Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients.

Pemphigus refers to a group of autoimmune blistering skin diseases, mainly identified as pemphigus vulgaris and pemphigus foliaceus, both characterized by the presence of autoantibodies against keratinocyte adhesion molecules, leading to loss of cell-cell adhesion with consequent blister formation. Pemphigus vulgaris is reported to be associated with human leukocyte antigen DR4 and/or DR6 whereas no data are available on pemphigus foliaceus, except for the endemic Brazilian form (fogo selvagem), which is reported to be associated with DR1 and DR4. We here report human leukocyte antigen molecular typing on a total of 87 patients, 61 with pemphigus vulgaris and 26 with pemphigus foliaceus, versus 128 healthy matched controls. Generic typing showed an increase of DRB1*04 and DRB1*14 and a decrease of DRB1*07 in both pemphigus vulgaris and pemphigus foliaceus patients. Molecular subtyping of DR4+ and DR14+ subjects showed a highly significant association between the DRB1*1401 and both pemphigus vulgaris (p < 0.0001) and pemphigus foliaceus patients (p < 0.0001) together with a significant increase of the linked DQB1*0503 (pemphigus vulgaris p < 0.0001; pemphigus foliaceus p < 0.0001). Moreover, whereas the association between DRB1*0402 and pemphigus vulgaris (p < 0.0001) has been confirmed, no significant association between a specific allele of the DR4 group and pemphigus foliaceus, has been found. Therefore, at least in Italian patients, pemphigus vulgaris and pemphigus foliaceus share DRB1*1401 and DQB1*0503, as susceptible human leukocyte antigen alleles, whereas DRB1*0402 is only found associated with pemphigus vulgaris. The observation that both diseases, pemphigus vulgaris and pemphigus foliaceus, carry the same susceptible human leukocyte antigen alleles has been interpreted as a common genetic background predisposing to pemphigus as, like in other autoimmune disorders, it is not sufficient to explain the onset of the disease on the basis of the sole aforementioned alleles. Other linked genes and/or environmental factors should play a facilitating role in the outbreak of pemphigus, either pemphigus vulgaris or pemphigus foliaceus.     

The health impact of pemphigus vulgaris and pemphigus foliaceus assessed using the Medical Outcomes Study 36-item short form health survey questionnaire

BACKGROUND: Pemphigus vulgaris and pemphigus foliaceus are rare, potentially life-threatening, autoimmune disorders characterized by antibodies to epidermal adhesion molecules. Clinical characteristics are painful chronic erosions of mucous membranes and of the skin. There are only few published studies on the impact of the disease on the health status (HS) of patients with these conditions. OBJECTIVES: To assess the impact of disease on the HS of patients with pemphigus. METHODS: Fifty-eight patients enrolled at the Bullous Skin Diseases Unit of IDI-IRCCS in the period January-June 2006 were assessed for their HS using the Medical Outcomes Study 36-item short form health survey (SF-36) questionnaire and for anxiety and depression using the Institute for Personality and Ability Testing questionnaires. RESULTS: A compromised HS on both the physical and the psychosocial scales was observed, similar to other chronic dermatological diseases such as psoriasis. Patients with anxiety had severe disease as measured by the Physician's Global Assessment and the degree of mucocutaneous involvement, as well as those with a more recent disease onset. A better HS was observed in patients whose clinical condition was rated as nonsevere, and also in patients with pemphigus foliaceus. In pemphigus vulgaris, antidesmoglein 3 antibody levels directly correlated with clinical severity and with lower SF-36 scores. CONCLUSIONS: HS evaluated with the SF-36 can be a very useful additional outcome criterion in clinical studies with pemphigus. The management of the disease must take into account its impact on various aspects of life of the patient.     

