JL. Oral and topical corticosteroids in bullous pemphigoid. The New England Journal of Medicine. 2002;347(2):143
  82. 82. Chu J, Bradley M, Marinkovich MP. Topical tacrolimus is a useful adjunctive therapy for bullous pemphigoid. Archives of Dermatology. 2003;139(6):813
  83. 83. Chuh AA. The application of topical tacrolimus in vesicular pemphigoid. The British Journal of Dermatology. 2004;150(3):622
  84. 84. Ko MJ, Chu CY. Topical tacrolimus therapy for localized bullous pemphigoid. The British Journal of Dermatology. 2003;149(5):1079
  85. 85. Lebeau S et al. Localized childhood vulval pemphigoid treated with tacrolimus ointment. Dermatology. 2004;208(3):273
  86. 86. Patton T, Korman NJ. Bullous pemphigoid treatment review. Expert Opinion on Pharmacotherapy. 2006;7(17):2403
  87. 87. Wojnarowska F et al. Guidelines for the management of bullous pemphigoid. The British Journal of Dermatology. 2002;147(2):214
  88. 88. Siegel J, Eaglstein WH. High-dose methylprednisolone in the treatment of bullous pemphigoid. Archives of Dermatology. 1984;120(9):1157
  89. 89. Savin JA. The events leading to the death of patients with pemphigus and pemphigoid. The British Journal of Dermatology. 1979;101(5):521
  90. 90. Bohm M et al. Bullous pemphigoid treated with mycophenolate mofetil. Lancet. 1997;349(9051):541
  91. 91. Burton JL et al. Azathioprine plus prednisone in treatment of pemphigoid. British Medical Journal. 1978;2(6146):1190
  92. 92. Gurcan HM, Ahmed AR. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. The British Journal of Dermatology. 2009;161(4):723
  93. 93. Heilborn JD et al. Low-dose oral pulse methotrexate as monotherapy in elderly patients with bullous pemphigoid. Journal of the American Academy of Dermatology. 1999;40(5 Pt 1):741
  94. 94. Kjellman P, Eriksson H, Berg P. A retrospective analysis of patients with bullous pemphigoid treated with methotrexate. Archives of Dermatology. 2008;144(5):612
  95. 95. Nousari HC, Griff WA, Anhalt GJ. Successful therapy for bullous pemphigoid with mycophenolate mofetil. Journal of the American Academy of Dermatology. 1998;39(3):497
  96. 96. Paul MA, Jorizzo JL, Fleischer AB Jr, White WL. Low-dose methotrexate treatment in elderly patients with bullous pemphigoid. Journal of the American Academy of Dermatology. 1994;31(4):620
  97. 97. Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline and niacinamide. A preliminary report. Archives of Dermatology. 1986;122(6):670
  98. 98. Kolbach DN et al. Bullous pemphigoid successfully controlled by tetracycline and nicotinamide. The British Journal of Dermatology. 1995;133(1):88
  99. 99. Bouscarat F et al. Treatment of bullous pemphigoid with dapsone: Retrospective study of thirtysix cases. Journal of the American Academy of Dermatology. 1996;34(4):683
  100. 100. Person JR, Rogers RS 3rd. Bullous pemphigoid responding to sulfapyridine and the sulfones. Archives of Dermatology. 1977;113(5):610
  101. 101. Venning VA, Millard PR, Wojnarowska F. Dapsone as fist line therapy for bullous pemphigoid. The British Journal of Dermatology. 1989;120(1):83
  102. 102. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. Journal of the American Academy of Dermatology. 2001;45(6):825
  103. 103. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Archives of Dermatology. 2003;139(8):1051
  104. 104. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: Analysis of current data. Journal of the American Academy of Dermatology. 2001;44(1):83
  105. 105. Silva N et al. Bullous pemphigoid successfully treated with rituximab. Acta Médica Portuguesa. 2017;30(3):243
  106. 106. Nguyen T, Ahmed AR. Positive clinical outcome in a patient with recalcitrant bullous pemphigoid treated with rituximab and intravenous immunoglobulin. Clinical and Experimental Dermatology. 2017;42(5):516
  107. 107. Bilgiç Temel A et al. Successful treatment of a bullous pemphigoid patient with rituximab who was refractory to corticosteroid and omalizumab treatments. Case Rep Dermatol. 2017;9(1):38
  108. 108. Nousari HC, Anhalt GJ. Bullous pemphigoid treated with leflunomide: A novel immunomodulatory agent. Archives of Dermatology. 2000;136(10):1204
  109. 109. Milligan A, Hutchinson PE. The use of chlorambucil in the treatment of bullous [110] pemphigoid. Journal of the American Academy of Dermatology. 1990;22(5 Pt 1):796
  110. 110. Bara C et al. Methotrexate for bullous pemphigoid: Preliminary study. Archives of Dermatology. 2003;139(11):1506
  111. 111. Bernard P, Reguiai Z, Tancrède-Bohin E, et al. Risk factors for relapse in patients with bullous pemphigoid in clinical remission: A multicenter, prospective, cohort study. Archives of Dermatology. 2009;145:537-542
  112. 112. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008

Written By

Derya Yayla, Pelin Hizli and Yeşim Yayla

Submitted: May 15th, 2017 Reviewed: January 5th, 2018 Published: January 29th, 2018