Autoimmune bullous dermatoses

Abstracts

Dermatoses bolhosas autoimunes são doenças cuja manifestação cutânea primária e fundamental consiste em vesículas e bolhas. Classificam-se conforme a localização da bolha, em intraepidérmica e subepidérmica. Os pacientes produzem autoanticorpos contra estruturas específicas da pele detectáveis por técnicas de imunofluorescência, immunobloting e Elisa. Os recentes avanços da biologia molecular e celular têm permitido conhecer esses autoantígenos, contra os quais os pacientes se sensibilizam e que estão localizados na epiderme ou na junção dermoepidérmica. São doenças de baixa incidência, porém de elevada morbidade e por vezes letais. O objetivo deste trabalho é revisar e descrever os progressos nos conhecimentos de quatro doenças vésico-bolhosas autoimunes: pênfigo foliáceo endêmico (fogo selvagem), pênfigo vulgar, penfigóide bolhoso e dermatite herpetiforme.

Alergia e imunologia; Dermatite herpetiforme; Dermatopatias vesiculobolhosas; Penfigo; Penfigóide bolhoso

CONTINUING MEDICAL EDUCATION

Autoimmune bullous dermatoses

Paulo R. Cunha^I; Silvia Regina C. S. Barraviera^II

^IFaculty Professor of Dermatology, Faculdade de Medicina de Jundiaí (FMJ), PhD in Dermatology, Universidade de São Paulo, Post-Doctorate Degree, Faculdade de Medicina da Universidade de São Paulo – São Paulo (SP), Brasil. Post-Doctorate, New York University – New York (NY), USA

^IIAssistant Professor, Department of Dermatology and Radiation Therapy, Faculdade de Medicina de Botucatu (FMB) – São Paulo (SP), Brazil

Mailing Address

ABSTRACT

Autoimmune bullous dermatoses are diseases in which blisters and vesicles are the primary and fundamental types of skin lesion. Their classification is based on the location of the blister: intraepidermal and subepidermal. Patients produce autoantibodies against self-specific structures of the skin detectable by immunofluorescence techniques, immunoblotting and ELISA. Recent advances in molecular and cellular biology have brought to knowledge these self-antigens, against which patients are sensitized, and which are found in epidermis or in the dermo-epidermal junction. These are low incidence, but high morbidity diseases that may be fatal. The aim of this article is to review and describe the progress of four autoimmune vesiculobullous disorders: endemic pemphigus foliaceous (wild fire), pemphigus vulgaris, bullous pemphigoid and dermatitis herpetiformis.

Keywords: Allergy and immunology; Bullous pemphigoid; Dermatitis herpetiformis; Pemphigus; Skin diseases vesiculobullous

INTRODUCTION

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.

HISTORY AND EPIDEMIOLOGY

The first record of WF in Brazil was Paes Leme's, in a thesis submitted to the School of Medicine of Rio de Janeiro in 1903.¹ Along the 1930's, the number of WF cases increased significantly in the State of São Paulo. ^2,3 Epidemiological studies show that the incidence of WF tends to go down, a fact related to the improvement of living conditions in the populations, as seen in the State of São Paulo.^4,5 Today, the main foci of the disease are located in the States of Goiás, Federal District, Mato Grosso, Mato Grosso do Sul, Minas Gerais, Paraná, and São Paulo.⁶ These epidemiological aspects suggest it is a disease triggered by an environmental agent.⁷

PATHOGENESIS

When studying the etiology of WF, it is inevitable to consider three factors: the immunologic, genetic and environmental. WF is an autoimmune disease of unknown cause, provoked by pathogenic antiepithelial autoantibodies, responsible for the phenomenon of acantholysis. The autoantibodies are of the immunoglobulin G (IgG) type, with a predominance of subtype IgG4.⁸8 They can be detected in serum through the technique of indirect immunofluorescence assay (IIF) and its levels correlate directly with the extension and activity of the disease.^5,9-11 In this manner, WF is an autoimmune and, at the same time, endemic disease. The autoantigen against which the antiepithelial antibodies react is desmoglein 1 (Dsg1), a molecule of the cadherin family, which comprise desmosomes, a transmembrane glicoprotein with an intracellular part (endodomain) and many extracellular domains (ectodomains - EC). WF autoantibodies have been shown to react against ectodomains EC1 and EC2, which are the extracellular domains of Dsg1 furthest away from the cellular membrane. ⁶