Nonendemic pemphigus foliaceus presenting as fatal bullous exfoliative erythroderma

Pemphigus foliaceus is a cutaneous autoimmune blistering disease that is characterized by lower morbidity and mortality than those observed in pemphigus vulgaris or paraneoplastic pemphigus. However, erythrodermic forms of the endemic variant of pemphigus foliaceus have been associated with a higher mortality. We report a case of nonendemic pemphigus foliaceus that presented as fatal bullous exfoliative erythroderma, and thus, we will emphasize the inclusion of this entity in the differential diagnosis and the use of skin direct immunofluorescence in the evaluation of patients with erythroderma.     

The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic

Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.     

Treatment of severe refractory pemphigus vulgaris with rituximab

Pemphigus vulgaris is a potentially fatal autoimmune bullous disease. High doses of immunosuppressive drugs are used in managing severe cases of pemphigus. Rituximab, an anti-CD20 monoclonal antibody, has proven to be effective in patients with refractory pemphigus vulgaris and pemphigus foliaceus. We review cases of pemphigus vulgaris and pemphigus foliaceus not associated with lymphoma that were treated with rituximab, and we report a new case of severe refractory pemphigus vulgaris successfully treated with rituximab.     

Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus

Pemphigus is an autoimmune blistering disease characterized by circulating autoantibodies directed against the keratinocyte cell surface. The two variants, pemphigus foliaceus and pemphigus vulgaris, can be distinguished at the molecular level by immunochemical studies. The large majority of patients with pemphigus develop the disease spontaneously; however, there is a small group of patients who develop pemphigus after treatment with certain medications, of which penicillamine and captopril are the best documented. Most patients with drug-induced pemphigus have circulating and/or tissue bound epidermal cell surface autoantibodies; however, the molecular specificity of these autoantibodies has not been studied. We performed immunoprecipitation studies utilizing extracts of 125I-labeled suction blister epidermis and the sera of three patients with drug-induced pemphigus foliaceus (two due to penicillamine and one due to captopril) and one patient with captopril-induced pemphigus vulgaris. We found that the three patients with drug-induced pemphigus foliaceus had circulating autoantibodies that are directed against the pemphigus foliaceus antigen complex and that the one patient with drug-induced pemphigus vulgaris had circulating autoantibodies that are directed against the pemphigus vulgaris antigen complex. This study demonstrates that autoantibodies from drug-induced pemphigus patients have the same antigenic specificity, on a molecular level, as do autoantibodies from other pemphigus patients.     

Bilateral herpes simplex virus keratitis in a patient with pemphigus vulgaris

Pemphigus is a group of chronic blistering diseases in which acantholysis and blister formation occur within the epidermis. Immunoglobulins and complement are found in the circulation and are bound to the cell surfaces of keratinocytes. Pemphigus is classified into several types hut may he divided into two major variants, pemphigus vulgaris and pemphigus foliaceus. The primary skin lesion of pemphigus vulgaris which was often fatal before the introduction of systemic glucocorticoid therapy, is a flaccid, fragile blister which can occur anywhere. The most common skin lesions arc erosions, which are often painful; suprabasal elefting within the epidermis is also present. In the majority of these patients, painful mucous membrane erosions will be the first symptom, while sometimes the conjunctiva is affected but corneal involvement is very rare.     

Diagnosis and clinical features of pemphigus vulgaris

Autoimmune bullous diseases are associated with autoimmunity against structural components that maintain cell-cell and cell-matrix adhesion in the skin and mucous membranes. They include those where the skin blisters at the basement membrane zone and those where the skin blisters within the epidermis (pemphigus vulgaris, pemphigus foliaceus, and other subtypes of pemphigus). The variants of pemphigus are determined according to the level of intraepidermal split formation. There are 5 main variants of pemphigus: pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus. This review focuses only on pemphigus vulgaris.     

