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Fogo selvagem (Brazilian endemic pemphigus foliaceus)

Fogo selvagem (Brazilian endemic pemphigus foliaceus)
Literature review current through: May 2024.
This topic last updated: Feb 14, 2022.

INTRODUCTION — Endemic pemphigus foliaceus is a variant of pemphigus, a group of autoimmune intraepithelial blistering skin diseases characterized by keratinocyte detachment (acantholysis) and consequent intraepithelial blister formation. Endemic pemphigus foliaceus primarily occurs in Brazil, where it is known as fogo selvagem (FS). Other major subtypes of pemphigus include nonendemic pemphigus foliaceus, pemphigus vulgaris, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

Similar to nonendemic pemphigus foliaceus, the pathogenesis of FS involves the formation of autoantibodies against desmoglein 1 (Dsg1), a transmembrane glycoprotein integral for cell-to-cell adhesion in the superficial epidermis. Environmental and genetic factors also likely contribute to the development of FS. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pathogenesis'.)

FS and nonendemic pemphigus foliaceus have similar clinical manifestations, both presenting with a localized or generalized eruption of superficial, flaccid vesicles and bullae, erosions, and skin erythema (picture 1A-B). The pathologic findings of these conditions are also similar, demonstrating subcorneal acantholysis and blistering in the epidermis. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Clinical features' and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Histopathology'.)

The pathogenesis, clinical manifestations, diagnosis, and management of FS will be reviewed here. Other variants of pemphigus are reviewed separately.

(See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

(See "Initial management of pemphigus vulgaris and pemphigus foliaceus".)

(See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

(See "Paraneoplastic pemphigus".)

HISTORY AND TERMINOLOGY — FS was first reported in Brazil in 1903 and was initially misdiagnosed as a dermatomycosis known as "tinea imbricata" or "Tokelau" [1]. "Fogo selvagem" is a Portuguese term that translates to "wild fire." The term reflects the skin discomfort that often occurs in FS. (See 'Clinical presentation' below.)

EPIDEMIOLOGY — Endemic sites of FS are concentrated in rural areas of Brazil, with a geographic distribution that varies over time [2]. The disease is most prevalent in the southeastern and midwestern regions of the country, and the main foci follow the course of rivers. FS occurs in both children and adults and most often begins during young adulthood. There is no sex predilection, and familial clustering is common [2-4].

Outside of endemic areas, pemphigus foliaceus is rare. In contrast, the prevalence of FS is estimated to be 3 percent in the Amerindian reservation of Limão Verde in the state of Mato Grosso do Sul in Brazil, a region considered to have one of the highest prevalence rates for FS [5]. Long-term data suggest urbanization of rural areas is associated with a reduction in the prevalence of FS [4,6].

Minor clusters of endemic pemphigus foliaceus have been described in other South American countries and Tunisia [7-9]. In contrast to the even sex distribution in FS, reports of endemic pemphigus foliaceus from Colombia and Tunisia demonstrate a predominance of females [8,9].

PATHOGENESIS — The pathogenesis of FS involves the production of pathogenic autoantibodies that trigger detachment of epidermal keratinocytes (acantholysis) [10-12]. Environmental and genetic factors may also be important contributors.

Autoimmunity — Studies demonstrating that passive transfer of total immunoglobulin G (IgG) or the immunoglobulin G4 (IgG4) fraction of anti-desmoglein 1 (anti-Dsg1) autoantibodies from sera of individuals with FS into neonatal mice induces a blistering eruption that mimics FS support a key role for autoantibodies targeting Dsg1 in the pathogenesis of FS [11,13]. Dsg1 is a transmembrane glycoprotein in the cadherin family that is integral for keratinocyte-to-keratinocyte adhesion and the primary autoantigen implicated in the development of both FS and nonendemic pemphigus foliaceus (figure 1) [14,15]. Dsg1 is primarily located in the upper layers of the epidermis, which correlates with the superficial location of blistering that is characteristic of pemphigus foliaceus.

