Enfermedad de Grover, una patología ampollar poco frecuente: a propósito de 2 casos / Grover's disease, a pathology blistering unusual: About 2 cases

Grover's disease (GD) or transient acantholytic dermatosis, is a papulovesicular pruritic disease of unknown etiology. It´s most important histopathological finding is the presence of focal acantholysis. The incidence has not been firmly established. Case report: We report two cases of papulovesicular rashes, the first one in a 79 year old man with good response to second line treatment and the second one, in a 30 year old woman. Both with different suspected triggering factors. Comment: GD predominates in white men with an average age of presentation of 61. Clinically, it presents as erythematous papules, crusted-papule and is usually pruritic. The etiopathology is still unknown, but it is associated with triggers such as: ultraviolet radiation (UVR), ionizing radiation, heat, sweat, friction and chemotherapy. Acantholysis is the classic histological finding. Management includes general measures, topical corticosteroids, calcineurin inhibitors, tretinoin, calcipotriene and antihistamines. In refractory cases, second-line treatment is used: oral isotretinoin, systemic corticosteroids and phototherapy. Paradoxically, phototherapy can also trigger GD. Conclusions: Due to the low prevalence of GD in Chile, 2 new cases are provided to the literature. In both cases, the diagnostic presumption was based on an exhaustive clinical history, confirmed by histopathological findings. (AU)

Mimickers of classic acantholytic diseases.

Acantholysis is a commonly encountered histological pattern which typically generates a differential of the pemphigus variants, Hailey-Hailey, Darier's and Grover's diseases. In addition to these diseases, the dermatologist and dermatopathologist must be aware of entities that mimic classic acantholytic dermatoses and of rare disease variants, which are characterized by acantholysis.

Detection of apoptosis in pemphigus vulgaris by TUNEL technique.

BACKGROUND: Pemphigus is part of a group of blistering diseases that affect the skin and mucous membranes. Based on its autoimmune origin, autoantibodies develop in pemphigus that are directed toward cell surface components of keratinocytes. However, some data cannot be explained, such as the lack of a relationship between autoantibody levels and the severity of clinical manifestations, treatment resistance, the presence of inflammatory infiltrates and the potential occurrence of apoptosis as determinants of vesicle formation. OBJECTIVE: To examine the presence of apoptosis in pemphigus vulgaris by TUNEL technique. METHODS: In this cross-sectional study, we selected 15 paraffin-embedded tissues from subjects who were diagnosed with pemphigus vulgaris by hematoxylin and eosin staining. The samples were subjected to TUNEL assay and examined under an Olympus BX61 fluorescence microscope. Positivity was categorized dichotomously, and the statistical analysis was performed using the X2 test. RESULTS: Positivity was observed in basal layer cells in 14 (93.3%) cases. In 13 (86.7%) of the positive cases, we noted espinosum and granular layers that formed the blister roof, and in 12 cases (80%), positive acantholytic cells were observed. CONCLUSIONS: TUNEL positivity was observed in pemphigus vulgaris, implicating apoptosis in the pathophysiology of this condition, which can help guide the development of apoptotic blockers as therapeutics.

Detection of apoptosis in pemphigus vulgaris by TUNEL technique

Abstract: Background: Pemphigus is part of a group of blistering diseases that affect the skin and mucous membranes. Based on its autoimmune origin, autoantibodies develop in pemphigus that are directed toward cell surface components of keratinocytes. However, some data cannot be explained, such as the lack of a relationship between autoantibody levels and the severity of clinical manifestations, treatment resistance, the presence of inflammatory infiltrates and the potential occurrence of apoptosis as determinants of vesicle formation. Objective: To examine the presence of apoptosis in pemphigus vulgaris by TUNEL technique. Methods: In this cross-sectional study, we selected 15 paraffin-embedded tissues from subjects who were diagnosed with pemphigus vulgaris by hematoxylin and eosin staining. The samples were subjected to TUNEL assay and examined under an Olympus BX61 fluorescence microscope. Positivity was categorized dichotomously, and the statistical analysis was performed using the X2 test. Results: Positivity was observed in basal layer cells in 14 (93.3%) cases. In 13 (86.7%) of the positive cases, we noted espinosum and granular layers that formed the blister roof, and in 12 cases (80%), positive acantholytic cells were observed. Conclusions: TUNEL positivity was observed in pemphigus vulgaris, implicating apoptosis in the pathophysiology of this condition, which can help guide the development of apoptotic blockers as therapeutics.