IgA pemphigus

Pemphigus is a life-threatening autoimmune blistering disease. Pemphigus is divided into 4 major types; pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, and IgA pemphigus. Among them, IgA pemphigus is characterized by tissue-bound and circulating IgA antibodies targeting desmosomal or nondesmosomal cell surface components in the epidermis. Histopathologically, slight epidermal acantholysis and extensive neutrophilic infiltration in either the upper part or all layers of the epidermis were observed. IgA pemphigus is subdivided into intraepidermal neutrophilic IgA dermatosis-type (IEN-type), whose target antigen is still unknown (probably nondesmosomal cell surface protein), and subcorneal pustular dermatosis-type (SPD-type), whose target antigen is desmocollin 1 (Dsc1). We summarize reported cases of IgA pemphigus and describe current knowledge including epidemiology, clinical manifestations, pathology, laboratory tests, pathophysiology, associated diseases, prognosis and treatment, and future perspectives of IgA pemphigus.     

Prevalence of Metabolic Syndrome and its components in a Brazilian sample of pemphigus patients

BACKGROUND

Pemphigus foliaceus and pemphigus vulgaris are endemic in the northeastern region of São Paulo State, Brazil. They are treated mainly with systemic corticosteroids, which may provoke osteoporosis; atherosclerosis, higher blood pressure, insulin resistance, glucose intolerance, hyperlipidemia and abdominal obesity. These side effects of corticoids also constitute criteria for the diagnosis of metabolic syndrome.

OBJECTIVE

The prevalence of metabolic syndrome and each component of metabolic syndrome in Pemphigus foliaceus and pemphigus vulgaris groups was compared with Brazilian casuistic samples.

METHODS

Data of 147 patients (pemphigus foliaceus 48.9% and pemphigus vulgaris 51.1%) were compiled from medical records regarding metabolic syndrome and its components, and included in the analysis.

RESULTS

There was no significant difference regarding the prevalence of metabolic syndrome in pemphigus groups compared with the Brazilian casuistic samples. The analysis of each component of metabolic syndrome showed a higher prevalence of: higher blood pressure in male subjects with pemphigus vulgaris, and in pemphigus foliaceus in both genders; diabetes mellitus in both genders for pemphigus vulgaris and pemphigus foliaceus; obesity in females for pemphigus vulgaris and pemphigus foliaceus, and hypertriglyceridemia in both genders for pemphigus vulgaris and pemphigus foliaceus groups that were statistically significant compared to the Brazilian reports. Furthermore, the study noted a higher incidence of cardiovascular events in both genders in pemphigus foliaceus and pemphigus vulgaris groups than in Brazilian casuistic samples.

CONCLUSION

The components of metabolic syndrome are more numerous in pemphigus when compared with Brazilian casuistic samples. Future studies are necessary to assure that metabolic syndrome may be associated with pemphigus per se, including a greater casuistic sample of patients who have not taken corticoids.     

天疱疮发病机制的研究进展

天疱疮是自身免疫引起表皮棘层细胞松解导致的慢性复发性表皮内大疱性皮肤病,典型表现为红斑基础上的疱壁松弛性水疱、糜烂、尼氏征阳性.依据天疱疮的临床表现,分为寻常型、增殖型、落叶型和红斑型天疱疮.天疱疮主要的发病机制是患者存在针对角质形成细胞桥粒芯(糖)蛋白的自身抗体,但棘层松解的详细机制尚不清.近年来,随着对蛋白组学、免疫学和分子生物学技术的发展以及天疱疮发病机制研究的不断深入,发现天疱疮的发病机制中除传统的桥粒芯(糖)蛋白自身抗体外,非桥粒芯(糖)蛋白抗体因素也参与了棘层松解的形成,为天疱疮提供了新的潜在治疗靶位.     

