Pemphigus foliaceus, endemicL10.3

Endemic variant of pemphigus foliaceus (PF), occurring mainly in South America (especially Brazil).

An endemic variant, which is observed in southern Tunisia, is characterized by a significantly higher incidence rate compared to the sporadic form in northern countries, the occurrence mainly in young women and the absence of childhood cases (Masmoudi H et al. 2019).

Endemic in some rural areas along rivers, especially in Brazil, Colombia, El Salvador, Paraguay, Peru, Argentina and Tunisia.

Prevalence: up to 5% of the population of endemic areas.

Occasional sporadic cases have also been described.

Autoimmune disease with formation of IgG4 autoantibodies against desmoglein 1.

Environment: Infectious (viral) genesis, associations with frequently occurring insect bites by Simulium sp. ("black fly"; Simulium nigrimanum) as well as reactions against environment-specific antigens in endemic areas are discussed. In the endemic variants of pemphigus foliaceus (PF) in Brazil and Tunisia, IgG4 antibodies are found against salivary proteins of sand flies that react with desmoglein 1 (Dsg1). The extent to which these salivary proteins play a triggering role in EPF from Brazil (Lutzomyia longipalpis) and Phlebotomus papatasi (P. papatasi) in EPF from Tunisia remains speculative at present. Nevertheless, molecular mimicry and "epitope spreading" are being discussed (Li N et al. 2022).

Genetics: Several genetic polymorphisms and variable expression levels in the leukocyte receptor complex (LRC) have been shown to be associated with this genetic form of pemphigus foliaceus. Several SNPs (single nuclear polymorphisms) are associated with different susceptibility to PF:

• The intergenic variant rs465169, which is located in a region that may regulate several immune-related genes, including VSTM1, LILRB1/2, LAIR1/2, LILRA3/4 and LENG8.
• The SNPs rs35336528 and rs1865097 in the LENG8 and FCAR genes.
• A further four haplotypes with SNPs within the genes KIR3, DL2/3, LAIR2 and LILRB1 have been shown to be associated with PF. These polymorphisms occur in genes involved in B cell development and antibody production (Farias TDJ et al. 2019)

Different clinical pictures depending on the severity of the disease. There are always flat, rapidly bursting blisters, so that disseminated small-area erosions may predominate. With prolonged persistence, large plaques with blisters, erosions, coarse lamellar scaling, flat crusts. Burning of the skin ("wild fire").

No mucositis!

Transition to secondary erythroderma possible after years (see illustration). This is characterized by coarse lamellar scaling and extensive erosions.

Polymorphic pictures are usually found, which are characterized by the simultaneous occurrence of bullous, papillomatous, verruciform, pustular and sometimes hyperpigmented skin changes.

Nikolski phenomenon I always positive.

See below Pemphigus foliaceus. Acantholytic blistering. Nonspecific inflammatory infiltrates in the upper dermis.

In active disease, there are always detectable deposits of IgG and/or C3 in the intercellular spaces of the epidermis. The biopsy must be taken from apparently normal skin in the vicinity of the FS lesion.

A complete blood count, creatinine, serum sodium and potassium, alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase, alkaline phosphatase, serum proteins, blood glucose, hepatitis B and C serology, HIV serology and a chest X-ray should be ordered before starting treatment. Additional recommendations include exclusion testing for IgA deficiency before administration of intravenous immunoglobulin, determination of thiopurine methyltransferase enzyme activity before administration of azathioprine, abdominal ultrasound (optional), tuberculin skin test or quantiferon TB test if TB risk is high, glucose-6-phosphate dehydrogenase deficiency, bilirubin level and reticulocyte parameters before dapsone; β-HCG test to rule out pregnancy, bone mineral density before corticosteroid therapy and ophthalmologic examination to rule out glaucoma and cataract. In addition to coproparasitology, prophylaxis against strongyloidiasis is recommended.

In localized forms with a limited number of lesions (up to 1 % of the body surface), topical corticosteroids (with medium to high potency), intralesional corticosteroids (triamcinolone acetonide 2-3 mg/ml) or calcineurin inhibitors are used. In conjunction with topical therapy, dapsone may be prescribed at a dosage of 50-100 mg per day. In some patients, low-dose prednisone (0.25 mg/kg/day) may be prescribed.

Systemic corticosteroids (prednisone/prednisolone) are prescribed at a dose of 0.5 mg/kg/day if topical treatment is not sufficient to control disease activity or if the skin condition worsens with an increase in lesions. In severe disseminated forms, the dose is 1 mg/kg/day prednisone or prednisolone. Systemic corticosteroid therapy is still the most commonly used and recognized treatment option.

The early addition of "corticosteroid-sparing drugs" such as methotrexate, azathioprine and mycophenolate mofetil is important. When choosing an adjuvant therapy, the availability, costs and side effects of the medication must be taken into account.

Immunosuppressants (adjuvant therapy of first choice):

• Optimal adjuvants are azathioprine and mycophenolate mofetil. Azathioprine (AZA) is used at a dose of 1-3 mg/kg/day, starting at 50 mg/day and gradually increasing; if possible, thiopurine methyltransferase activity should be checked before starting treatment, as low concentrations of the drug may affect the bone marrow. Mycophenolate mofetil (MFM) or mycophenolic acid is administered at a dose of 2 g/day, starting at 1 g/day and increasing by 500 mg/week to improve gastric tolerance. This is an excellent but expensive option.
• Methotrexate (MTX) is an interesting option due to its low cost and easy availability, but is hepatotoxic. It is administered at a dose of 7.5 to 25 mg/week for one day or two consecutive days. After 24 hours, folic acid must be prescribed at a dose of 5 mg. Alcohol, sulphonamides and allopurinol must not be used at the same time.
• In mild forms, dapsone (DDS) 100 mg/day or up to 1.5 mg/kg/day can be used as it also has a corticosteroid-sparing effect; however, glucose-6-phosphate dehydrogenase (G6PD) activity should be checked beforehand. The efficacy of dapsone in this disease is controversial.
• Cyclophosphamide at a dose of 500 mg IV bolus or 2 mg/kg/d has a corticosteroid-sparing effect, but the possibility of sterility, hemorrhagic cystitis and secondary malignant neoplasms should be considered.

Alternative:

• Rituximab (anti-CD20 monoclonal antibody) is indicated if the patient has previously failed to respond to treatment or if prednisone is required in doses greater than 100 mg/day in conjunction with immunosuppressive therapy for more than 6 months. It has been used as pulse therapy at a dose of 1 g i.v., repeated after 15 days (rheumatoid arthritis protocol), or even 375 mg/m2/week in four sessions (lymphoma protocol). Lower doses are ineffective. If necessary, treatment can be repeated after 6 months. It can be combined with prednisone in a remission regimen of up to 4 months or an immunosuppressive regimen of up to 12 months. Side effects include infections (about 10%) and, in rare cases, Stevens-Johnson syndrome and progressive multifocal leukoencephalopathy (the latter is a potentially fatal complication).
• Intravenous immunoglobulin (IVIg) is also indicated in patients with severe treatment resistance or in patients with significant side effects. It was initially used in severe disseminated cases of pemphigus as the clinical response appears to be more rapid. Doses of 2 to 3 g/kg/cycle (cycle of 4 to 5 consecutive days) every 30 days are recommended. Systemic corticosteroids and adjuvant drugs used in combination with rituximab are maintained. Aseptic meningitis has been reported as a rare side effect. IgA deficiency should be excluded before starting this treatment.

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