The mechanism through which autoantibodies targeting Dsg1 lead to keratinocyte detachment involves disruption of the binding interaction between Dsg1 and other desmosomal proteins called desmocollins, impairing adhesive function (figure 1) [12]. Specifically, IgG4 anti-Dsg1 autoantibodies recognize a calcium-dependent, conformational epitope located on the extracellular 1 (EC1) domain of Dsg1 [16,17]. Autoantibodies to EC5, another extracellular domain of Dsg1, can be found prior to the onset of disease in patients who subsequently develop FS as well as in patients in remission from FS and are not considered pathogenic [17].

Pathogenic IgG4 anti-Dsg1 autoantibodies that recognize EC1 may induce acantholysis through two possible mechanisms. Direct binding of the autoantibodies to the EC1 epitope may impair the heterophil interaction of Dsg1 and desmocollins through steric hindrance, triggering cell detachment [12,18]. The second proposed mechanism involves autoantibody binding to Dsg1, triggering intracellular signaling pathways that lead to cell detachment [19].

A rise in IgG4 anti-Dsg1 autoantibodies may predict the development of clinical findings of FS [16,20]. A study in Limão Verde, Brazil, that assessed serum from five patients with FS both before and after the onset of clinical disease found more than a 100-fold rise in the mean level of IgG4 anti-Dsg1 autoantibodies at the onset of clinical disease [16]. In addition, subclass switching from immunoglobulin G1 (IgG1) to IgG4 anti-Dsg1 autoantibodies was associated with a transition from remission of FS to active disease.

IgG1 anti-Dsg1 autoantibodies are nonpathogenic autoantibodies that target the EC5 rather than the EC1 domain of Dsg1 and have been found at similar levels in inhabitants of endemic areas with and without FS [16]. Nonpathogenic autoantibodies contribute to the relatively high prevalence of anti-Dsg1 autoantibodies in unaffected individuals in endemic areas. In a study in Limão Verde that did not assess the subclass of IgG anti-Dsg1 autoantibodies, 51 of 93 individuals (55 percent) without FS had these autoantibodies [21].

Immunoglobulin M (IgM) and immunoglobulin E (IgE) anti-Dsg1 autoantibodies are also common in patients with FS and may be a marker of exposure to an environmental trigger [22,23]. In support of this theory, a study found that in the United States and Japan, IgM anti-Dsg1 autoantibodies were much less prevalent in healthy individuals and individuals with nonendemic pemphigus foliaceus than in healthy and FS populations in Limão Verde [23]. In addition, a correlation between levels of IgE anti-Dsg1 autoantibodies and IgG4 anti-Dsg1 autoantibodies has been detected in the sera of patients with FS, similar to the correlation seen between IgE and IgG4 antibodies in response to allergens [22].

T cells may play a supportive role in the autoantibody response in FS. T cells that recognize epitopes on the ectodomain of Dsg1 have been detected in affected patients [24]. These T cells exhibit a CD4+ memory T cell phenotype, produce a T helper type 2 (Th2)-like cytokine profile (interleukins 4, 5, and 6), and are postulated to contribute to FS through stimulating B cell production of anti-Dsg1 autoantibodies. Expression of human leukocyte antigen (HLA)-DR molecules on antigen-presenting cells appears to be necessary for the proliferation of these T cells in response to Dsg1 [24].

Environment — Environmental factors are postulated to contribute to FS based upon the epidemiology of the disease and the evidence suggesting an immunologic trigger. Exposure to hematophagous insects in endemic areas is considered the most likely environmental risk factor [25-27].

In support of the environment as a trigger, FS occurs in subtropical communities in which open-reed and thatched-roof dwellings are common and nearby rivers and streams are infested with a variety of hematophagous insects, such as black flies (Simulium spp), sandflies (Lutzomyia longipalpis), and kissing bugs (Triatoma spp) [2,28,29]. Moreover, IgG4 anti-Dsg1 autoantibodies cross-react with LJM11 and LJM17, sandfly salivary proteins, suggesting that such proteins could be antigenic triggers [30,31].