Clinical features of pemphigus

Pemphigus is an autoimmune, blistering disease that affects the skin and mucous membranes.¹ It affects all ages. Pemphigus has been reported in children and young adults. The mean age of onset is the sixth decade in most large series, the range being 12–88 years.^2–4 The majority of patients are often in their fourth, fifth, and sixth decades. Thus it appears that pemphigus attacks individuals at the peak of their adult lives. This often has a deleterious effect on the psychology of the patient and the patient's family. Age of anset is important because the prognosis in older patients is not as good as that in younger patients.⁵

Pemphigus affects men and women equally. The incidence is slightly higher in Jewish women than men.⁶ When large series are compared, and patients below the age of 20 are studied, it appears that there is a predilection for women in that group.⁷

The exact incidence of pemphigus is unknown. Since it is not a reportable disease it is difficult to establish the incidence. This reproblem is further compounded by the fact that several drugs are now believed to induce pemphigus (Chapter 4). The establishment of a registry would greatly facilitate the study not only of incidence but other epidemiological features and clinical perspectives as well.

In 1941, less than 1% of all cases seen in a large New York City hospital dermatology clinic accounted for pemphigus⁶; however, at that time, pemphigus was not differentiated from other blistering diseases.⁸ In 1976 in southern Arizona, the incidence was reported to be 0.5 cases per 100,000 population per year.⁹ In 1977 in a study from Hartford County in Connecticut, the annual incidence was 0.42 cases per 100,000 people in general.¹⁰ In the same area, the incidence was 3.2 per 100,000 in the Jewish population. It is generally believed that the incidence is significantly higher in patients of Jewish descent or origin. In a study from Jerusalem, the incidence was reported to be 1.62 cases per 100,000 population.¹¹ Pemphigus has been reported worldwide, and it affects all races.

It is important to emphasize that pemphigus is a rare disease. It is nonetheless one of the few potentially fatal skin diseases. Early diagnosis is often associated with good response to therapy and a better prognosis. Direct and indirect immunofluorescent studies have greatly facilitated the diagnostic armamentarium of the clinician. The availability of these tests by mail has increased their practical utilization.

There are four described variants of pemphigus: (1) pemphigus vulgaris, (2) pemphigus vegetans, (3) pemphigus foliaceus, and (4) pemphigus erythematosus.

The four variants have different clinical presentations. The clinical presentation is dissimilar insofar as that each variant can be clinically differentiated. If the right kind of lesion is biopsied, they can frequently be differentiated histologically. The four variants can also be differentiated in most cases on direct immunofluorescence. On indirect immunofluorescence, the staining pattern is quite similar. It is universally agreed that pemphigus vegetans is a variant of pemphigus vulgaris.¹² Similarly, pemphigus erythematosus is considered a variant of pemphigus foliaceus.¹²     

Pemphigus

Pemphigus is a group of organ-specific autoimmune mucocutaneous disorders with an established immunologic basis. The presence of intraepithelial blisters and erosions of the skin and variable involvement of the mucous membranes characterize its three major variants, pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Prior to the use of corticosteroids in the 1950s, the natural history of pemphigus vulgaris was relentless progression, with a 50% mortality at 2 years, and almost 100% at 5 years. Today, with mortality rates less than 5%, the focus has changed towards reducing corticosteroid side effects and maintaining optimal quality of life under treatment. This can be achieved by the appropriate use of steroid-sparing agents. This article addresses the comprehensive management of patients with pemphigus.     

Spectrum of autoantibodies other than anti‐desmoglein in pemphigus patients

Background Pemphigus is a life‐threatening autoimmune blistering disease mediated by autoantibodies against adhesion molecule of the skin. Its concurrence with systemic and organ‐specific autoimmune disease was described in case reports. Objectives To evaluate the presence of a broad spectrum of organ‐specific and non‐organ‐specific autoantibodies other than anti‐desmoglein antibodies in pemphigus patients. Patients and methods Serum samples were obtained from 105 pemphigus foliaceus (PF) patients, 51 pemphigus vulgaris (PV) patients and 50 controls. Both indirect immunofluorescence assay and ELISA were used to assess the presence of autoantibodies related to connective tissue diseases, autoimmune hepatitis, vasculitis, rheumatoid arthritis, coeliac disease, diabetes and thyroiditis. Results Significant difference was observed between the three groups for anti‐thyroglobulin antibodies in the pemphigus foliaceus group (18% vs. 4%, P = 0.03). A significantly higher occurrence of IgM anti‐cardiolipin (P = 0.03), IgG anti‐reticulin (P = 0.01) and IgG anti‐gliadin antibodies (P = 0.008) were observed in the PV group. Cases with more than four autoantibodies were frequently positives for both anti‐desmoglein 1 and anti‐desmoglein 3. Conclusion Autoantibodies other than anti‐desmoglein antibodies are not rare in pemphigus patients. Clinical and serological follow‐up of pemphigus patients with positive autoantibodies are needed to clarify their impact in disease evolution.     

