Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus - Brazilian Society of Dermatology*

Pemphigus are intraepidermal autoimmune bullous dermatoses that occur with lesions on the skin and / or mucous membranes. The most frequent types are pemphigus vulgaris and pemphigus foliaceus (classic and endemic). This consensus aims to present a complete and updated review of the treatment of these two more frequent forms of pemphigus, based on the literature and the personal experience of the authors. In moderate and severe cases of pemphigus vulgaris and foliaceus, systemic corticosteroid therapy (prednisone or prednisolone) is the treatment of choice. Adjuvant drugs, usually immunosuppressive drugs (azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide) may be prescribed as corticosteroid sparers in refractory cases or with contraindications to corticosteroids to minimize side effects. In severe and nonresponsive cases, corticosteroids in the form of intravenous pulse therapy, immunoglobulin and plasmapheresis / immunoadsorption can be administered. Immunobiological drugs, particularly rituximab, appear as a promising alternative. For milder cases, smaller doses of oral corticosteroid, dapsone and topical corticosteroids are options. At the end flowcharts are presented as suggestions for a therapeutic approach for patients with pemphigus vulgaris and pemphigus foliaceus.

# Introduction
Pemphigus is a group of rare autoimmune bullous diseases that affect the skin and mucous membranes. Its estimated incidence in central Europe is 2 new cases/million inhabitants/year.
They undergo a chronic evolution, with significant morbidity and mortality, and significantly impair quality of life. [bib_ref] Mortality and cause of death in Israeli patients with pemphigus, Kridin [/bib_ref] [bib_ref] Comorbidities and inpatient mortality for pemphigus in the USA, Hsu [/bib_ref] They result from the production of pathogenic autoantibodies (usually IgG) that are directed against various desmosomal proteins (the desmogleins Dsg3 and Dsg1). The binding of these autoantibodies to desmosomal components compromises intraepidermal adhesion, leading to acantholysis and the formation of vesicles, blisters, and erosions on the skin and mucous membranes. [bib_ref] Immune response in pemphigus and beyond: progresses and emerging concepts, Zenzo [/bib_ref] [bib_ref] Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus..., Mahoney [/bib_ref] [bib_ref] The pathogenic role of autoantibodies in pemphigus vulgaris, Pan [/bib_ref] Various subtypes of pemphigus have been identified, based on their clinical and histopathological characteristics and the specific antigens against which autoantibodies are produced. The main types are pemphigus vulgaris (PV) and pemphigus foliaceus, but in the past several decades, nonclassical forms of pemphigus have been described, including paraneoplastic pemphigus, pemphigus herpetiformis, and IgA pemphigus. [bib_ref] Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis, brasiliensis), Joly [/bib_ref] Regardless of subtype, the formation of autoantibodies against desmosomal components has long been considered the chief event in the pathogenesis of pemphigus. In addition to the involvement of humoral immunity, the function of cellular immunity in it has been highlighted. 7

## Epidemiology
PV is the main clinical form of pemphigus, accounting for 70% of cases. [bib_ref] Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis, brasiliensis), Joly [/bib_ref] It is a rare disease, with an annual incidence that varies between 0.76 (Finland) and [bib_ref] S2 guideline for diagnosis and treatment-guided by the European Dermatology Forum (EDF)..., Hertl [/bib_ref].1 (Israel) cases/million inhabitants, depending on the study population. Although it is universally occurring, PV primarily affects adults, peaking in incidence between the fourth and sixth decades of life. In Brazil, it also develops in young adults. Most studies have noted a higher incidence in women, with the female:male ratio ranging from 1.1 (Finland) to 5.0 (US). PV is considered the most severe form of pemphigus. [bib_ref] Pemphigus group: overview, epidemiology, mortality, and comorbidities, Kridin [/bib_ref] ETIOPATHOGENESIS The etiology of PV is unknown. Possible triggering factors include environmental agents, infections, drugs, and tumors. It is linked to specific HLAs, such as HLA-DRB1*04:02 (Jewish) and HLADQB1*05:03. [bib_ref] Pemphigus: a Comprehensive Review on Pathogenesis, Clinical Presentation and Novel Therapeutic Approaches, Pollmann [/bib_ref] PV is characterized by acantholysis and the formation of intraepidermal blisters, resulting from the presence of IgG autoantibodies against the transmembrane desmosomal glycoprotein Dsg3 and, in certain cases, Dsg1 (160 kD). 11

