WILD FIRE+
Wild fire (WF), also know as endemic pemphigus foliaceous (EPF), is an autoimmune bullous disease of the skin, endemic in Brazil. Histologically, it can be described by the formation of intraepidermal blisters with acantholysis. Wild fire and Cazenave's pemphigus foliaceous (PF) share common clinical and histological characteristics and both present IgG4 subclass autoantibodies, whose target antigen is desmoglein 1, a 160kd desmosomal antigen.
WF affects more frequently children, adolescents and young adults who live in the rural areas of endemic regions and family cases are common, whereas PF has universal occurrence and usually there are no family cases
The most typical and primary skin lesion in WF are superficial blisters that break easily, leaving eroded areas, covered by a thin squamous layer and crusts. The disease usually starts on the head, neck and seborrheic regions, progressing in the craniocaudal direction, in a symmetric fashion. Practically all patients have lesions on the face and/or scalp. WF does not affect the oral mucosa, palms of the hands and plant of the feet. In most patients, the disease has a gradual onset, with skin lesions evolving for weeks or months. A smaller number of patients present a more acute onset, with extensive bullous lesions that affect large areas of the tegument.
Clinically, WF may evolve in two main ways: localized and generalized. In its localized form, most of the lesions are limited to the seborrheic areas of the skin – face, head, neck and upper trunk. In a considerable number of patients who have the localized form, lesions are on malar regions, looking very similar to the 'butterfly wing' seen in lupus erythematosus. Most of the patients with the localized form remain with the lesions confined to these areas; however, in some patients who have that form, lesions may spread, evolving to the generalized form. In the generalized form, lesions are numerous, affecting more intensely the trunk and limbs, in addition to the face and scalp. The generalized form has is maximum expression in the erythrodermal phase (Figure 1). There is a burning feeling, which led to the name "wild fire". In the generalized form, complications like pyodermitis, dermatophytosis, scabies, and viral warts are more common. The dissemination of the herpes virus leading to Kaposi's variceliform eruptions was responsible in the past for many deaths in this form of the disease and today it is still considered severe.
The application of pressure on the apparently normal skin, close to the lesion, leads to epidermal detachment (Nikolsky's sign), which indicates the disease is active. If the surface of the blister is pressured vertically, the blister extends laterally (Nikolsky's sign II or Asboe-Hansen sign).
Lastly, patients who have the generalized form may evolve, in the chronic phase, with lesions of the type of verrucous plaques, which have an extremely long course
1) Histopathology
WF lesions are histologically characterized by the formation of high intraepidermal acantholytic blisters, in the subcorneal or granular region (Figure 2). The sites of these blisters coincide with the distribution of Dsg1 on the epidermis, which have greater expression on the upper layers of the stratum corneum,21 although Dsg1 is also present, at o a lesser degree, in the deep epidermis, where Dsg3 has its greatest expression.22 Blisters have serum, acantholytic keratinocytes, and occasionally, neutrophils and eosinophils
2) Immunofluorescence
Direct immunofluorescence (DIF) of the perilesional skin of patients with WF shows deposits of IgG and C3 on the surface of keratinocytes in all active cases.24 As in other forms of pemphigus, an essential element for the diagnosis of WF is the detection of circulating intercellular antibodies (IA), which are classically detected through indirect immunofluorescence (IIF).25 IIF assay with the serum of active patients using normal human skin as substrate shows, in most WF cases, circulating IgG antibodies against the cellular surface of keratinocytes. The sensitivity of IIF for the detection of WF antibodies is strongly influenced by the type of substrate used. Cunha26 found that normal human skin is the most sensitive substrate for the detection of WF autoantibodies, followed in decreasing order of efficiency, by guinea pig esophagus, monkey esophagus and bovine tongue
3) Immunoblotting (IB)
Cunha et al.,29 studying the sensitivity of IIF and IB assays to detect WF autoantibodies, found that IIF (71%) is a more sensitive assay than IB (28%) to detect circulating intercellular antibodies in patients with WF
4) ELISA (Enzyme-Linked Immunosorbent Assay)
Today, there are commercially available solutions of desmoglein to be tested with the serums of patients to perform the ELISA, which presents high sensitivity and high specificity, and because it is quantitative, it has been indicated as the method of choice for the diagnosis and follow-up of WF patients.