Pemphigus

Pemphigus is an infrequent, organ-specific, autoimmune bullous disease, which affects the skin, mucous membranes and appendages. Histopathologically, it is characterized by acantholysis. Pemphigus has classically been divided into two major groups, pemphigus vulgaris and pemphigus foliaceus, with their respective clinical variants pemphigus vegetans and pemphigus erythematosus. In recent years, new variants of pemphigus have been described: paraneoplastic pemphigus, IgA pemphigus and pemphigus herpetiformis. This article reviews the epidemiology, etiopathogenesis, clinical symptoms, diagnosis, treatment and prognosis of pemphigus. Advances in molecular biology techniques have made it possible to more precisely identify the different antigens against which antibodies are directed, and to fine-tune ELISA diagnostic techniques. Treating pemphigus vulgaris and foliaceus with general steroids has modified their prognosis; it is estimated that mortality in recent decades is less than 10 %. Managing the clinical complications that appear during the evolution of the pemphigus has contributed to reducing morbidity and mortality.     

A clinico-pathological study of 70 cases of pemphigus

A clinicopalhological study of 70 cases of pemphigus observed over a span of four and a half years from January 1992 to June 1996 at the Sir J.J. Group of Hospitals and Grant Medical College, Mumbai is reported. Pemphigus vulgaris constituted the single largest group of 43 cases, followed by pemphigus foliaceus (25 cases) and pemphigus vegetans (2 cases). Majority of the cases were seen in the age group of 21-60 years, with a slight male predominance. The youngest patient was 14 years while the eldest was aged 75 years. Mucosal involvement was seen in 31 cases of pemphigus vulgaris, as opposed to only 5 cases of pemphigus foliaceus. Flaccid bullae were present in 100% cases. Pruritus was complained of in 14 cases, though it was more common in pemphigus vegetans and vulgaris. Salient histopathological features of pemphigus vulgaris observed were (I) intraepidermal suprabasal blisters (35 cases), (2) presence of acantholytic cells (40 cases), (3) "Row of tombstone appearance" (I8 cases) and (4) acantholysis involving follicular sheath (20 cases). Main histopathological features of pemphigus foliaceus were (1) subcorneal blister (15 case), (2) acantholysis (24 cases) and (3) bulla cavity containing inflammatory infiltrate (12 cases). Both cases of pemphigus vegetans showed hyperkeratosis, papillomatosis and irregular acanthosis with intra-epidermal eosinophilic abscesses besides suprabasal lacunae.     

Pemphiguserkrankungen bei Kindern und Jugendlichen

The pemphigus diseases, which include some of the most severe bullous autoimmune skin reactions, are seen predominantly in middle-aged and elderly individuals. Only endemic pemphigus foliaceus in South America most frequently affects juveniles and children. All non-endemic pemphigus diseases, including paraneoplastic pemphigus, have been reported to occur in adolescents and even very rarely in children younger than 10 years. Pemphigus vulgaris in pregnancy represents a frequently overseen medical problem and may result in fetal growth retardation, intrauterine death, premature delivery and – in about 30% – in neonatal pemphigus vulgaris of the newborn. Contrary to pemphigus vulgaris, the transplacental crossing of autoantibodies against desmoglein1 in pregnant women with pemphigus foliaceus hardly ever leads to neonatal skin lesions in the offspring. This phenomenon can be explained by differences in the distribution and cross-compensation of the pemphigus antigens desmoglein3 and 1 in neonatal and adult skin or mucosa, respectively.     