Sun exposure may also play a role in the pathogenesis of FS. Ultraviolet B (UVB) radiation-induced acantholysis has been demonstrated in uninvolved skin in patients with FS [32].

Genetic susceptibility — Familial occurrences of FS are common, suggesting a role for genetic susceptibility to the disease [2,5,28].

HLA alleles associated with susceptibility to FS include HLA-DRB1-0404, 1402, and 1406. The same amino acid sequence (LLEQRRAA) has been detected in the third hypervariable region of the DRB1 gene of these alleles, suggesting an important role for this amino acid sequence [33].

Polymorphisms in the CD59 gene that contribute to higher transcriptional levels of CD59 are additional proposed genetic contributors to susceptibility to FS [34]. The CD59 glycoprotein is an essential complement regulator that impacts signal transduction and activation of T lymphocytes.

Single nucleotide polymorphisms in long noncoding RNA genes are also proposed risk factors [35].

CLINICAL PRESENTATION — The dermatologic findings of FS are indistinguishable from nonendemic pemphigus foliaceus. The primary skin lesions are superficial, flaccid vesicles and bullae. Associated erosions and underlying erythema are often also present. Mucous membranes are characteristically spared. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus'.)

Skin involvement may be localized or generalized. The face, neck, scalp, and upper trunk are common sites for localized disease [3,36,37]. Generalized FS presents with a widespread, blistering eruption (bullous invasive FS) or exfoliative erythroderma with diffuse erythema, scaling, and crusting [3,37,38]. Associated pruritus, burning sensations, or skin pain is common in both localized and generalized disease.

The onset of FS is typically gradual, with slow, progressive development of lesions occurring over weeks to months. Rare patients develop an acute, fulminating disease in which widespread blistering occurs over one to three weeks [39]. Persistent disease may evolve to demonstrate subacute and chronic features, including hyperpigmented, hyperkeratotic, verrucous papules and plaques that resemble seborrheic keratoses (picture 2) [3,4,36,37].

Rare clinical variants include tinea imbricata-like FS and pemphigus herpetiformis (also known as herpetiform pemphigus). Tinea imbricata-like FS presents with blister formation in a circinate or annular pattern and scale at the site of ruptured blisters, resembling the superficial fungal infection tinea imbricata (picture 3). The pemphigus herpetiformis clinical variant demonstrates blistering in a herpetiform pattern (picture 4) [40]. (See "Dermatophyte (tinea) infections", section on 'Tinea imbricata'.)

DIAGNOSIS — The diagnostic approach to FS involves confirmation of pemphigus foliaceus with the detection of consistent clinical, histologic, and immunopathologic findings.

The clinical, histologic, and immunopathologic findings in FS are similar to those of nonendemic pemphigus foliaceus. There is no definitive way to distinguish FS from nonendemic pemphigus foliaceus, except that FS occurs in individuals residing in certain endemic areas of Brazil. There is also absence of evidence of an alternative cause, such as drug-induced pemphigus foliaceus (table 1). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Drug exposure'.)

Our approach — FS should be suspected in individuals from endemic areas of Brazil who develop erythematous, scaly, or crusted plaques and shallow erosions, particularly on the head, neck, or upper trunk or in a generalized distribution. Our typical approach to confirm the diagnosis if suspicion for FS remains after the clinical assessment is as follows:

A lesional skin biopsy for routine hematoxylin and eosin (H&E) staining

A perilesional skin biopsy for direct immunofluorescence (DIF)

The presence of clinical, histologic, and DIF findings consistent with pemphigus foliaceus confirms this diagnosis. (See 'Routine histopathology' below and 'Direct immunofluorescence' below.)

Serum testing with enzyme-linked immunosorbent assay (ELISA) to detect desmoglein 1 (Dsg1) or indirect immunofluorescence (IIF) to detect autoantibodies that bind to the surface of epidermal keratinocytes are additional tests that can provide support for the diagnosis. However, in isolation, a positive serum test cannot confirm a diagnosis of FS given that many individuals without FS in endemic areas also have anti-desmoglein 1 (anti-Dsg1) autoantibodies. (See 'Autoimmunity' above.)