## Clinical condition
The condition generally begins with mucous lesions that, after several weeks or months, start to affect the skin. Among mucous membranes, the most frequently involved is the oral mucosa, in 70% of cases, followed by the genital in 20%. Oral lesions are painful ulcers or eroded lesions that form in any area in the oral ca-vity, usually accompanied by dysphagia and weight loss. Other mucous membranes can be affected, such as the conjunctiva, pharynx, larynx, esophagus, and anal mucosa.
Vesicles and flaccid blisters develop on the skin, throughout the integument, predominating on the scalp, face, and upper chest.
These lesions rupture, giving rise to considerable areas of erosion that are painful. If the lesions are extensive, there might be disruptions in hydroelectrolyte balance, protein loss, and anemia. In addition, rupture of the cutaneous-mucosal barrier facilitates secondary infections. Pemphigus vegetans is a rare clinical subtype of PV that is characterized by vegetant cutaneous lesions in folds of the armpits, groin, and inframammary region. [bib_ref] Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis, brasiliensis), Joly [/bib_ref] [bib_ref] Autoimmune bullous diseases with skin and eye involvement: Cicatricial pemphigoid, pemphigus vulgaris,..., Broussard [/bib_ref] [bib_ref] Pemphigus vulgaris and vegetans, Becker [/bib_ref] The main clinical differential diagnoses in PV are bullous pemphigoid, paraneoplastic pemphigus, and Stevens-Johnson syndrome. PV should be confirmed by histopathological examination of the skin and mucosal lesions with immunofluorescence techniques.

## Laboratory diagnosis 10
Histopathological examination: Whenever possible, an entire vesicle should be removed by skin biopsy. PV shows low suprabasal intraepidermal cleavage with acantholytic (rounded) cells. These cells can also be viewed, isolated or in groups, from blisters or erosion smears by Tzanck test. Acantholysis is also present in hair follicles and sebaceous gland ducts. In vegetans pemphigus, there is also papillomatosis, in addition to neutrophil and eosinophil infiltrates.
Direct immunofluorescence: IgG and C3 autoantibodies can be detected in a perilesional skin fragment (lacy pattern in the stratum spinosum).
Indirect immunofluorescence: Autoantibodies can be detected and titrated in serum in 80% to 90% of patients. Usually, the serum titer of autoantibodies correlates with the clinical activity of the PV.

## Treatment
The treatment of autoimmune bullous dermatoses, including PV is usually based on systemic medications, because they comprise a severe group of mucosal and cutaneous diseases with significant morbidity and mortality. Treatment should be started as early as possible, and its goal is to achieve and maintain disease remission. Thus, the treatment is often prolonged and can last many years (average 5 to 10 years increase the dose in cases of recurrence. Generally, relapse is milder than the initial presentation of the disease and requires doses of prednisone that are equal to or lower than the initial dose for control. [bib_ref] Associations and management guidelines: Facts and controversies, Ruocco [/bib_ref] [bib_ref] British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017, Harman [/bib_ref] -Pulse therapy: Corticosteroids can also be administered as pulse therapy for cases in which control with prednisone at dosages of over 1mg/kg/day is not achieved. To this end, methylprednisolone 1g/day IV and dexamethasone 300mg/day IV are used, both for 3 consecutive days. The advantage of pulse therapy is that it allows for a faster reduction in the prednisone dose, minimizing its side effects. [bib_ref] Pulse therapy and its modifications in pemphigus: a six year study, Rao [/bib_ref] [bib_ref] Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris, Chams-Davatchi [/bib_ref] Although corticosteroids are effective in controlling PV in most patients, they have frequent and potentially severe side effects, the most significant of which are hypertension, diabetes mellitus, cutaneous and systemic infections, gastric ulcer, osteoporosis, femoral head necrosis, glaucoma, and cortisone cataract. These side effects are partly responsible for the morbidity and lethality of the disease, often due to the increase in the frequency of consultations, laboratory tests, and hospital admissions. All patients should receive gastric mucosal protectors and vitamin D supplementation. [bib_ref] Death in pemphigus, Ahmed [/bib_ref] To minimize the side effects, morbidity, and mortality of PV, contrary to what was advocated several decades ago, it is recommended that the daily dosage of prednisone does not exceed 1.5mg/kg/ day-above this value, the likelihood of skin infection and evolution to septicemia (the main death cause in these patients) increases progressively. Thus, other drugs are recommended, in association with corticosteroids-termed adjuvant drugs (corticosteroid-sparing agents). 23