Pruritic eruption on the chest.

The fact that this patient's rash was limited to his chest provided an important diagnostic clue.

Evaluation of olfaction in patients with pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune disease characterized by acantholysis. PV decreases quality of life and leads to morbidity and mortality. Although the association between PV and otolaryngeal disease has been studied, its effect on olfaction has not been investigated objectively and quantitatively. METHODS: Twenty-eight patients with PV and 28 healthy volunteers were included in the study. Lesions were identified via nasal endoscopic examination. Nasal symptoms (itching, obstruction, pain, bleeding, and crusting) were recorded. Volunteers were asked to evaluate their olfactory function via a visual analog scale. The Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test was performed (butanol threshold test and identification test), and the score was calculated as the mean ± SD. RESULTS: The mean age of the PV group (group 1: 10 male 18 female subjects) was 48.7 ± 8.9 years. The mean age of the control group (group 2: 17 male and 11 female subjects) was 48.0 ± 1.1 years. All nasal symptoms, except itching, were more severe in the PV group (p < 0.05). Nasal lesions were more common in the PV group (p = 0.0001). Evaluation of olfactory function revealed significantly lower scores in the PV group for both the butanol threshold test and the identification testing as well as the CCCRC total score (p = 0.001). PV patients with nasal lesions had significantly more nasal symptoms (p < 0.05). A negative correlation was found between the number of lesions and the olfactory scores in group 1 for the butanol threshold test, identification testing, and the CCCRC total scores, respectively (p = 0.002, p = 0.010, and p = 0.001, respectively). CONCLUSION: PV causes olfactory dysfunction leading to eventual hyposmia that decreases quality of life. We suggest that olfactory testing be included in PV evaluation for the diagnosis and treatment of hyposmia, when necessary.

Urban legends: pemphigus vulgaris.

Pemphigus vulgaris (PV) is the most common type of pemphigus. PV pathogenesis is still debated, and treatment remains challenging. We investigated five controversial topics: (1) What are the target antigens in PV? (2) Do desmogleins adequately address PV pathophysiology? (3) How does acantholysis occur in PV? (4) Is PV still a lethal disease? (5) What is the role of rituximab (RTX) in PV treatment? Results from extensive literature searches suggested the following: (1) Target antigens of PV include a variety of molecules and receptors that are not physically compartmentalized within the epidermis. (2) PV is caused by a variety of autoantibodies to keratinocyte self-antigens, which concur to cause blistering by acting synergistically. (3) The concept of apoptolysis distinguishes the unique mechanism of autoantibody-induced keratinocyte damage in PV from other known forms of cell death. (4) PV remains potentially life-threatening largely because of treatment side effects, but it is uncertain which therapies carry the highest likelihood of lethal risk. (5) RTX is a very promising treatment option in patients with widespread recalcitrant or life-threatening PV. RTX's cost is an issue, its long-term side effects are still unknown, and randomized controlled trials are needed to establish the optimal dosing regimen.

Captopril modulates acetylcholinesterase in human keratinocytes.

Human keratinocytes synthesize and secrete non-neuronal acetylcholine, which acts as a local cell signaling molecule, regulating functions like proliferation, cell adhesion, motility, desmosomal cell contact, and glandular activity. The keratinocyte acetylcholine axis is composed of the enzymes mediating acetylcholine synthesis (acetyltransferase) and degradation (acetylcholinesterase), and two classes of acetylcholine receptors. In this study we investigated the effect of captopril, an ACE-inhibitor, on acetylcholinesterase and acetylcholine secretion in human keratinocytes. We analyzed the level of acetylcholinesterase in HaCat and NHEK cells by RT-PCR and Western blotting analysis. In addition, the effect of captopril on AChE activity was evaluated. We found that captopril induces a strong AChE up-regulation leading to ACh degradation and reduced secretion. Our results suggest that acantholysis induced by ACE-inhibitors might be linked to altered level of Ach.