History and physical examination — The patient history serves to identify characteristics consistent with FS and should include assessment of the onset and course of disease, associated symptoms, medications, and history of residence in an endemic area. FS most often develops in individuals living and working in rural areas of endemic regions, such as subsistence farmers.

FS most often presents with a slow onset of blistering and erythema over weeks to months and skin pain, pruritus, or burning sensations in involved areas. Onset is often, but not exclusively, in young adulthood. Patients may also report exacerbations associated with sun exposure. A medication review allows for the identification of patients who may have drug-induced pemphigus foliaceus rather than FS (table 1). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Drug exposure'.)

A full skin examination should be performed to identify lesions consistent or inconsistent with FS and to determine the extent of disease. An absence of erosions should raise suspicion for an alternative diagnosis. Mucous membranes should be carefully examined; mucosal involvement does not occur in FS. (See 'Differential diagnosis' below.)

Skin biopsy — Skin biopsies for routine histopathologic examination and DIF are important for the diagnosis of FS and should be performed whenever feasible.

Routine histopathology — The specimen for histopathologic examination should be taken from lesional skin (ie, an area of active blistering). A 4 mm punch biopsy is typically sufficient. Ideally, the specimen should include a portion of a blister and immediately adjacent, erythematous skin. For blisters smaller than the punch tool diameter, the entire blister can be included in the specimen.

The pathologic findings of FS are similar to nonendemic pemphigus foliaceus. Subcorneal or intramalpighian cleavage and acantholysis are the key findings. Additional features may include eosinophilic spongiosis or an eosinophilic dermal infiltrate.

Direct immunofluorescence — In contrast to biopsies for routine histopathologic examination, biopsies for direct immunofluorescence (DIF) should be taken from perilesional skin (ie, normal-appearing skin adjacent to a pemphigus lesion). A 4 mm punch biopsy is usually sufficient.

Specimens for DIF should not be placed in formalin. Options for transport include Michel's medium, Zeus medium, or saline. Appropriate handling of specimens for DIF is reviewed separately. (See "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)

The DIF finding consistent with FS is IgG deposition in epidermal intercellular spaces (picture 5). This finding is estimated to be present in 90 to 100 percent of patients [41]. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Direct immunofluorescence'.)

Serology — Serologic tests identify the presence of circulating antibodies to epidermal cell surface antigens. The two primary methods used in clinical practice are ELISA and IIF. Immunoblotting and immunoprecipitation are additional tests that may detect the relevant circulating autoantibodies but are more difficult to perform and are infrequently used in the clinical setting. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Other'.)

Enzyme-linked immunosorbent assay — Enzyme-linked immunosorbent assay (ELISA) tests for pemphigus assess for anti-Dsg1 and anti-desmoglein 3 (anti-Dsg3) autoantibodies in serum. ELISA testing for anti-Dsg1 autoantibodies is considered a highly sensitive test for FS; in one study, 59 of 60 patients (98 percent) with FS tested positive for Dsg1 autoantibodies with ELISA [21]. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Enzyme-linked immunosorbent assay'.)

However, ELISA testing does not distinguish between autoantibodies recognizing pathogenic and nonpathogenic epitopes of Dsg1, and Dsg1 autoantibodies are also common in unaffected individuals residing in or near endemic areas [21]. Therefore, a positive ELISA for anti-Dsg1 alone does not confirm the diagnosis.

The detection of high levels of IgG4 anti-Dsg1 autoantibodies, the pathogenic autoantibodies in FS, has been proposed as a marker of active FS; however, testing that identifies the subclass of IgG anti-Dsg1 autoantibodies is not commercially available. A study in Limão Verde that utilized an ELISA to detect anti-Dsg1 autoantibodies and labeled monoclonal antibodies to distinguish the IgG subclasses found a sensitivity and specificity of testing for IgG4 anti-Dsg1 autoantibodies of 92 and 97 percent [20]. The positive predictive value in Limão Verde, which has a 3 percent prevalence of FS, was 49 percent.