## Adjuvant drugs
When the condition is not controlled solely with corticosteroids or when the patient has clinical contraindications to high-dose corticosteroids (e.g., hypertension, diabetes mellitus, glaucoma, osteoporosis-all of which are frequent in the age group in which the prevalence of PV peaks), other drugs, called adjuvants or corticosteroid-sparing agents, should be incorporated. Adjuvant drugs also prevent relapses in previously controlled patients. 24

## Azathioprine (aza)
Azathioprine is a cytotoxic drug that is used in most autoimmune diseases. It is an imidazole derivative of mercaptopurine, which antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It can also interfere with cellular metabolism and impede mitosis. AZA affects several aspects of the immune system. It reversibly reduces the number of monocytes and Langerhans cells and inhibits gamma globulin synthesis, T lymphocyte function, T helper-dependent B cell responses, and B cell suppressor function. [bib_ref] Azathioprine: old drug, new actions, Maltzman [/bib_ref] The efficacy of AZA as a corticosteroid-sparing agent in autoimmune bullous diseases, particularly in PV, is well documented and is the oldest and most prescribed immunosuppressive medication in this context. [bib_ref] British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017, Harman [/bib_ref] [bib_ref] Randomized double blind trial of prednisolone and azathioprine, vs. prednisolone and placebo,..., Chams-Davatchi [/bib_ref] [bib_ref] High dose oral prednisone vs. prednisone plus azathioprine for the treatment of..., Chaidemenos [/bib_ref] The recommended dosage of AZA in PV is 100 to 200mg/ day (1 to 3mg/kg/day), orally, divided into 2 doses. Its therapeutic effect begins after 4 to 6 weeks, which restricts its use as monotherapy. Three months of use should elapse before replacing it with another adjuvant when there is no satisfactory clinical response. [bib_ref] Associations and management guidelines: Facts and controversies, Ruocco [/bib_ref] [bib_ref] Japanese guidelines for the management of pemphigus, Amagai [/bib_ref] Its main side effects are leukopenia, thrombocytopenia, anemia, pancytopenia, and hepatotoxicity. Long-term immunosuppression can increase the risk of infections and neoplasms. Individuals with a genetic deficiency in thiopurine methyltransferase (TPMT) present with greater sensitivity to AZA-induced myelotoxicity. This medication is contraindicated in pregnant women and nursing mothers. 17

## Mycophenolate mofetil (mmf)
After oral administration, MMF is absorbed and converted into its active metabolite, mycophenolic acid. This, in turn, selectively inhibits inosine monophosphate dehydrogenase, impeding purine synthesis in B and T cells and thus slowing their proliferation. [bib_ref] Mycophenolate mofetil-a new atheropreventive drug, Olejarz [/bib_ref] MMF has been used as an adjuvant to corticosteroids in patients with PV as first-line treatment and in non-responders to AZA.
Several groups prefer MMF to AZA as the first-line adjuvant therapy in PV, due to its lower hepatotoxicity and comparable efficacy.
Compared with AZA, MMF is a poorer corticosteroid-sparing agent but is more effective in controlling PV. [bib_ref] Associations and management guidelines: Facts and controversies, Ruocco [/bib_ref] [bib_ref] Management of Pemphigus Vulgaris, Cholera [/bib_ref] [bib_ref] Mycophenolate mofetil as a first-line steroid sparing agent in the treatment of..., Vyas [/bib_ref] [bib_ref] A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus..., Martin [/bib_ref] The recommended dosage of MMF in PV is 2-3g/day, divided into 2 doses. Its main side effects are altered bowel habits, neutropenia, lymphopenia, and myalgia. Therapeutic failure should be considered only after 3 months of use at a dosage of 3g/day. [bib_ref] Management of Pemphigus Vulgaris, Cholera [/bib_ref] [bib_ref] Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo..., Beissert [/bib_ref] An Bras Dermatol. 2019;94(2 Suppl 1):S20-32.

