Fogo Selvagem

Fogo selvagem (FS), or endemic pemphigus foliaceus (PF), is an autoimmune, organ-specific blistering disease, in which autoantibodies specific for desmoglein 1 may lead to acantholysis (ie, cell-cell detachment). Desmoglein 1 is a glycoprotein that belongs to the cadherin superfamily (ie, calcium adhesion molecules present in the desmosomal core). Other target antigens are also postulated to be relevant in the pathogenesis of pemphigus foliaceus.

Pemphigus foliaceus is characterized by clinical involvement of healthy-appearing skin that may blister when rubbed, a finding named after Dr Piotr Nikolsky ^[1] who initially described this finding.

Six types of pemphigus foliaceus exist. Fogo selvagem is an endemic form of pemphigus foliaceus and was formerly known as Brazilian pemphigus foliaceus because it was originally observed in specific river valleys of rural Brazil. It is also reported in Columbia; El Salvador; Paraguay; Peru; and, most recently, in Tunisia. ^[2] A possibly new variant of endemic pemphigus foliaceus with autoantibodies against arrector pili muscle has been described. ^[3]

The epidemiology, age distribution, and human leukocyte antigen (HLA) associations distinguish fogo selvagem from nonendemic pemphigus foliaceus. Fogo selvagem is Portuguese for wild fire. The description wild fire refers to photosensitivity and the common symptom of severe stinging or burning that occurs with ultraviolet (UV) exposure. In fact, in patients with pemphigus foliaceus, exposure to UV-B may induce acantholysis in uninvolved skin. Epidermal exposure to UV light may enhance autoantibody epidermal binding and preferential neutrophil adhesion, which can contribute to acantholysis in endemic pemphigus foliaceus.

Pierre Louis Alphee Cazenave, founder of the first journal dedicated entirely to dermatology, inserted into this journal the first description of pemphigus foliaceus in 1844 in a 47-year-old woman who consulted him at l'Hopital Saint Louis in Paris for a generalized eruption of several years duration.

Bites of black flies, in particular Simulium nigrimanum, may initiate this disorder, possibly due to salivary proteins that contain pharmacologically active compounds. ^[4]

See Pemphigus Foliaceus for more specific information on this topic.

The precise etiology is unknown, but immunogenetic, immunologic, and environmental factors contribute to its pathogenesis. ^[5] It may be due to a pathogenic IgG4 response triggered by hematophagous insect bites. ^[6] A 15-year surveillance of the Limao Verde Amerindian reservation in Brazil has elucidated a preclinical stage linked with IgM anti-Dsg1, IgE, and non-IgG4 autoantibodies against Dsg1 transitioning over years into fogo selvagem with the rise of pathogenic IgG4 anti-Dsg1 autoantibodies. The concept of antigenic mimicry in people genetically predisposed may be pivotal. ^[7] Oxidative stress occurs in disease expression in patients with endemic pemphigus foliaceus. ^[8]

Immunogenetic factors

A strong association between fogo selvagem and class II HLA antigens exists. In one study, 37 (88%) of 42 patients with fogo selvagem had one or both of the HLA DR1 and DR4 genes, whereas these genes were evident in only 22 (34%) of the 64 control subjects. The HLA-DR1-Dw20 (DRB1*0102) gene is related to susceptibility to fogo selvagem, whereas absence of the HLA-DQw2 (DQB1*0201) allele is linked with resistance. Not surprising, familial cases have been described.

A common epitope in the third hypervariable (positions 67-74) of the DRB1 gene is involved in susceptibility to fogo selvagem. It seems that healthy family members of patients with fogo selvagem have the dominant allele HLA-DQw2, which may be protective. Thus, susceptibility and resistance haplotypes may exist in people at risk for fogo selvagem. Differential susceptibility was not found to be associated with polymorphisms at the cytogenetic location 1p13.2. ^[9]

Environmental factors

Fogo selvagem is endemic in certain areas of Brazil (ie, Goias, Mato Grosso, Mato Grosso do Sul, Minas Gerais, Parana, Sao Paulo), and in other parts of Latin America (ie, Paraguay, Colombia, Peru, Bolivia, Argentina, El Salvador, Venezuela ^[10] ). The disease follows the course of streams and creeks and vanishes after urbanization of the endemic areas. ^[11]