Comparative study of pemphigus vulgaris and pemphigus foliaceus in Singapore

This is a retrospective study of all patients diagnosed to have pemphigus in our centre over a 3 year period. The case records of all patients with pemphigus from January 1995 to December 1997 were analysed. Fifty patients were diagnosed to have pemphigus during the study period. The diagnoses were pemphigus vulgaris in 31 patients, pemphigus foliaceus in 16, paraneoplastic pemphigus in two and IgA pemphigus in one. The average titre of anti-intercellular antibodies in patients with pemphigus vulgaris (1:96) was higher than the titre in patients with pemphigus foliaceus (1:69). The average initial dose of prednisolone required for disease control in patients with pemphigus vulgaris (62 mg/day) was significantly higher than that required for patients with pemphigus foliaceus (44 mg/day). In our study population, pemphigus vulgaris is a more severe and chronic disease than pemphigus foliaceus, as reflected in the higher titre of anti-intercellular antibodies, higher dose of systemic corticosteroids required for control of the disease, the longer duration to achieve complete remission and longer follow-up period.     

The treatment of mild pemphigus vulgaris and pemphigus foliaceus with a topical corticosteroid

Seven patients with mild pemphigus vulgaris (n = 3) or pemphigus foliaceus (n = 4) were treated with a very potent topical corticosteroid alone. Clobetasol propionate 0.05% cream was applied to mucosal lesions and involved skin twice a day for at least 15 days, then progressively tapered. Pemphigus was considered to be controlled if healing of lesions was obtained, with a 75% decrease in the number of new lesions per week without addition of any systemic treatment. In all seven patients, the disease was controlled initially with healing of cutaneous lesions within 15 days, while healing of mucosal lesions took at least 1 month. In four patients, remission was maintained with topical corticosteroid alone for a mean 19-month follow-up. In three patients, relapse occurred after 2-11 months, requiring a systemic treatment.     

The value of trichoscopy in the differential diagnosis of scalp lesions in pemphigus vulgaris and pemphigus foliaceus

BACKGROUND

Trichoscopy is becoming increasingly popular in diagnosing hair and scalp diseases. Scalp involvement in pemphigus is common. The scalp may be the first or only site of clinical manifestation of the disease.

OBJECTIVE

The aim of this study was to analyze whether trichoscopy may be useful in aiding differential diagnosis of scalp lesions in patients with pemphigus vulgaris and pemphigus foliaceus.

METHODS

Trichoscopy was performed in 19 patients with scalp lesions in the course of pemphigus (9 patients with pemphigus vulgaris and 10 with pemphigus foliaceus). In all patients, the diagnosis of scalp pemphigus was confirmed by histopathology. The working magnification was 20-fold and 70-fold.

RESULTS

The most frequently observed trichoscopy features of pemphigus lesions were: extravasations (18/19; 94.7%) and yellow hemorrhagic crusts (11/19; 57.9%). Yellow dots with whitish halo were observed in 6/19 (31.6%) patients with pemphigus. White polygonal structures were observed in pemphigus foliaceus (6/10; 60%), but not in pemphigus vulgaris. Vascular abnormalities were more frequent in pemphigus vulgaris, when compared to pemphigus foliaceus, and were associated with a severe course of disease. Linear serpentine vessels were the most frequent vascular abnormality in patients with pemphigus vulgaris and pemphigus foliaceus (77.8% and 30%, respectively).

CONCLUSION

Trichoscopy may serve as a useful supplementary method in the differential diagnosis of pemphigus, especially in cases of desquamative or exudative lesions limited to the scalp. Extravasations, yellow hemorrhagic crusts, yellow dots with whitish halo, white polygonal structures and linear serpentine vessels are trichoscopy features which may suggest the diagnosis of pemphigus.