Recent studies have demonstrated that the prevalence of autoantibodies against Dsg1 is also high amongst normal individuals living in wild fire endemics areas, suggesting that the production of these autoantibodies against Dsg1 may be triggered by exposure to an unknown agent in the environment. No infectious agent or vector has been identified for the disease yet.¹² There is deposit of antibodies on the mucosa, but without blisters, in patients with WF.¹³

In addition to the well-defined concept about the role of humoral immunity through the pathogenicity of IgG4 subclass antibodies against Dsg1, it has been demonstrated that T lymphocytes of patients with WF present proliferative responses when exposed to the ectodomain of recombinant Dsg1 produced by the baculovirus expression system, thus proving the involvement of cellular immunity in the process. ^14,15

As to possible etiologies, the genetic factor is important, and there is a strong association between WF and four specific HLA-DRB1, namely DRB1 0404, 1402, 1406 and 1404.¹⁶

Simuliidae have been mentioned as agents that could trigger WF in immunogenetically susceptible people. A case-control study indicates bites of winged insect as a risk factor (odds ratio: 4.7, p<0.001) in a questionnaire for case-control patients.¹⁷

Another potential etiological agent for WF could be nutritional factors, but the only study conducted¹⁸ was nonconclusive.

The possibility that the ingestion of toxic substances that might be present in the water consumed by genetically predisposed individuals is a hypothesis¹⁹ that lacks experimental data and further studies to prove it.

Recent studies show that the serum of patients with leishmaniasis, oncocercosis and Chagas disease, as well as normal people living in endemic areas or patients in remission, have significant titers of anti-Dsg1 autoantibodies restricted to the EC5 domain of Dsg1 molecule, suggesting that the antigens of arthropodes may have a cross-reaction with epidermal Dsg1, thus triggering the formation of autoantibodies in individuals exposed to these arthropodes. These findings provide strong evidence of the possible role of insects in the pathogenesis of WF. All these diseases are produced or transmitted by hematophage insects. There is a hypothesis that one component in the saliva of the vector insect, more than the parasite itself, may trigger the response of antibodies against EC5. In people with a known susceptibility HLA and living in endemic areas, a response to domain EC1-2 may develop subsequently by epitope spreading, with clinical signs associated to WF.²⁰

CLINICAL ASPECTS AND CLASSIFICATION

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.

LABORATORY DIAGNOSIS

1) Histopathology

Figure 2²¹²³

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. Cunha5 found that the value of WF autoantibody titers is correlated to the extension of the disease, in that titers are greater in the generalized forms than in localized forms. Cunha5 and Squiquera et al,²⁷ using normal human skin as substrate for IIF, conducted a seroepidemiological study focusing on endemic WF and found the absence antiepithelial WF autoantibodies in blood-related relatives, cohabitants and neighbors of the patients living in endemic areas. Cunha et al.,²⁸ studying though IIF the fluorescence pattern of the serum of 23 patients with WF against normal human skin found that 83% of the patients reacted to intercellular antigen(s) present on the superficial layer of the epidermis, in a distribution identical to that of the Dsg1 pattern by AE23 monoclonal antibody. However, the antibodies of 17% of the patients reacted to antigen(s) equally expressed in all layers of the epidermis, including deep layers, where Dsg1 cannot be detected (Figure 3). They concluded that the results indicate that the response of antibodies against the skin of patients with WF is more complex than we currently believe. In some patients, autoantibodies are directed to antigens that differ from Dsg1 in their distribution in the epidermis.

3) Immunoblotting (IB)

It is a technique in which protein is extracted from normal human epithelium, after the solubilization and separation of these proteins through electrophoresis and their transfer to nitrocellulose paper. These proteins are tested against the serums of sick people. The antibodies of pemphigus vulgaris (PV) react to 130kD antigen while WF's do so against the 160kD antigen (Figure 4).