Although the presence of anti-Dsg3 autoantibodies is associated with pemphigus vulgaris, Dsg1 and Dsg3 autoantibodies are detected in a minority of patients with FS; in one study, 9 of 23 patients (39 percent) with FS had both Dsg1 and Dsg3 autoantibodies [42].

Indirect immunofluorescence — A positive indirect immunofluorescence (IIF) for pemphigus foliaceus displays intercellular IgG deposition within the epidermis. Normal human foreskin is the most sensitive substrate for IIF studies for FS.

IIF is estimated to be positive in up to 90 to 100 percent of the patients with FS. Similar to ELISA, evaluation to specifically detect the IgG4 subclass of autoantibodies may enhance the sensitivity of IIF [13,43].

Other — The findings of a Tzanck smear may support a diagnosis of FS through the detection of acantholytic cells. Performance of a Tzanck smear is not necessary for diagnosis and does not confirm the diagnosis. (See "Office-based dermatologic diagnostic procedures", section on 'Tzanck smear'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of FS is broad and dependent upon the clinical manifestations [3,4].

One of the most important conditions to exclude in patients with suspected FS is drug-induced pemphigus foliaceus given that cessation of the causative drug is usually indicated. Drug-induced pemphigus should be suspected in patients receiving medications known to induce pemphigus (table 1). There are no clinical features or tests that definitively distinguish drug-induced pemphigus from non-drug-induced pemphigus. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Drug exposure' and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus vulgaris and pemphigus foliaceus'.)

Additional disorders often in the differential diagnosis of FS are listed below. In general, skin biopsies for histopathologic examination and direct immunofluorescence will distinguish FS from other conditions (see 'Diagnosis' above):

Localized FS – Localized FS may resemble other diseases that present with erythema, scale, erosions, or crusts on the head, neck, or upper trunk, such as seborrheic dermatitis, subacute cutaneous lupus erythematosus, or bullous impetigo:

Seborrheic dermatitis – Seborrheic dermatitis is a common condition in adolescents and adults. Characteristic features include scale and/or erythema with a predilection for the scalp, face, upper trunk, and intertriginous areas (picture 6). Yellowish, greasy scale is a common feature. (See "Seborrheic dermatitis in adolescents and adults".)

Subacute cutaneous lupus erythematosus – Subacute cutaneous lupus erythematosus may occur as an independent disorder or in the presence of systemic lupus erythematosus. Typical clinical manifestations are psoriasiform or annular, erythematous, scaly plaques on the shoulders, neck, arms, or upper trunk (picture 7). Rare vesicobullous presentations can occur. (See "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)

Bullous impetigo – Bullous impetigo is a Staphylococcus aureus infection characterized by the development of flaccid bullae that rupture easily, leaving well-demarcated, erythematous erosions with collarettes of scale and crusting (picture 8). The infection most often occurs in young children. (See "Impetigo".)

Generalized FS – Generalized FS presenting as exfoliative erythroderma should be distinguished from erythroderma of other causes, such as psoriasis, drug exposure, atopic dermatitis, and cutaneous T cell lymphoma. The diagnostic approach to erythroderma is reviewed in detail separately. (See "Erythroderma in adults", section on 'Determining the underlying cause'.)

Generalized FS presenting as the bullous, invasive form should be distinguished from pemphigus vulgaris. Histopathology, direct immunofluorescence testing, and enzyme-linked immunosorbent assay (ELISA) testing can differentiate pemphigus foliaceus and pemphigus vulgaris. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus vulgaris and pemphigus foliaceus'.)

Rare variants may also be confused with other entities. Hyperkeratotic FS and tinea imbricata-like FS may resemble extensive seborrheic keratoses and tinea imbricata (picture 9), respectively. FS presenting with features of pemphigus herpetiformis should be distinguished from herpetiform presentations of other blistering disorders, such as bullous pemphigoid and epidermolysis bullosa acquisita. (See "Dermatophyte (tinea) infections", section on 'Tinea imbricata' and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Epidermolysis bullosa acquisita".)