## Rituximab
Chimeric anti-CD20 monoclonal antibody (which depletes normal and pathogenic B lymphocytes) has been used for cases of severe and refractory PV since 2006. [bib_ref] Treatment of pemphigus vulgaris with rituximab and intravenous immuneglobulin, Ahmed [/bib_ref] Following the administration of rituximab, there is a rapid and sustained depletion of circulating and tissue B lymphocytes that persists for at least 6 to 12 months.
Recent evidence demonstrates that it also affects T lymphocytes. [bib_ref] Rituximab exerts a dual effect in pemphigus vulgaris, Eming [/bib_ref] In June 2018, the US FDA approved rituximab for PV.
There are many prospective and retrospective studies that have proven its efficacy, leading to complete and sustained remission in most patients in 3 to 4 months. 34,36-39 A recent systematic review that included 114 studies and 1085 patients concluded that rituximab is an excellent treatment for refractory cases. [bib_ref] Sixteen-year history of rituximab therapy for 1085 pemphigus vulgaris patients: A systematic..., Tavakolpour [/bib_ref] Rituximab should be administered IV as a slow infusion (4 to 6 hours). There are no standardized protocols for the use of rituximab in autoimmune bullous diseases, but studies have been published using the lymphoma protocol (375mg/m 2 , 1x/week for 4 weeks) and that for rheumatoid arthritis (1000mg with an interval of 2 weeks; can be repeated after 6 months). [bib_ref] Future therapies for pemphigus vulgaris:Rituximab and beyond, Huang [/bib_ref] [bib_ref] Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study..., Cianchini [/bib_ref] [bib_ref] Durable remission of pemphigus with a fixed-dose rituximab protocol, Heelan [/bib_ref] [bib_ref] Clinical and immunological outcomes of high and low dose rituximab treatments in..., Kanwar [/bib_ref] There seems to be no difference in percentage in remission or disease-free interval between these protocols. Rituximab can be used alone or in combination with IVIG, plasmapheresis, or immunoadsorption (the latter appears to prolong the response time with respect to rituximab alone). It can also be administered to patients who are already taking prednisone and immunosuppressants, and the dose reduction and suspension of the latter should be accelerated due to the increased risk of infection. [bib_ref] Sixteen-year history of rituximab therapy for 1085 pemphigus vulgaris patients: A systematic..., Tavakolpour [/bib_ref] [bib_ref] An assessment of treatment history and its association with clinical outcomes and..., Amber [/bib_ref] [bib_ref] A single cycle of rituximab for the treatment of severe pemphigus, Joly [/bib_ref] [bib_ref] Intermediate doses of rituximab used as adjuvant therapy in refractory pemphigus, Londhe [/bib_ref] [bib_ref] First line treatment of pemphigus vulgaris with a novel protocol in patients..., Ahmed [/bib_ref] [bib_ref] Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical..., Behzad [/bib_ref] [bib_ref] Treatment of pemphigus vulgaris with rituximab and intravenous immuneglobulin, Ahmed [/bib_ref] Rituximab is generally well tolerated, and serious adverse effects are rare. Infusion reactions (which can be reduced with prior administration of analgesics, antihistamines, and corticosteroids) include anaphylaxis, fever, hypotension, chills, headache, nausea, pruritus, and skin rash. In addition, neutropenia, hypogammaglobulinemia, and infections, including sepsis, are rarely reported. Certain authors and expert groups recomend rituximab as a first-line treatment option for PV. [bib_ref] Associations and management guidelines: Facts and controversies, Ruocco [/bib_ref] [bib_ref] Future therapies for pemphigus vulgaris:Rituximab and beyond, Huang [/bib_ref] [bib_ref] First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment..., Joly [/bib_ref] [bib_ref] First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency..., Ingen-Housz-Oro [/bib_ref] [bib_ref] Sixteen-year history of rituximab therapy for 1085 pemphigus vulgaris patients: A systematic..., Tavakolpour [/bib_ref] [bib_ref] Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab,..., Graves [/bib_ref] [bib_ref] Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients, Lunardon [/bib_ref] [bib_ref] Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts, Murrell [/bib_ref] [bib_ref] Successful treatment of pemphigus with biweekly 1-g infusions of rituximab: a retrospective..., Leshem [/bib_ref] Cyclophosphamide Cyclophosphamide is an alkylating agent that selectively affects B lymphocytes and antibody production. It can be administered orally in PV (1 to 3mg/kg/day) or intravenously, with or without dexamethasone IV, in the form of pulse therapy. [bib_ref] S2 guideline for diagnosis and treatment-guided by the European Dermatology Forum (EDF)..., Hertl [/bib_ref] In such cases, dexamethasone is administered at 100mg/day IV for 3 days, with cyclophosphamide 500mg/day IV being administered on the first day. This pulse therapy is repeated every 2 to 4 weeks, between which an oral dose of cyclophosphamide 50mg/day and prednisone 1mg/kg/day is maintained. Treatment failure should be considered after 3 months of use at 2mg/kg/day. [bib_ref] British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017, Harman [/bib_ref] [bib_ref] Future therapies for pemphigus vulgaris:Rituximab and beyond, Huang [/bib_ref] [bib_ref] Corticosteroid /cyclophosphamide pulse treatment in south African patients with pemphigus, Shaik [/bib_ref] Its main toxic effects are infertility, predisposition to neoplasia, lymphopenia, and sepsis. Due to its greater toxicity, it can be considered as an adjuvant only in cases that are refractory to AZA and MMF. [bib_ref] British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017, Harman [/bib_ref] [bib_ref] Randomized double blind trial of prednisolone and azathioprine, vs. prednisolone and placebo,..., Chams-Davatchi [/bib_ref] [bib_ref] Pemphigus Vulgaris: An Evidence-Based Treatment Update, Zhao [/bib_ref] [bib_ref] Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroid in..., Sharma [/bib_ref] [bib_ref] Intravenous dexamethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients..., Rose [/bib_ref] [bib_ref] Randomized open comparative trial of dexamethasone-cyclophosphamide pulse and daily oral cyclophosphamide versus..., Sethy [/bib_ref] [bib_ref] Assessment of the therapeutic benefit of dexamethasone cyclophosphamide pulse versus only oral..., Parmar [/bib_ref] Methotrexate Based on its anti-inflammatory activity and inhibition of cell proliferation through the suppression of dihydrofolate reducta-se, methotrexate can be added as an adjuvant in PV at 10 to 20mg/ week in cases of therapeutic failure to other adjuvants. The most frequent side effects are gastrointestinal intolerance, hematological toxicity, and infection. [bib_ref] Analysis of current data on the use of methotrexate in the treatment..., Gurcan [/bib_ref] [bib_ref] Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris, Baum [/bib_ref] [bib_ref] Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients, Tran [/bib_ref] Dapsone Drug with anti-inflammatory and anti-TNF activity that can be attempted as adjuvant medication in PV at 50 to 200mg/day orally, but there are conflicting reports in the literature. Its side effects are usually dose-dependent and reversible. [bib_ref] British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017, Harman [/bib_ref] [bib_ref] Efficacy of dapsone in the treatment of pemphigus and pemphigoid: analysis of..., Gurcan [/bib_ref] [bib_ref] Efficacy of Dapsone in the treatment of pemphigus vulgaris: a single-center case..., Baum [/bib_ref] Cyclosporine Cyclosporine is a calcineurin inhibitor with potent immunosuppressive activity against B and T lymphocytes. It is effective as an adjuvant in the treatment of PV in rare cases at dosages of 3 to 5mg/kg/day, po or IV. 64

