Bullous pemphigoid. Occurrence in psoriasis treated with psoralens plus long-wave ultraviolet radiation.

The occurrence of bullous pemphigoid during treatment for psoriasis has been described in the literature. We saw a case of psoriasis that was complicated by bullous pemphigoid in a patient receiving orally administered psoralen followed by long-wave ultraviolet radiation (PUVA) therapy. In our patient the localization of bullous lesions to psoriatic plaques demonstrates that the PUVA-treated psoriatic skin may have a decreased threshold for the development of clinical bullous pemphigoid. This suggests factors other than simple coexistence of the two diseases. Therapy with PUVA might induce bullous pemphigoid in psoriasis, either primarily or by facilitating the expression of a previously existing subclinical form of the bullous disorder.     

Lack of expression of interleukin 8 and RANTES in autoimmune bullous skin diseases.

BACKGROUND: In autoimmune bullous skin diseases, accumulation of neutrophils and/or eosinophils in the affected skin represents a characteristic feature. So far, however, the induction of this granulocyte infiltration has not been elucidated. OBJECTIVE: Regarding their biological effects, the chemokines interleukin 8 (IL-8) and RANTES (regulated upon activation normal T lymphocyte expressed and secreted) could play a role in this granulocyte accumulation. METHODS: Immunohistochemical examination of lesional skin from patients with bullous pemphigoid, pemphigus, dermatitis herpetiformis and linear IgA disease was performed using a set of different antibodies against IL-8 and RANTES. Additionally, blister fluids were screened for soluble RANTES peptide using an ELISA. RESULTS: No difference in chemokine expression was found in lesions of autoimmune bullous diseases compared to normal skin. CONCLUSION: In contrast to chronic inflammatory diseases like psoriasis and eczema, where keratinocyte IL-8 immunoreactivity was found to differ from normal skin, keratinocyte immunoreactivity is not altered in autoimmune bullous diseases.     

Repeat direct immunofluorescence (DIF) test, using, 1 M NaCl treated skin, in the subepidermal autoimmune bullous diseases that contain IgG at the dermal epidermal junction

Knowledge of autoimmune bullous diseases has greatly increased with the recognition of new entities, and the use of the direct immunofluorescence (DIF) using 1 molar per liter of sodium chloride (1 M NaCl) treated skin has been proposed. To estimate the frequency with which the different DIF patterns are present, we performed a systematic study of the skin or oral mucosa samples in which linear deposits of IgG at the basement membrane zone were detected by routine DIF in the last 6 years. The DIF tests were done on 56 samples before and after splitting the epidermis from the dermis with 1M NaCl. In 40 biopsies (72%) IgG was found on either the epidermal side or on both sides after 1M NaCl split. These cases corresponded to bullous pemphigoid (n=33), herpes gestationis (n=5) and cicatricial pemphigoid (n=2). In 6 cases (10.7%), IgG deposits were observed only on the floor, five corresponding to bullous pemphigoid and one to bullous pemphigoid-like eruption induced by amoxicillin. Repeat direct immunofluorescence using 1M NaCl split skin indicates that at least 12% of patients who were initially diagnosed as bullous pemphigoid, may in fact suffer a different entity, requiring other techniques to achieve the right diagnosis. This test can be a useful routine screening for autoimmune bullous diseases.     

Sequence of reconstitution of seven basement-membrane components following split-thickness wound induction in primate skin