How does acantholysis occur in pemphigus vulgaris: a critical review.

BACKGROUND: Pemphigus vulgaris is a life-threatening autoimmune blistering disease targeting skin and mucous membranes, characterized by disruption of keratinocytes' adhesion termed acantholysis. Today multiple classes of targets are considered to play a role in the genesis of the acantholysis; of these, the classical pemphigus antigens, desmosomal cadherins (desmoglein 1 and 3) are the best characterized and considered as the most important. Additional antigens include the novel epithelial acetylcholine receptors (alpha9 and pemphaxin). Thus, acantholysis in pemphigus seems to result from a cooperative action of antibodies to different keratinocyte self-antigens, but the mechanisms by which epithelial cleft occurs are not yet clearly understood. In fact, the binding of the autoantibodies to these targets generates a plethora of biological effects due, on one hand, to their direct interference with adhesive function and, on the other, to more complex events involving intracellular pathways that modify proteases activity or calcium metabolism, leading to loss of cell-cell adhesion.

In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. The mechanism of blister formation in pemphigus has not been defined; however, in vitro data suggest a role for activation of intracellular signalling cascades. OBJECTIVES: To investigate the contribution of these signalling pathways to the mechanism of PV IgG-induced acantholysis in vivo. METHODS: We used the passive transfer mouse model. Mice were injected with IgG fractions of sera from a patient with PV, with or without pretreatment with inhibitors of proteins that mediate intracellular signalling cascades. RESULTS: Inhibitors of tyrosine kinases, phospholipase C, calmodulin and the serine/threonine kinase protein kinase C prevented PV IgG-induced acantholysis in vivo. CONCLUSIONS: These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced acantholysis.

Desmosomes and disease: pemphigus and bullous impetigo.

Desmosomal cadherins are the pathophysiologic targets of autoimmune or toxin-mediated disruption in the human diseases pemphigus and bullous impetigo (including its generalized form, called staphylococcal scalded skin syndrome). Experiments exploiting the production of both pathogenic and nonpathogenic antidesmoglein antibodies in pemphigus patients' sera have afforded data that make an invaluable contribution towards identifying the functional domains of the desmogleins involved in intercellular adhesion. Conformational epitopes of antidesmoglein autoantibodies in pemphigus patients' sera and the specific cleavage site of desmoglein 1 by exfoliative toxin have been identified, implicating the N-terminal extracellular domains of the desmogleins as critical regions for controlling intercellular adhesion. Furthermore, the development of active autoimmune mouse models for pemphigus allows in vivo characterization of the disease and its pathogenesis. These studies offer new insight into the potential mechanisms of acantholysis in pemphigus and staphylococcal-associated blistering disease, with implications for the role of desmogleins in desmosomal structure and function.

Pênfico familiar benigno crônico / Chronic benign familial pemphigus

A doença de Hailey-Hailey, ou pênfigo familiar benigno crônico (PFBC), foi descrita em 1939 pelos irmäos Heiley. É uma rara afecçäo hereditária que se caracteriza por lesões vesicobolhosas frágeis, sobre base eritematosa, deixando áreas erosivas e vegetantes em locais de atrito, como axilas, virilhas e pescoço. A histopatologia lembra o pênfigo vulgar, pois as lesões se formam por acantólise suprabasal epidérmica. Os autores relatam o caso de uma paciente cuja doença apresentava 30 anos de evoluçäo, com ocorrência de erupções semelhantes em outros familiares, mas de variada intensidade

Different patterns of in vitro acantholysis in normal human skin samples explanted from different sites of the body.