TREATMENT — FS is a chronic, symptomatic, potentially fatal disorder; therefore, treatment to induce remission is generally indicated. Data on the treatment of FS are limited, and therapeutic guidance is primarily based upon the experience of experts in FS and data from nonendemic pemphigus foliaceus.

Similar therapies are used for FS and nonendemic pemphigus foliaceus. Systemic glucocorticoid therapy is the mainstay of treatment for FS.

General approach — The approach to treatment for FS resembles the approach for nonendemic pemphigus foliaceus. Systemic glucocorticoid therapy is the mainstay of treatment. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus".)

Systemic glucocorticoid therapy can have serious adverse effects, such as adrenal insufficiency and osteoporosis, particularly when treatment is prolonged or doses are high. Thus, adjuvant therapies are sometimes incorporated into the treatment regimen in an attempt to reduce dependence on systemic glucocorticoids. (See "Major adverse effects of systemic glucocorticoids".)

Systemic glucocorticoids — Systemic glucocorticoid therapy is the most common initial treatment for FS [39]. Doses for prednisone therapy typically range from 0.5 to 1 mg/kg per day, with the 0.5 mg/kg dose utilized for less severe disease (eg, ≤10 percent total body surface area [TBSA]) and 1 mg/kg per day utilized for severe disease. Similar to nonendemic pemphigus foliaceus, cessation of blistering is expected within two to three weeks, and disease control is often obtained within two months. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Administration'.)

In our experience, FS usually responds to systemic glucocorticoid therapy. Once disease control is achieved, tapering of the systemic glucocorticoid should be attempted. A sample tapering regimen for prednisone therapy for pemphigus is reviewed separately. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Administration'.)

The efficacy of systemic glucocorticoids specifically for FS has not been evaluated in randomized trials. Support for the use of systemic glucocorticoids for FS is based upon extensive clinical experience and trials supporting the efficacy of systemic glucocorticoids for nonendemic pemphigus foliaceus. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Systemic glucocorticoids and adjuvant immunosuppressive therapy'.)

Potential adverse effects of systemic glucocorticoid therapy are reviewed in detail separately. (See "Major adverse effects of systemic glucocorticoids".)

Nonsteroidal adjuvant therapies — As with nonendemic pemphigus foliaceus, adjuvant therapy may be added to glucocorticoid therapy in an attempt to minimize glucocorticoid exposure. Adjuvant drugs are usually added when tapering of systemic glucocorticoids results in disease flares or patients experience adverse events from systemic glucocorticoids.

Mycophenolate mofetil and azathioprine are the most commonly used adjuvant therapies and are administered in a similar manner as in other forms of pemphigus [44]. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Adjuvant conventional immunosuppressive therapies'.)

Side effects of mycophenolate mofetil and azathioprine are reviewed in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Alternative therapies — Alternative initial therapies for FS include topical agents, rituximab, and dapsone.

Clinical experience suggests that medium to high-potency topical corticosteroids (groups 1 to 4 (table 2)) or topical calcineurin inhibitors can be an effective treatment for FS involving small areas of skin (eg, <1 percent TBSA) [39]. Patients who do not respond sufficiently may be transitioned to systemic therapy.

Rituximab may be an alternative first-line treatment based upon benefit demonstrated for pemphigus vulgaris and nonendemic pemphigus foliaceus. However, studies evaluating the effect of rituximab in FS are lacking, and the high cost of this drug inhibits use in most patients with FS. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Rituximab and systemic glucocorticoids'.)

Dapsone is sometimes used as a nonsteroidal adjuvant therapy for pemphigus, particularly for presentations consistent with pemphigus herpetiformis. However, data conflict on the efficacy of this therapy for pemphigus, and its role in the treatment of FS remains uncertain. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Dapsone'.)

Skin care — Ultraviolet radiation may exacerbate FS [32]. Therefore, sun avoidance and use of sun-protective measures during periods of sun exposure is advised for all patients. (See "Selection of sunscreen and sun-protective measures".)