Epidemiologic findings indicate that peasants exposed to black fly bites are 4.7 times more likely to develop fogo selvagem than those who were not exposed, as indicated by the odds ratio. A recent study performed at an Amerindian reservation in Mato Grosso do Sul, Brazil, revealed the predominance of a certain black fly species, Simulium nigrimanum. A 2015 study suggested that IgE anti-LJM11 sand fly salivary antigen may facilitate the development of fogo selvagem. ^[12]  A sandfly endemic to parts of Brazil was found to have salivary protein that induces cross-reactive antibodies to pemphigus autoantigen desmoglein 1. ^[13]

A sero-epidemiological study of the Terena reservation of Limao Verde, known to have a high prevalence and incidence of fogo selvagem, suggested that the environmental antigen or antigens triggering the autoimmune response in fogo selvagem may be linked to exposure to hematophagous insects. ^[14]

Epidemiological evidence shows outbreaks in Brazil occurring on the banks of rivers where there is mercury contamination from alluvium gold mining and deforestation. ^[15] A similarity has been observed to pemphigus induced by sulphydryl (SH-) drugs. Thus, chronic methyl mercury poisoning may trigger the onset of fogo selvagem.

Immunologic factors

In the 1960s, the presence of anti–immunoglobulin G (IgG) circulating autoantibodies and in situ autoantibodies was described in patients with fogo selvagem. These autoantibodies were detected by means of indirect and direct immunofluorescence (IF), and intracellular staining was demonstrated within the epidermis. The autoantigen related to EPF is desmoglein 1, a 160-kd glycoprotein of the desmosomal core, targeted by in situ and circulating IgG autoantibodies, mainly of the IgG4 subclass. ^[11]

The IgG fraction from fogo selvagem was shown to be pathogenic by means of passive transfer in BALB/c mice. These animals develop the clinical, histologic, and immunologic features of the human disease within 24 hours after the intraperitoneal injection of human IgG. The predominant IgG subclass in fogo selvagem is IgG4.

Fogo selvagem is mediated by pathogenic antibodies to the EC1-2 domains of desmoglein-1. ^[16] A preclinical phase has been described with antibodies to only EC5. One hypothesis is that a component of insect vector saliva triggers an antibody response to EC-5. In susceptible individuals, a response to the EC1-2 domains may subsequently develop by epitope spreading with development of fogo selvagem. Inflammatory cytokines and apoptosis are also involved. ^{[17, 18]}

Its etiology is unknown, but blister formation appears to be mainly IgG4 mediated. The anti-Dsg1 response in fogo selvagem is probably initiated by sensitization to an environmental allergen, with cross-reactive IgE, IgM, and pathogenic IgG4 anti-Dsg1 responses as their serological markers. ^[19] However, the LJM11 salivary protein of the sandfly is recognized by fogo selvagem antibodies. ^[20] Thus, insect bites provide salivary antigens that initiate a cross-reactive IgG4 antibody response in genetically susceptible individuals, likely to induce fogo selvagem. Accordingly, both desmoglein-1 autoantigen and LJM11 sand fly salivary gland antigen may provide the first antigenic stimulants for the IgG4 autoimmune responses seen in fogo selvagem. ^[21] Higher CD59 transcriptional levels may be related to susceptibility, particularly in women. ^[22]

Burning sensation

The intense cutaneous burning sensation with this disease was evaluated in testing for neural autoreactivity in patients affected by a new variant seen in Colombia. Autoreactivity to neural structures, mechanoreceptors, nerves, perineural cell layers of the arachnoid envelope around the optic nerve, brain structures, and to neuromuscular spindles was detected, with antibodies also colocalized with desmoplakins 1 and 2. These findings may explain the "burning sensation." ^[23]

Long noncoding RNA variants may play a pivotal role in the immunopathogenesis of both endemic and sporadic forms of pemphigus foliaceus. ^[24]

The precise etiology of fogo selvagem is unknown. Familial cases are reported.