BACKGROUND: The factors that contribute to a preferential anatomic localization of pemphigus lesions are not well known. In particular, the question arises as to whether certain skin areas may be more acantholysis-prone than others. OBJECTIVE: To verify whether, in pemphigus patients, a different susceptibility to acantholysis exists among different cutaneous regions, the technique of tissue cultures was used. METHODS: Normal human skin explants from two distinct anatomic regions (back and buttocks) of two former pemphigus patients were cultured in vitro in the presence of enalapril (6 mM) or cystamine (10 mM), two substances with a proven biochemical acantholytic effect. After 4 days of culture, the tissues were processed for standard histology. RESULTS: Diffuse acantholysis, with large intraepidermal splits, was observed in the explants taken from the backs of both subjects and cultured with either enalapril or cystamine. Mild to moderate acantholytic changes were detected in the explants taken from the buttocks of both subjects and cultured with either enalapril or cystamine. No structural changes were seen in the control cultures. CONCLUSIONS: Pemphigus patients present different thresholds of acantholysis in different areas of their bodies. This might explain, at least in part, certain preferential anatomic localizations of pemphigus lesions.

Langerhans cells in the development of skin cancer: a qualitative and quantitative comparison of cell markers in normal, acanthotic and neoplastic ovine skin.

The distribution of Langerhans cells in normal, acanthotic and neoplastic ovine epithelium was examined using the enzyme marker Acetylcholinesterase (AchE) and monoclonal antibodies (MoAb) to CD1 (20.27) and MHC Class II (49.1 and 28.1) molecules. In normal skin, where Langerhans cells were regularly spaced within the basal layer, qualitative observations and direct pairwise testing showed that AChE was superior to the MoAb in detecting these cells. Significantly more (P < 0.01) dendritic cells were also detected with MoAb 49.1 than MoAb 20.27 or 28.1, suggesting differential expression of MHC Class II subsets and the presence of CD1- MHC Class II+ granule- dendritic cells in sheep analogous to indeterminate cells of man. In acanthotic skin, compared to normal skin, Langerhans cells were less numerous, irregular and more suprabasal in distribution and their morphology was occasionally swollen and indistinct. No difference was seen in the ability of AChE and MoAb in detecting Langerhans cells, however pairwise testing of markers did demonstrate that significantly more (P < 0.05) cells without dendritic processes were stained with MoAb 49.1 than with 20.27 or 28.1. In all squamous cell carcinomas examined dendritic cells that stained for AChE, CD1 or MHC Class II antigens were concentrated at the peripheral areas of neoplastic epithelium. Many dendritic cells were detected with MoAb to MHC Class II antigens, whereas CD1 and AChE positive dendritic cells were rare in tumor bearing tissue. The quantitative differences in the immunohistochemical staining of Langerhans cells between normal, acanthotic and neoplastic epithelium were consistent with ultrastructural studies. When compared with those of a newborn lamb, which had had very little exposure to antigens or ultraviolet radiation (UVR), the Langerhans cells of the aged sheep were deformed and contained far fewer Birbeck granules. The abnormalities were progressively more severe in acanthotic and neoplastic skin. These observed changes may have resulted from UVR induced damage and may be indicative of impaired function involved in the development of skin cancer.

Gaining more insight into the pathomechanisms of thiol-induced acantholysis.

Acantholysis is considered the initial and the main pathogenetic event of pemphigus. The first step in drug-induced acantholysis (biochemical and/or immunological) involves binding of the drug to the cell membrane and the formation of 'drug-cysteine' instead of 'cysteine-cysteine' bondings. We suggest that the reaction of D-penicillamine with cystine disulfides that results in cysteine-penicillamine disulfides is not a terminal reaction, but rather a primary initiating step of a chain reaction. It is reasonable to consider that the cysteine-penicillamine disulfide is continuing to be enzymatically reduced by various thiol reductants, in particular glutathione reductase, thereby generating a 'new' penicillamine molecule which, in turn, reacts with other cystine disulfides and does so in an unending cycle. A chain reaction is thus created in which the drug is repeatedly generated so that one molecule of the drug may attack thousands of cystine disulfide bonds. It is highly possible that normal individuals have their own endogenous means of controlling this deleterious chain reaction, whereas pemphigus-prone individuals lack the ability to stop this potentially damaging reaction. Drug-induced pemphigus should thus be added to the ever-growing list of adverse drug reactions related to pharmacogenetic disorders in drug metabolism.