Recent studies have shown an orderly sequence of expression of structural antigens within the skin basement-membrane zone of the human fetus. Interestingly, these findings differ from those reported following split-thickness would induction in Yorkshire pigs. To readdress this apparent disparity, as well as to further extend such studies to include other basement-membrane antigens more recently identified, we produced split-thickness wounds in a primate species and serially examined the wounds by immunofluorescence technique for the expression of seven antigens normally found in intact primate skin basement membrane. By the fourth day following wounding, laminin, type-IV collagen, and fibronectin were all detectable along the dermoepidermal junction. In contrast, bullous pemphigoid antigen, epidermolysis bullosa acquisita antigen, cicatricial pemphigoid antigen, and KF-1 antigen were undetectable until days 6, 8, 10, and 11, respectively. These latter findings are in complete agreement with those previously reported in the developing human fetus. On the basis of the results of this study, we would suggest that primate rather than pig skin may be a more appropriate animal model for wound-healing studies. These data are consistent with previous reports suggesting that the basement-membrane antigens recognized by bullous pemphigoid and cicatricial pemphigold autoantibodies are indeed distinct. Finally, these data bring into question the functional role of bullous pemphigoid antigen during the early phase of wound healing in humans.     

Two Cases of Atypical Bullous Disease Showing Linear IgG and IgA Deposition in the Basement Membrane Zone

Patients showing coexistent linear IgG and IgA deposition along the basement membrane zone on direct immunofluorescence have been described as either bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, or cicatricial pemphigoid, depending on the clinical features and laboratory findings. In the present report, we describe two cases showing atypical clinical features distinct from those of other known bullous diseases. No circulating antibodies were detected by indirect immunofluorescence of normal human skin. Indirect immunofluorescence of 1 M NaCl split skin revealed IgG and/or IgA antibodies reactive with the dermal side of the split. Immunoblotting of normal human epidermal and dermal extracts showed no apparent reactivity with known autoantigens. The results suggest that there may be a unique and distinct bullous disease with linear IgG and IgA deposition at the basement membrane zone.     

Coexistence of bullous pemphigoid, vitiligo, and thyroid disease: a multiple autoimmune syndrome?

Bullous pemphigoid is the most common autoimmune blistering skin diseases. The significance of the association of bullous pemphigoid with other autoimmune diseases is still unknown. There have been reports of an association with many autoimmune skin diseases. We report the simultaneous occurrence of bullous pemphigoid and thyroid disease in a 76-year-old patient who also suffered from vitiligo. It is possible that there is a common underlying pathogenic mechanism involved in the co-existence of these three diseases. The association adds to the documentation of bullous pemphigoid co-existing with other autoimmune disorders. This association is probably not fortuitous and suggests a pathogenic relationship.     

C3d在大疱性类天疱疮患者皮损组织中的表达

目的 探讨C3d在石蜡包埋的大疱性类天疱疮患者皮损组织中的表达及临床意义。方法 免疫组化SP法在25例大疱性类天疱疮、10例大疱性表皮松解症及10例正常成人皮肤组织标本中进行C3d、IgG、IgA进行检测,并对其在大疱性类天疱疮皮损中阳性率进行比较。结果 大疱性类天疱疮皮损中C3d、IgG、IgA的阳性率分别为96%、72%、0%。C3d、IgG在BP组织中表达阳性率的差异有统计学意义（χ2 = 4.17,P < 0.05）,C3d、IgA在BP组织中表达阳性率的差异有统计学意义（χ2 = 22.04,P < 0.01）。C3d、IgG、IgA在10例EB及正常成人皮肤组织标本中表达均为阴性。结论 免疫组化方法检测C3d的表达可以协助在石蜡组织中进行大疱性类天疱疮的诊断。     

The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen

A series of previous studies have indicated that the NC16a domain of the 180-kDa bullous pemphigoid antigen (BP180) is the most immunogenic and probably pathogenic region in both bullous pemphigoid and herpes gestationis. To confirm these previous results by a large-scale study, we examined serum from 154 bullous pemphigoid and 43 herpes gestationis patients using an immunoblot technique with the BP180 NC16a domain fusion protein, which had been prepared using cDNA obtained from a human keratinocyte cDNA library by polymerase chain reaction amplification. This fusion protein was recognized by 90% of bullous pemphigoid and 79% of herpes gestationis serum samples, but not by any other disease or normal control serum samples. These results indicate that this system is very sensitive and specific for the detection of anti-BP180 antibodies and should be useful for the diagnosis of various subepidermal bullous diseases. Received: 17 October 1995     