## Intravenous immunoglobulin (ivig)
Derived from a donor pool, the mode of action of IVIG in PV is complex, with several mechanisms acting synergistically (selectively removing pathogenic antibodies; altering the expression and function of Fc receptors; affecting the activation, differentiation, and effector functions of T and B cells; and interfering with the activation of cytokines and complement). Its advantage is its safety profile, with few side effects (headache, dyspnea, tachycardia, abdominal discomfort). IVIG is used in cases of PV that do not respond to other treatments or those that present with severe side effects, and it is effective in certain cases at a dosage of 0.4g/kg/day for 5 days, always as an adjunct to corticosteroid therapy once per month. It is expensive and takes 3 to 6 cycles on average. It can be used in pregnant women. [bib_ref] A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus..., Martin [/bib_ref] [bib_ref] Mechanisms of action of intravenous immunoglobulin, Chaigne [/bib_ref] [bib_ref] IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects, Svecova [/bib_ref] [bib_ref] A randomized double-blind trial of intravenous immunoglobulin for pemphigus, Amagai [/bib_ref] Anti-TNF drugs TNF- is one of the cytokines that are involved in acantholysis. Case reports with the use of infliximab and etanercept have suggested its efficacy in PV, but other studies contradict these findings. [bib_ref] Current and future treatment options for pemphigus: Is it time to move..., Tavakolpour [/bib_ref] [bib_ref] Pemphigus vulgaris: approach to treatment, Sinha [/bib_ref] Plasmapheresis/Immunoadsorption Plasmapheresis was first used in 1978 for PV to remove pathogenic autoantibodies from circulation. However, it triggered a rebound effect, causing greater production of these autoantibodies after their withdrawal from circulation. For this reason, it is recommended that corticosteroids and immunosuppressants (e.g., pulsotherapy with methylprednisolone and cyclophosphamide) be used in monthly cycles for up to 1 year. 18,68 IVIG can be used in place of cyclophosphamide to prevent the rebound effect in autoantibody production. Plasmapheresis is an exceptional alternative for severe cases of PV that are unresponsive to other therapeutic modalities. [bib_ref] Current and future treatment options for pemphigus: Is it time to move..., Tavakolpour [/bib_ref] It is available in few hospitals and is expensive. Its main side effect is septicemia.
Immunoadsorption, introduced in 1984, is a more selective method that does not remove other antibodies or plasma components from circulation, unlike plasmapheresis. Performed in cycles of 4 consecutive days every 4 weeks, it has fewer side effects than plasmapheresis. [bib_ref] Prolonged clinical remission of patients with severe pemphigus upon rapid removal of..., Eming [/bib_ref] [bib_ref] Immunoadsorption in dermatology, Meyersburg [/bib_ref] An Bras Dermatol. 2019;94(2 Suppl 1):S20-32.