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. Cunha et al.,³⁰ in a study comparing the sensitivity of indirect immunofluorescence and ELISA for the detection of intercellular antibodies in WF, demonstrated that the antibodies of patients with WF were detected more frequently by the ELISA (rDsg1) in 91% of the cases, while positivity with indirect immunofluorescence was 81%. In this same study, the authors concluded that, although previous studies associated Dsg3 with pemphigus vulgaris, 12% of the patients with WF also have antibodies against Dsg3. Furthermore, they concluded that we do not have an assay with 100% accuracy to differentiate WF from PV. Anti-Dsg3 antibodies were detected in 53/146 (36%) of the normal individuals living in a WF endemic region.³¹

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). In the dose reduction period, topic or even intralesional steroids can be used. If there are signs of secondary bacterial infection, systemic antibiotics are used and baths with potassium permanganate diluted in water at 1/40.000 can be used. Even with negative parasitological feces examination, it is convenient to prescribe antiparasite medications, especially those effective against strongyloids, which may disseminate with steroid therapy.

During the treatment of WF, it is necessary to order the complementary tests necessary to ensure absolute control of the undesirable effects of steroid therapy.

As therapy alternatives, there are immunosuppressants like azathioprine and cyclophosphamide, at the usual doses of 50 to 100mg per day, but they are little effective in WF.6 When there is no improvement with systemic steroid therapy, it is possible to associate mycophenolate mofetil at the dose of 35-45mg/kg/day (maximum dose 3g/day). According to the personal experience of the author, chloroquine diphosphate, at the dose of 250mg per day, may also be used as a therapy alternative, preferably when lesions are in areas exposed to sunlight. The author also recommends the association of tetracycline at the dose of 2,0 grams per day, nicotinamide, at the dose of 1.5 grams per day, and 100mg per day of sulfona. All these alternative treatments can be used concomitantly with systemic steroids, as adjuvants and to save steroids. In addition to these orientations, sun protection should be used, because ultraviolet light may induce the formation of blisters, as the sun is one of the most important environmental factors for the development and worsening of WF.

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. Recent studies have shown that patients with PV with lesions chiefly on mucosa membranes have only anti-Dsg3 antibodies. Later, with the progression of the disease, involving mucosa membranes and skin, these patients also develop antibodies against Dsg1. These recent findings have led to the classification of PV as mucous PV and mucocutaneous PV. In the mucous form, patients only have 130kD anti-Dsg3 antibody, and later, when lesions also develop on the skin (mucocutaneous), they have antibodies against both Dsg1 and Dsg3.^41-43 The blisters in PV result from the loss of cohesion of keratinocytes (acantholysis), very much likely as a consequence of the interference on the adherence function of the desmosomal protein, through circulating anti-desmoglein antibodies.⁴⁴

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.^46,47 Cunha et al. described the case of one PV patient with involvement of the cervix, who did not respond to conventional treatments (Figure 6), and was successfully treated with thalidomide (100mg/day). ⁴⁸

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 (Figure 7). The histopathology of pemphigus vegetans is similar to that of PV; however, in that form, there is papillomatosis and acantholysis, with occasional formation of intra-epidermal eosinophilic abscesses.⁵¹ The course of the disease is long, with remission and recurrence periods. One of the complications is the frequent secondary bacterial infection of PV and there may be malnutrition and cachexia.

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.

DIFFERENTIAL DIAGNOSIS

All other forms of pemphigus and other bullous diseases should be ruled out, such as bullous pemphigoid, mucous membrane pemphigoid and acquired epidermolysis bullosa.