Frequency of IgA antibodies in pemphigus, bullous pemphigoid and mucous membrane pemphigoid

Circulating and bound IgA antibodies can be found in the autoimmune blistering diseases, but their prevalence, clinical relevance and target antigens remain unknown. Thirty-two patients with pemphigus, 73 with bullous pemphigoid and 28 with mucous membrane pemphigoid were studied retrospectively. Direct immunofluorescence (DIF) analysis of IgG, IgA, IgM and C3 was carried out for all cases. Sera were studied by standard indirect immunofluorescence, indirect immunofluorescence on salt-split skin, immunoblotting for bullous pemphigoid and mucous membrane pemphigoid and ELISA for pemphigus. With DIF, we found IgA autoantibodies in 22 of all 133 cases. Circulating IgA antibodies to skin were detected in 2 of 3 IgA-DIF-positive patients with pemphigus, in 3 of 6 with bullous pemphigoid, and in 6 of 13 with mucous membrane pemphigoid. We confirm that the IgA reactivity is more frequently associated with mucous membrane involvement, especially in cases without critical involvement (5/8). The role of IgA and its antigenic specificity in these diseases remain unclear.     

Respective contribution of neutrophil elastase and matrix metalloproteinase 9 in the degradation of BP180 (type XVII collagen) in human bullous pemphigoid.

Bullous pemphigoid is a blistering disorder associated with autoantibodies directed against two components of hemidesmosomes, BP180 and BP230. Autoantibodies to the extracellular collagenous domain of BP180 are thought to play a key role in the pathogenesis of the disease. In a murine model of bullous pemphigoid, neutrophil elastase and 92 kDa gelatinase (matrix metalloproteinase 9) have been implicated in subepidermal blister formation via proteolytic degradation of BP180. In this study we sought to elucidate the contribution of these two enzymes to subepidermal blister formation by assessing the expression, localization, and activity of the two proteases in lesional skin, serum samples, and blister fluids obtained from 17 patients with bullous pemphigoid. The results indicate that (i) neutrophil elastase is found in skin biopsy specimens from bullous pemphigoid lesions and is recovered as active enzyme in blister fluids, and (ii) although proform of matrix metalloproteinase 9 is present in lesional skin, it is present only as proenzyme in blister fluids, which also contain high levels of tissue inhibitor of metalloproteinase-1. Next, the capacity of matrix metalloproteinase 9 and neutrophil elastase to degrade a recombinant protein corresponding to the extracellular collagenous domain of the BP180 was studied. Our data illustrate that (i) recombinant matrix metalloproteinase 9, neutrophil elastase, and blister fluid from bullous pemphigoid patients are all able to hydrolyze recombinant BP180; (ii) the pattern of recombinant BP180 proteolysis with blister fluid was similar to that obtained with neutrophil elastase; and (iii) recombinant BP180 degradation by blister fluid could be inhibited by chloromethylketone, a specific elastase inhibitor, but not by batimastat, a wide spectrum matrix metalloproteinase inhibitor. Our results confirm the importance of neutrophil elastase but not matrix metalloproteinase 9 in the direct cleavage of BP180 autoantigen and subepidermal blister formation in human bullous pemphigoid.     

Immune phenotyping of mononuclear infiltrate in bullous pemphigoid]

In bullous pemphigoid, autoantibodies alone are not capable of blister formation. In addition, they need complement and various inflammatory cells. The role of mononuclear cells, however, is poorly understood. Therefore, we studied the inflammatory infiltrate in 21 patients with bullous pemphigoid and 11 controls (normal skin, n = 5; eczematous skin, n = 6) using a panel of monoclonal antibodies. In bullous pemphigoid, 60% of the mononuclear infiltrate consists of CD3+ T-lymphocytes, while 25% represents monocytes/macrophages (MOMA); B-lymphocytes are absent. In the area of the basement zone (BMZ), which was studied separately, MOMA predominate. In 30% of bullous pemphigoid biopsies we found a close, almost linear attachment of MOMA to the BMZ. Along the BMZ, lymphocytes belong to the CD3+, CD4+ T-helper subset. CD8+ T-cytotoxic-suppressor cells, however, are rarely encountered there, and other cytotoxic lymphocytes are not found at all. All lymphocytes along the BMZ are memory cells. In small, early bullous pemphigoid lesions, MOMA are frequently the only effector cells. Eosinophilic granulocytes are rare in these lesions. Our findings suggest that mononuclear cells, and particularly MOMA, may be more important than believed hitherto in the inflammatory process resulting in separation of the BMZ.     