Desmosomal dissolution in Grover's disease, Hailey-Hailey's disease and Darier's disease.

Proteins involved in the formation of desmosomes and simpler adherens junctions were studied in three types of non-immune acantholytic diseases; specifically, four cases of Grover's disease (GD), one case of Hailey-Hailey's disease (HHD) and one case of Darier's disease (DD), and these were compared to two cases of immune-mediated acantholytic disease pemphigus vulgaris (PV). The proteins studied included: 1. The intracellular desmosomal proteins, desmoplakin I and II and plakoglobin; 2. The intercellular desmosomal proteins, desmoglein and CD44; and 3. vinculin, which is a major intracellular protein of the simpler aherens junctions. In GD, HHD and DD, immunostaining showed a loss of desmoplakin I and II and plakoglobin from the desmosomes, and a diffuse staining in the cytoplasm. In contrast, in pemphigus vulgaris, these proteins seemed intact and were localized to dot-like spots on the cell surface. Also, desmoglein, and CD44 were slightly affected in GD, and moderately affected in HHD and DD. Absence of desmosomal attachment plaques, the lack of labeling with desmoglein in the affected desmosomes and a diffusion of the labels into cytoplasm were demonstrated with electron microscopy using an immunogold technique. In PV, desmoglein III is one of the target antigens for the autoantibodies in this disease and was only partially preserved in a small number of lesional cells, while CD44 was mostly preserved. Vinculin was intact in GD, HHD and DD, but was lost in PV. This study, our previous work, and that of others, suggest that: 1. In GD, HHD and DD, the proteins of the desmosomal attachment plaque are primarily affected; 2. In PV, the intercellular glycoproteins are primarily involved; and 3. Simple adherens junctions are intact in GD, HHD and DD, but are damaged in PV.

Ultrastructural alterations associated with in vivo and in vitro bound pemphigus antibodies in cultured oral epithelial cells.

Pemphigus vulgaris is characterized by bound and circulating IgG antibodies to an epithelial antigen, antibody binding resulting in acantholysis. This study examines the role of pemphigus serum in the initiation and perpetuation of acantholysis. Oral epithelial cells derived from a patient with pemphigus vulgaris were cultured in vitro in the presence of normal serum. Also, normal oral epithelial cells were cultured in pemphigus serum for between 0.5 and 72 h or exposed to pemphigus serum for 72 h and then cultured in normal serum for 2 wk. Oral epithelial cells from the pemphigus patient continued to display acantholysis for the 3-wk duration of the culture. Normal oral epithelial cells showed acantholysis within 30 min exposure to pemphigus serum and the acantholysis persisted in the cultures, pulse exposed to pemphigus serum, for the duration of the explant culture. These results support the notion that pemphigus serum is directly responsible for acantholysis which may then be persistent.

Vesiculobullous mucocutaneous disease: pemphigus vulgaris.

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous disease in which oral lesions may be the initial and predominant manifestation. The disease is characterized by acantholysis in the immediately suprabasal layers of the stratified squamous epithelium, giving rise to blisters which readily rupture leaving erosions which show little tendency to heal. Immunogenetic studies indicate a marked genetic susceptibility to the disease, with the immune response-associated HLA-DR4 and DRw6 alleles being especially important. The trigger for autoantibody formation is unknown. The antigen in pemphigus vulgaris is probably a 130-140 kD cell adhesion molecule located in the cell membrane of basal and immediately suprabasal keratinocytes. Antibody binding to this antigen is likely to interfere with normal intercellular adhesion, leading to desmosomal detachment. Propagation of acantholysis and cell damage are attributable to complement activation, with deposition of the membrane attack complex on the keratinocyte cell membrane, and proteolysis due to increased plasminogen activator production. Steroid therapy is the treatment of choice, but significant mortality is still associated with the disease.