Recommendations for wound care are similar to recommendations for other forms of pemphigus. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Skin care'.)

Refractory disease — The best course of treatment for patients who respond poorly to standard therapy is unclear. Therapies utilized for refractory nonendemic pemphigus foliaceus may be attempted. (See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

PROGNOSIS — FS is a potentially fatal disorder. Death is estimated to occur in 5 to 10 percent of patients with FS or nonendemic pemphigus foliaceus, and mortality prior to the availability of systemic glucocorticoids was estimated to be around 90 percent in patients with generalized disease [2,3].

The major causes of death are complications of prolonged, systemic immunosuppressive therapy and secondary infections. Opportunistic infections, such as Nocardia, cytomegalovirus, Legionella, Listeria, Pneumocystis, Sarcoptes, and Trichosporon inkin, have been reported [45]. Severe herpes simplex virus infections, disseminated Strongyloides stercoralis, or bacterial sepsis can be fatal [4,37,38,45].

Spontaneous remission of FS is estimated to occur in 10 percent of patients, based upon observations prior to the use of systemic glucocorticoids [29,36]. Localized FS may spontaneously resolve, remain stable, or progress to generalized forms [46].

Progression of FS to other autoimmune blistering diseases has been reported (eg, bullous pemphigoid, epidermolysis bullosa acquisita). The phenomenon of epitope spreading, in which an inflammatory process contributes to the exposure and immune recognition of previously hidden antigens, is a proposed contributor [47,48].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pemphigus".)

SUMMARY AND RECOMMENDATIONS

Fogo selvagem (FS) is an autoimmune blistering disease characterized by the development of superficial blisters and an absence of mucosal involvement. FS is an endemic variant of pemphigus foliaceus that occurs in individuals residing in certain regions of Brazil. The disorder often begins during childhood or young adulthood. (See 'Epidemiology' above.)

FS shares immunologic and clinical features with the nonendemic form of pemphigus foliaceus. Like nonendemic pemphigus foliaceus, the pathogenesis involves the production of autoantibodies that target desmoglein 1 (Dsg1), an adhesion molecule integral for keratinocyte-to-keratinocyte adhesion. Immunoglobulin G4 (IgG4) anti-desmoglein 1 (anti-Dsg1) autoantibodies are the primary pathogenic antibodies in FS. (See 'Pathogenesis' above.)

Environmental and genetic factors are postulated to contribute to the development of FS. Exposure to hematophagous insects is considered the most likely environmental trigger. (See 'Environment' above and 'Genetic susceptibility' above.)

FS classically presents with flaccid, superficial vesicles and bullae as well as erosions, erythema, scale, and crusting. The disorder may appear as a localized condition that exhibits a predilection for the face, neck, scalp, and upper trunk or with generalized bullae or exfoliative erythroderma. (See 'Clinical presentation' above.)

The diagnosis of FS involves the recognition of consistent clinical, histologic, and immunopathologic findings. Therefore, skin biopsies for routine histopathologic examination and direct immunofluorescence (DIF) should be performed whenever feasible. Similar to nonendemic pemphigus foliaceus, the characteristic DIF finding in FS is immunoglobulin G (IgG) in the epidermal intercellular spaces. Enzyme-linked immunosorbent assay (ELISA) testing for Dsg1 and indirect immunofluorescence (IIF) studies are additional tests that can support a diagnosis of FS. Drug-induced pemphigus should always be considered in the differential diagnosis of FS. (See 'Diagnosis' above.)

FS is a potentially fatal disorder, and treatment is generally indicated. Most patients require systemic treatment to achieve disease control. We recommend a systemic glucocorticoid as initial therapy (Grade 1B). Because prolonged, systemic glucocorticoid therapy is associated with risk for serious adverse effects, nonsteroidal immunomodulatory drugs are often added at the start of therapy or later in the course of treatment in an attempt to reduce dependence on systemic glucocorticoids. (See 'Treatment' above and 'Prognosis' above and "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Systemic glucocorticoids and adjuvant immunosuppressive therapy'.)

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Topic 110145 Version 6.0

References

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