Complement activation in bullous skin diseases.

Pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, and herpes gestationis are members of the chronic vesiculobullous skin diseases of man. The complement system, including both the classical and alternative pathways, may be important in the pathogenesis of these diseases. In pemphigus, early complement components (C1, C4, and C2) appear to be activated in addition to later components (C3 and C5), suggestive of classical pathway activation. Participation of properdin in addition to early complement components suggests local activation of both complement pathways in bullous pemphigoid and cicatricial pemphigoid. Herpes gestationis and dermatitis herpetiformis may be bullous skin diseases entirely mediated by the alternate or properdin pathway. The specific immunopathologic findings in these diseases are discussed.     

How many people have bullous pemphigoid in England?

Bullous pemphigoid is a distressing disease that causes blisters and itching of the skin. Our study, from England, aimed to find out how many people get bullous pemphigoid for the first time each year (incidence), how many people are living with bullous pemphigoid at any given point (prevalence), and whether people with bullous pemphigoid are more likely to die than similar people without the disease (mortality). We used anonymised information that is regularly collected and shared for research purposes by general practices and hospitals to identify all adults with bullous pemphigoid between 1998 and 2017 (the “Clinical Practice Research Datalink” and “Hospital Episode Statistics Admitted Patient Care” databases). We found that eight in 100 000 people got bullous pemphigoid for the first time each year. Bullous pemphigoid was more common in older people, particularly older men. Although bullous pemphigoid occurred more commonly in older people, we cannot be sure that this is because of the ageing process alone. This pattern could be because older people are more likely to be prescribed medications or have other conditions which are linked to bullous pemphigoid. We found that the total number of people with bullous pemphigoid almost doubled between 1998 and 2017, up to 48 in 100 000 people in 2017. In fact, about one in 1000 people aged over 60 years had bullous pemphigoid in 2017. We have shown that bullous pemphigoid should not be considered a “rare disease” in older people. Finally, after taking age, gender, time period, and location into account, we found that people with bullous pemphigoid were almost three times more likely to die in the two years after getting the disease compared to people without the disease. This may be due to the side effects of treatment, the presence of other diseases that are linked to bullous pemphigoid, frailty, as well as the disease itself. Linked Article:   Persson et al. Br J Dermatol 2021; 184 :68–77 .     

Resolution of bullous pemphigoid and improvement of vitiligo after successful treatment of squamous cell carcinoma of the skin

The significance of the association of malignant diseases with bullous pemphigoid is still unknown. We report a case of squamous cell carcinoma of the skin associated with both bullous pemphigoid and vitiligo. It is possible that there is a common underlying pathogenic mechanism involved in the co-existence of these three skin diseases as successful treatment of the carcinoma was accompanied by resolution of the bullous pemphigoid and improvement of the vitiligo.     

Immunohistochemical examination of P-cadherin in bullous and acantholytic skin diseases

Autoimmune blistering diseases (pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, dermatitis herpetiformis) and certain genodermatoses with acantholysis (Darier-disease, Hailey-Hailey disease) have different aetiological factors, but all result in bulla formation and/or in acantholysis. Cadherins are Ca++-dependent cell-cell adhesion molecules which play an important role in the cellular connection between normal cells. P-cadherin is involved in the selective adhesion of epidermal cells, and is expressed only on the surfaces of the two basal layers. We examined the expression of P-cadherin in some autoimmune bullous skin diseases and Darier's disease using immunohistochemistry and found P-cadherin to be strongly upregulated. We believe the upregulation is compensatory to the primary pathophysiological events in the various bullous dermatoses.     