TREATMENT
WF is treated chiefly with oral prednisone at the dose of 1 to 2mg/kg/day (maximum dose, 100 to 120mg day). The reduction of the steroid should start after lesions are completely healed and there are no new blisters. The dose should be reduced by 10mg per week, until the dose of 30mg/day. Then, the reduction should be slower, 5 to 10mg/month until the dose of 10mg/day. Withdrawal should be made with 2.5mg reductions every 1 or 2 months, according to the clinical course. Treatment can be suspended after one year with low daily doses or on alternated days, without the appearance of new lesions and with negative serology (IIF)
PEMPHIGUS VULGARIS
INTRODUCTION
Pemphigus vulgaris (PV) is a potencially fatal intraepidermal bullous disease that affects the skin and mucosas.32,33 It has universal distribution, but is more common among the Jewish. Immunogenetic studies have demonstrated an increase in the incidence of HLA-DR4 (in Ashkenazi Jewish) or DRw6 (in other ethnic groups).34-36 About 90% of patients with PV have oral involvement and 50-70% of patients have at onset exulcerating lesions on the oral mucosa.32 PV affects equally both sexes33 and occurs chiefly in patients between a 4th and 6th decades of life;37 however, individuals of any age can be affected, including children and newborns of mothers with PV.38
ETIOPATHOGENESIS
Patients with PV have pathogenic IgG4 antibodies against Dsg3,39,40 a 130kD transmembrane glicoprotein, molecule that belongs to the family of the cadherins, which provides the desmosome with the function of cellular adherence on the epidermis
CLINICAL ASPECTS
The primary lesions of PV are flaccid blisters that emerge on the normal or erythematous skin.32,33,37,45 The blisters are fragile and break rapidly, forming painful erosions (Figure 5) that bleed easily and are covered by bloody crusts. The application of pressure on the seemingly normal skin, close to the lesion, induces epidermal detachment (Nikolsky's sign)45, which indicates that the disease is active. If the surface of the blister receives vertical pressure, it will extend laterally (Nikolsky's sign II or Asboe-Hansen Sign).45 PV blisters can be localized or generalized and any area of the skin can be involved, although the most frequent areas are: face, axilla and oral cavity, and this may be due to the fact that Dsg3 has its highest expression in these areas.46 Lesions can affect the entire mouth mucosa, but they predominate on the mucosa of the cheeks, on the palate and gums. PV may present itself as flaking gingivitis. Oral lesions in the advanced phase make eating difficult, thus compromising the nutritional status. They may affect the conjunctival, nasal, pharyngeal, laryngeal, esophageal, labial, vaginal, cervical, urethral, and anal mucosas
Pemphigus vegetans is a rare variant of PV (1% to 2% of cases), in which tumid vegetating lesions occur specifically between skin folds. 49,50 In the initial course, lesions are similar to those of PV; however, in the late course, lesions become hypertrophic, vegetating and verrucous, particularly between skin folds.
LABORATORY DIAGNOSIS
1) Histopathology
The lesion is characterized by the formation of intraepidermal blisters located, in most cases, immediately above the basement layer of the epidermis (suprabasal). The location of PV blisters on this area correlated well with the distribution of Dsg3 on the epidermis, where Dsg3 has its greatest expression.
2) Immunofluorescence
Direct immunofluorescence (DIF) using perilesional tissue shows in all cases with disease in activity, IgG and complement deposits on the surface of the keratinocytes all over the epidermis. In patients with lesions restricted to the oral mucosa, DIF of healthy skin, the buttocks, for example, can be positive, permitting an early diagnosis.45
Indirect immunofluorescence (IIF), using normal human skin or monkey esophagus as substrate, shows circulating IgG antibodies on the surface of keratinocyte cells.52 Immunofluorescence sensitivity is 83% using human skin as substrate and 90% when monkey esophagus is used as substrate. 53
3) ELISA (Enzyme-Linked Immunosorbent Assay)
Circulating IgG antibodies in PV can be detected through ELISA, using recombinant Dsg1 and Dsg3.54 130kD Dsg3 can be found in mucous pemphigus vulgaris and Dsg1 and Dsg3 (160kD and 130kD) in pemphigus vulgaris mucocutaneous
TREATMENT
Before the advent of steroids, mortality rates ranged between 60 and 90%.55 Today, in spite of all new modalities of therapy, the disease is still severe, with a mortality rate of 5% . Many patients die because of complications of treatments rather than from the disease itself. The usually indicated treatment is prednisone at the dose of 1-2mg/kg/day according to the severity of the disease. If there is no improvement with steroid therapy alone within one week, an immunosuppressant drug should be associated. The first indication of immunosuppressant is azathioprine at the dose of 2mg/kg/day. As a second option, mycophenolate mofetil at the dose of 35-45mg/kg/day can be used. Patients who do not present significant improvement can be treated with pulse therapy with IV metilprednisolone at the dose of 1g/day for 3 consecutive days.6 Intravenous immunoglobulin at the total dose of 2g/month, divided in 5 consecutive days, is another option for the difficult-to-treat cases and it can be effective as a concomitant therapy or monotherapy
BULLOUS PEMPHIGOID
Bullous pemphigoid (BP) is an autoimmune, chronic and limited disease with the formation of blisters, mainly in the elderly, of all races
IgG autoantibodies have been identified and are directed against 230 KD and 180 KD antigens, designated respectively as BP 230 Ag1 and BP 180 Ag2. BP 230 is on the intracellular hemidesmosome plaque and 180 BP is a transmembrane glicoprotein, whose extracellular domain goes beyond the lamina lucida on the basement membrane zone, corresponding to filament anchorage.