Fogo selvagem is endemic in certain areas of Brazil and in other parts of Latin America. Epidemiologic studies indicate that peasants exposed to black fly bites are 4.7 times more likely to have fogo selvagem than those who were not exposed, as indicated by the odds ratio. One study performed at an Amerindian reservation in Mato Grosso do Sul, Brazil, revealed the predominance of a certain black fly species, S nigrimanum. In 1967, Beutner et al ^[25] first reported the presence of anti-IgG circulating autoantibodies or in situ autoantibodies in patients with fogo selvagem. Herpes simplex virus 1 and cytomegalovirus may be associated with pemphigus vulgaris, but are not associated with pemphigus foliaceus disease. ^[26]

Frequency

The incidence of pemphigus foliaceus varies depending on the population studied. Pemphigus foliaceus is rare and sporadic worldwide. In contrast to pemphigus vulgaris, no predominance of pemphigus foliaceus exists in Jews and people of Mediterranean descent. This endemic variety of pemphigus foliaceus occurs with a high frequency in central and southwestern Brazil and in Colombia. The Terena reservation in Brazil, a recently identified focus, has a prevalence of 3.4% of the population. In endemic regions of Brazil, as many as 50 cases per million persons per year are seen. An endemic focus has been found in Tunisia. ^[2] Other foci may be present in the Maghreb; one case was described in Morocco.

In El Salvador, a similar female and age predisposition may also be present. An outbreak was described in 18 men and 3 women in rural Columbia. All were mestizos with an average age of 44 years (range, 22-82 y). Five were relatives. Most worked as farmers or gold miners. ^[27]

In Brazil, patients with fogo selvagem typically reside within 10-15 km of a river or stream, usually in the path of prevailing winds, as one might anticipate with a flying vector. The most likely candidate is a particular black fly, S nigrimanum, the predominant fly species in endemic but not in nonendemic regions in Brazil.

Data suggest patients with fogo selvagem in Peru share epidemiological, clinical, and immunological characteristics with those seen in Brazil and Colombia. ^[28]

Race

Pemphigus foliaceus is described in persons of all races. In contrast to pemphigus vulgaris, no predominance of pemphigus foliaceus exists in Jews and people of Mediterranean descent.

The role of genetic factors is evident in fogo selvagem, which is strongly associated with some HLA-DRB1 haplotypes, including DRB1*0404, DRB1*1402, DRB1*1406, and DRB1*1401. In France, persons with DRB1*0102 and DRB1*0404 have an increased risk for pemphigus foliaceus.

Sex

In general, the prevalence of fogo selvagem in men and women is about equal. However, in the Sousse region of Tunisia, an overwhelming predominance of women seem to be affected. ^[29]

An increased incidence of pemphigus foliaceus was noted in Tunisian women (6.6 cases per million per year), whereas in Western Europe the incidence of pemphigus foliaceus is about 0.5-1 case per million women per year. The annual incidence of endemic pemphigus foliaceus among women in the Sousse region of Tunisia peaks at 15.5 cases per million women aged 25-34 years. In El Salvador, a similar female and age predisposition may also be present. However, an outbreak was described in 18 men and 3 women in rural Columbia; this male predominance is impressive.

Age

The mean patient age of onset of pemphigus foliaceus is approximately 50-60 years. However, pemphigus foliaceus can occur in individuals of any age, from infancy onward. Fogo selvagem affects children and young adults. Fogo selvagem does not seem to cause neonatal fogo selvagem in children of mothers with fogo selvagem.

Fogo selvagem occurs in children and young adults and in their genetically related family members. The mean patient age is about 20-30 years.

The incidence of endemic pemphigus foliaceus among women in the Sousse region of Tunisia peaks in those aged 25-34 years. The incidence in genetically related family members does not appear to be increased.

In El Salvador, a similar age predisposition may be also present. However, in an outbreak in rural Columbia, the average patient age was 44 years (range, 22-82 y).

The average age of Peruvian patients was 31.4 years, with 55% of them being men. ^[30]

With therapy, the prognosis is good. Most patients respond well.

In young patients with fogo selvagem, the characteristics of stunted growth and diffuse cutaneous exfoliation are noteworthy. In patients with poorly controlled fogo selvagem, growth is arrested; this is alleviated by treatment.

This disorder affects young people in their prime, disrupting their academic and vocational pursuits. Personality changes may be manifested by blunted affect.

Azoospermia is described in adults who had fogo selvagem as children; however, some of the drugs used to treat this disease may also be associated with azoospermia.