Mortality from acquired bullous diseases of skin in Canadian adults 2000–2007

Background Bullous skin diseases are known to be associated with significant morbidity and mortality. There have been no studies on mortality from severe bullous skin diseases in Canada. Methods We used mortality data from the Statistics Canada website from 2000 to 2007 for three major bullous skin diseases: bullous pemphigoid; pemphigus; and toxic epidermal necrolysis (TEN). Crude and age‐standardized mortality rates were calculated and compared with the corresponding US mortality rates. Linear regression was used to assess time trend and effect of gender and age on mortality rates. Results During the period of eight years, there were 115 deaths attributed to pemphigoid, 84 to pemphigus, and 44 to TEN. The crude annual mortality rate was the highest for pemphigoid (0.045 per 100,000), followed by pemphigus (0.033), and TEN (0.017). None of these conditions demonstrated significant time trends in mortality rates over the eight‐year period, although a trend towards decreasing pemphigus mortality was observed (P = 0.07). No gender difference in mortality was observed, but advanced age was associated with mortality in all three conditions. Conclusion Among bullous skin diseases, pemphigoid is the leading cause of mortality in Canada. This is in contrast to the USA, where TEN is the leading cause of mortality from bullous skin diseases. It is not clear whether differences in healthcare systems explain these findings.     

A dilemma: bullous-pemphigoid-like eruption in scabies or scabies-induced bullous pemphigoid

Several diseases may be confused with scabies. Atypical manifestations of scabies have previously been reported, including urticaria, contact dermatitis, and dermatitis herpetiformis. There are also reports of scabies mimicking bullous pemphigoid. Here we report a case of scabies in a patient with manifestation similar to bullous pemphigoid. Direct smear of the bullous lesions was performed and was positive for scabies mites. The skin biopsy specimens submitted for light microscopy and direct immunofluorescence study were considered to be compatible with bullous pemphigoid. The patient treated with single dose oral ivermectin and prednisolone. The pruritus subsided and the eruption improved dramatically in 2 weeks.     

Skin-homing interleukin-4 and -13-producing cells contribute to bullous pemphigoid: remission of disease is associated with increased frequency of interleukin-10-producing cells.

Although evidence is accumulating that type 2 cytokines play a part in the pathogenesis of bullous pemphigoid, little information is available concerning characterization of the cellular source of these cytokines involved in the pathogenesis of bullous pemphigoid. By using multiparameter flow cytometry, we investigated T cells capable of producing interleukin-2, -4, -10, and -13, interferon-gamma, and tumor necrosis factor-alpha and their correlated expression of skin-homing receptor (cutaneous lymphocyte-associated antigen) in peripheral blood and skin blister of patients with bullous pemphigoid. In peripheral blood of bullous pemphigoid patients, significantly increased frequencies of interleukin-4- and interleukin-13-producing cells were found as compared with those of healthy controls, and the majority of these type 2 cells was found in the cutaneous lymphocyte-associated antigen-positive population. The frequency of interferon-gamma-producing cells was also increased as compared with healthy subjects; however, the majority of this subset was found in the cutaneous lymphocyte-associated antigen-negative population. In the skin blister, the frequencies of interleukin-13- and interleukin-4-producing cells were much higher than those in the peripheral blood of bullous pemphigoid, whereas that of interferon-gamma producing cells was significantly lower. Furthermore, in bullous pemphigoid patients after therapy with systemic corticosteroids, the frequency of cutaneous lymphocyte-associated antigen-positive, but not cutaneous lymphocyte-associated antigen-negative, interleukin-13-producing cells was significantly decreased accompanied by an increased frequency of interleukin-10-producing cells, which was associated with clinical improvement. Thus, our results suggest that bullous pemphigoid is a unique organ-specific autoimmune disease characterized by an expansion of skin-homing interleukin-13-producing cells. In addition, corticosteroids may control such type 2 biased inflammatory responses in bullous pemphigoid by promoting the expansion of interleukin-10-producing cells.     