CLINICAL MANIFESTATIONS
The disease is clinically characterized by the combination of erythematous maculas, wheals, plaques, vesicles, large tense blisters, and areas of erosion. Lesions are generalized and can affect the skin of joints and skin folds. Lesions of the mucous membranes (usually oral) occur in 10 to 30% of the cases and generally heal, but there may be pigmented lesions and miliums.6,63 Lesions are usually located on the extensor surface of limbs, head and neck. In the erythematous variety, maculas and erythemas predominate. There is also a vesicular variant, with clinical and histopathological lesions similar to dermatitis herpetiformis. 6,63
In the early stages of the disease there may be unspecific manifestations with intense pruritus, excoriations, with absence of blisters, initial or pre-64bullous phase of BP, and it is extremely difficult to establish the diagnosis in this phase. Hofmann SC, et al1, investigating the presence of antibodies against antigen BP180 and a group of elderly patients with pruritus of unknown cause, demonstrated that 3/25 (12%) presented antibodies against BP180, data which could provide support to the existence of a pre-bullous phase in BP.
The association of BP with neoplasms has been described; however, there are questions as to whether this correlation is real, because these two diseases occur at older age. What has to be done is to find if there are tumors in patients with bullous pemphigoid
Dx—Same but ELISA test have diferent antigens, the 230 and 180 kDa proteins
TREATMENT
In the localized forms, besides local care with cleaning, topic steroids can be used. 6,71 In the traditional forms of the disease, we can use a systemic steroid, like prednisone, at the dose of 1mg/kg/day associated to dapsone, at the dose of 100mg/day. It is preferable to reduce the steroid, keeping dapsone. 6,71 Other treatments can be used, like tetracycline 2g/day associated to nicotinamide 1.5g/day, metotrexate 5 mg/week, azathioprine 2mg/day, cyclophosphamide 2 mg/day, mycophenolate mofetil 25 to 35 mg/kg/day (up to the maximum dose of 3 g/day), cyclosporine 3mg/kg/day, intravenous immunoglobulin 2 mg/kg/month and plasmapheresis.6,71 The use of rituximab has been described for the treatment of refractory cases.
DERMATITIS HERPETIFORMIS (DUHRING DERMATITIS)
Dermatitis herpetiformis (DH) is a disease that is clinically characterized by urticariform lesions and blisters. It was described in 1884 and only in 1966 there were reports of the occurrence of abnormalities on the jejunal mucosa, and later, IgA deposits on the papillary dermis.6,73 It is a chronic bullous disease associated to gluten-sensitive enteropathy (celiac disease), clinical or subclinical in all cases. There is a genetic susceptibility for the manifestation of the disease, as demonstrated by the association between two specific HLAs, namely HLA-DQ2 and HLA-DQ8.6 In this disease, there is presence of IgA in the granular, lumpy, spot-like or fibrillar form along the basement membrane zone (BMZ) and papillary dermis below the BMZ in direct immunofluorescence.66,69 It affects more adults, and is more frequent amongst males. It evolves with episodes and does not compromise the overall status
CLINICAL MANIFESTATIONS
Patients present papulovesicular lesions that, when clustered, have a herpetiform aspect. DH lesions are symmetrically distributed and are located mainly on the external surfaces of elbows and knees, on the front, upper torso, sacral region and buttocks, scapular regions, and may occur in any part of the body. Lesions may look excoriated because of pruritus, which is a feature of DH and can be very intense and usually is not related to the extension of the clinical disease
DIAGNOSIS
The biopsy of the urticated lesion should be done close to blisters and histopathological examination shows subepidermal non-acantholytic vesicle-blisters with neutrophilic inflammatory infiltrate (microabscesses) on the papillary dermis.
Direct immunofluorescence will show IgA deposits of granular, fibrillar or spot-like form, concentrated on the dermal papillae and along the BMZ,69 important for the differential diagnosis with bullous pemphigoid, which presents linear IgG and C3 deposits along the BMZ
Indirect immunofluorescence is negative.
Seric antibodies directed against gliadin (a component of gluten), endomisium (connective tissue around smooth muscles) and tissue transglutaminase are present in the gluten-sensitive disease, and serological assays (IIF, ELISA) should be performed for these autoantibodies, in order to monitor response to treatment and compliance with the gluten-free diet.6,63,74 IgA antibodies against tissue transglutaminase (detected by ELISA) today are considered a serological marker for the diagnosis of DH and celiac disease. Epidermal transglutaminase is regarded as the autoantigen of DH skin lesions and there are cross-reactions between the antibodies that recognize epidermal and intestinal transglutaminases
TREATMENT OF DH
Diet must include a strict restriction to gluten and iodine, which may trigger the disease. We use dapsone at the doses of 100 to 400mg/day, associated or not steroid therapy. Riboflavin may also be associated, at the dose of 5mg, twice a day
Autoimmune Bullous dermatoses - Anais Brasileiros de dermatologia - Scielo
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