## Topical treatment
Always used as an adjuvant to systemic therapies, topical treatment of PV lesions aims to reduce pain and prevent secondary infections. It is usually applied as corticosteroid creams and antibiotics. There are reports on the use of tacrolimus, particularly in facial lesions. [bib_ref] Beneficial effects of topical tacrolimus on recalcitrant erosions of pemphigus vulgaris, Gach [/bib_ref] For extensive cases, antiseptic solutions, such as potassium permanganate (1:10,000 or 1:20,000) and chlorhexidine, can be used.
More potent corticoid gels (clobetasol dipropionate) can be applied to the oral mucosa. Triamcinolone acetonide (10 mg/ml) can be administered as an intralesional injection for refractory skin lesions (e.g., pemphigus vegetans). [bib_ref] Current and future treatment options for pemphigus: Is it time to move..., Tavakolpour [/bib_ref] 

## Maintenance of remission
The dose of the medication should be decreased gradually to minimize side effects. The ultimate goal is to keep the disease controlled with a dose of prednisone of up to 10mg/day. PV is a

## Treatment suspension
Complete remission can occur, having been observed in 38%, 50%, and 75% of patients after 3, 5, and 10 years after diagnosis, respectively. Another study found that 59% of patients were without treatment after 3 years. However, premature withdrawal should be avoided, being rarely possible before 1 year.
We present an algorithm for the treatment of pemphigus vulgaris [fig_ref] FIgure 1: Treatment algorithm for pemphigus vulgaris PV [/fig_ref].