DIFFERENTIATION OF BULLOUS PEMPHIGOID FROM EPIDERMOLYSIS BULLOSA ACQUISITA ON FROZEN SKIN BIOPSIES

Patients with bullous pemphigoid and epidermolysis bullosa acquisita may have similar clinical, histologic, and routine immunohistologic features. These two diseases can be distinguished by routine diagnostic studies either on a patient's serum tested by indirect immunofluorescence on salt-split normal skin or by obtaining a fresh perilesional skin biopsy, inducing a split at the lamina lucida, and testing for the site of IgG deposition by direct immunofluorescence. Often the serum studies are negative, while direct immunofluorescent studies yield the characteristic linear IgG staining of the basement membrane zone. To eliminate the need for a repeat biopsy to make a laboratory differential diagnosis, we studied the efficacy of salt-splitting perilesional skin biopsies that had been previously submitted and frozen for routine direct immunofluorescent studies. The biopsies were thawed, salt-split, and processed for direct immunofluorescence. Three epidermolysis bullosa acquisita biopsies and seven bullous pemphigoid biopsies examined demonstrated IgG staining at sites consistent with their respective diagnoses. The IgG appeared in the dermal side of the split biopsies in epidermolysis bullosa acquisita and predominantly, or exclusively, in the epidermal side in bullous pemphigoid. Thus the direct immunofluorescent study of previously frozen and subsequently salt-split skin biopsies may be used for the differential diagnosis of bullous pemphigoid from epidermolysis bullosa acquisita. In most cases, it may eliminate the need for a repeat biopsy.     

Dual diagnosis of Pemphigus and pemphigoid. Retrospective review of thirty cases in the literature.

BACKGROUND: Pemphigus and pemphigoid are two distinct groups of autoimmune blistering diseases. There are many reports of the simultaneous presence of clinical and serological features of both diseases in the same patient. OBJECTIVE: This study is a retrospective review of the present literature on reports of patients with features of both pemphigus and pemphigoid. We recommend that these patients be considered as having a dual diagnosis. METHODS: A review of the English language, peer-reviewed literature was conducted on patients described with features of pemphigus and pemphigoid. Available data on clinical profile, histology, immunopathology, treatment, follow-up and outcome were studied in 30 patients. They were divided into three groups: (1) bullous pemphigoid and pemphigus vulgaris, (2) mucous membrane or cicatricial pemphigoid and pemphigus vulgaris and (3) bullous pemphigoid and pemphigus foliaceus. RESULTS: In all three groups, most patients had a clinical phenotype resembling both diseases. In 17 patients with bullous pemphigoid and pemphigus vulgaris, 83% had a skin biopsy consistent with bullous pemphigoid, 70% had direct immunofluorescence studies typical of bullous pemphigoid and sera of 83% had antibodies typical of pemphigus vulgaris on indirect immunofluorescence. In 10 patients with mucous membrane or cicatricial pemphigoid and pemphigus vulgaris, a histology of mucous membrane pemphigoid was reported in 60% of the patients, direct immunofluorescence studies typical of mucous membrane pemphigoid were reported in 70% of the patients and in 80%, autoantibodies characteristic of pemphigus vulgaris were observed. In 3 patients with bullous pemphigoid and pemphigus foliaceus, the histologies were consistent with bullous pemphigoid, direct immunofluorescence was typical of pemphigus foliaceus and their sera had both autoantibodies. The majority of the 30 patients required long-term high-dose corticosteroids and immunosuppressive agents to control their disease. Three patients with bullous pemphigoid and pemphigus vulgaris (18%) died due to effects of prolonged immunosuppression. CONCLUSION: We characterize a group of patients who have clinical, histological and immunopathological features of bullous or mucous membrane or cicatricial pemphigoid with serological features of pemphigus. These patients did not achieve a prolonged clinical remission by conventional therapy. It is possible that early identification of these patients may improve their prognosis.