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. Monthly applications should be kept until clinical remission, and then the intervals between infusions should be reduced to ^{6, 8, 10, 12, 14} weeks and treatment should be discontinued after clinical remission with interval above 16 weeks.^56,57 There are recent reports of treatment of severe cases resistant to other therapies with Rituximab (antiCD20 chimeric monoclonal antibody) at the dose of 375 mg/mµIV weekly, during 4 consecutive weeks. The treatment is well tolerated, with reports of prolonged remission of the disease with a single treatment cycle. The adverse events associated to infusions are nausea, fever, chills, hives, pruritus, hypotension, and headache.⁵⁸

Sulfona, at the dose of 100mg/day, can be indicated in mild cases and mainly to keep the patient in remission. The reduction of steroid doses should be very slow and should start after lesions are completely healed. It is recommendable to provide treatment for strongyloidiasis, even when the parasitological feces test is negative in patients with PV treated with steroids. PV patients should use sun protection because lesions can exacerbate with ultraviolet light.⁵⁹ Pregnancy may trigger or worsen PV.^60,61

In conclusion, the near future indicates that biological treatment may become the first choice for the treatment of severe PV, thus avoiding the use of high doses of steroids and immunosuppressant therapies.

BULLOUS PEMPHIGOID

Bullous pemphigoid (BP) is an autoimmune, chronic and limited disease with the formation of blisters, mainly in the elderly, of all races. Some childhood cases also have been described⁶²62 (Figure 8). Cases occur sporadically and there is no evidence that there is a genetic component triggering the disease. ⁶³

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 anchorage⁶ (Figure 9).

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.⁶⁵

HISTOPATHOLOGY

The histopathology of BP shows non-acantholytic subepidermal blisters, intact epidermis and dermal inflammation. The inflammatory infiltrate is formed by lymphocytes, histiocytes, and the presence of eosinophils is suggestive of the disease. ^66,67

DIAGNOSIS

The clinical status, histopathology and direct and indirect immunofluorescence indicate diagnosis.

Direct immunofluorescence will show IgG and complement deposits on the basement membrane zone, with IgG in about 90 to 95% of the cases and C3 in 100% of the cases. IgG deposits are rarely present in the absence of C3, but the presence of IgA, IgM, IgE have been described.⁶⁶

In indirect immunofluorescence, we find IgG, subclass IgG4, important for the differential diagnosis of bullous pemphigoid from other dermatoses, like, for example, herpes gestationis, cicatricial pemphigoid, acquired epidermolysis bullosa, bullous systemic lupus erythematosus, dermatitis herpetiformis, and linear IgA dermatosis.⁶⁸

Electronic immunomicroscopy will show IgG deposits on the lamina lucida and hemidesmosomes on the basement membrane zone (BMZ).⁶⁹

To differentiate bullous pemphigoid from acquired epidermolysis bullosa (AEB) in indirect immunofluorescence, the technique of dermo-epidermal separation with NaCl (split skin) can be used; in these cases, fluorescence predominates on the top in cases of BP, and in AEB, it is on the floor.⁶⁹

Today, ELISA is already commercially available to detect BP circulating antibodies, against antigens BP180 and BP230. It is a convenient and easy to execute test, which can be useful to predict recurrences of the disease after the interruption of therapy.⁷⁰

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.⁷²

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. It affects individuals between 30 and 40 years of age, and is common among patients with celiac disease.⁷³ Although the relation between skin and intestine has not yet been well established, with a gluten-free diet, lesions improve considerably.^73,74

For most of the patients, it is a chronic disease, with periods of improvement.

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. Mucosas are not usually affected.^6,73,74 Other signs can follow DH, like anemia, osteopenia, osteoporosis, dental problems, infertility, miscarriages, and its association with other autoimmune diseases is very common.

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 (Figure 10).

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.

Patients with DH and celiac disease present an increased risk to develop gastrointestinal lymphoma and a gluten-free diet may protect against this risk.

In the differential diagnosis, one should consider the following conditions: pemphigoid, linear IgA dermatitis, neurotic excoriation, scabies, eczemas, insect bites, and polymorphic erythema.

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.⁷⁴

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*

Trabalho realizado na Faculdade de Medicina de Jundiaí (SP) – Brasil.

Publication Dates

• Publication in this collection
  03 June 2009
• Date of issue
  Apr 2009

History

• Received
  19 Dec 2008
• Accepted
  19 Dec 2008