## Evolution and prognosis
Before the advent of corticosteroids and immunosuppres- Drugs -Thiol drugs can induce PF and, less frequently, PV, of which penicillamine and captopril are the most common. Other drugs include penicillins, cephalosporins, enalapril, rifampicin, and non-hormonal anti-inflammatory drugs. [bib_ref] Cutting Edge: Brazilian Pemphigus Foliaceus Anti-Desmoglein 1 Autoantibodies Cross-React with Sand Fly..., Qian [/bib_ref] [bib_ref] Pemphigus foliaceus induced by penicillamine, Marsden [/bib_ref] Genetic -FS can occur in genetically related relatives (~20%) and is associated with the expression of certain DRB1 alleles (*0404, *1402, *1406) of the type II major histocompatibility complex. [bib_ref] Drug-induced pemphigus, Brenner [/bib_ref] [bib_ref] An epitope in the third hypervariable region of the DRB1 gene is..., Moraes [/bib_ref] Autoantigen -Desmoglein-1 is a 160-kD transmembrane glycoprotein of the cadherin family (calcium-dependent cell adhesion molecules) in desmosomes and has 5 ectodomains, EC1-5. Based on the desmoglein compensation theory, Dsg-1 expression is more intense in the upper portions of the epidermis, whereas in PV, Dsg-3 predominates in the lower layers of the epidermis and in mucous membranes. [bib_ref] Both qualitative and quantitative genetic variation of MHC class II molecules may..., Piovezan [/bib_ref] [bib_ref] Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of..., Amagai [/bib_ref] [bib_ref] Update on fogo selvagem, an endemic form of pemphigus foliaceus, Aoki [/bib_ref] [bib_ref] Endemic Pemphigus Foliaceus: Towards Understanding Autoimmune Mechanisms of Disease Development, Zenzo [/bib_ref] [bib_ref] Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are..., Amagai [/bib_ref] [bib_ref] Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope, Evangelista [/bib_ref] [bib_ref] Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: A..., Culton [/bib_ref] [bib_ref] Fogo selvagem: endemic pemphigus foliaceus, Hans-Filho [/bib_ref] Autoantibodies -Autoantibodies that trigger the disease belong to the IgG4 subclass. Normal controls in endemic areas have low levels of IgG1 and IgG4, but in FS patients, the IgG1 levels are the same but IgG4 is significantly elevated by up to 19-fold. IgG4 is pathogenic in the mouse model of FS. In the preclinical phase, IgG1 autoantibodies are directed against the EC5 ectodomains of Dsg-1, and in the disease phase, IgG4 autoantibodies react against EC1-2-a phenomenon that is known as epitope spreading. [bib_ref] The disease called wildfire, Counter [/bib_ref] [bib_ref] An active focus of high prevalence of fogo selvagem on an Amerindian..., Hans-Filho [/bib_ref] [bib_ref] Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope, Evangelista [/bib_ref] [bib_ref] Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: A..., Culton [/bib_ref] [bib_ref] Fogo selvagem: endemic pemphigus foliaceus, Hans-Filho [/bib_ref] [bib_ref] The desmosome and pemphigus, Waschke [/bib_ref] [bib_ref] Immunofluorescent studies of autoantibodies to intercellular areas of epithelia in Brazilian Pemphigus..., Beutner [/bib_ref] [bib_ref] Mechanisms of blister induction by autoantibodies, Sitaru [/bib_ref] [bib_ref] Ultrastructure of acantholysis in pemphigus foliaceus re-examined from the current perspective, Van Der Wier [/bib_ref] [bib_ref] Brazilian pemphigus foliaceus autoantibodies are pathogenic to BALB/c mice by passive transfer, Roscoe [/bib_ref] [bib_ref] The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in..., Warren [/bib_ref] [bib_ref] The Role of Subclass Switching in the Pathogenesis of Endemic Pemphigus Foliaceus, Warren [/bib_ref] [bib_ref] Nonpathogenic pemphigus foliaceus (PF) IgG acts synergistically with a directly pathogenic PF..., Yoshida [/bib_ref] [bib_ref] Pemphigus autoimmunity: hypotheses and realities, Grando [/bib_ref] [bib_ref] The IgM anti-desmoglein 1 response distinguishes Brazilian pemphigus foliaceus (fogo selvagem) from..., Diaz [/bib_ref] [bib_ref] Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus..., Mahoney [/bib_ref] Interleukins -Many proinflammatory and anti-inflammatory chemokines and cytokines are produced in the immune response in PF. Although their function in the disease and its pathophysiology remains unknown, they tend to generate a Th2 response, with increased levels of IL-6, TNF-, and IL-22. [bib_ref] Development of na IgG4-based predictor of endemic pemphigus foliaceus (fogo selvagem), Qaqish [/bib_ref] [bib_ref] Prevalence of anti-desmogleina-3 antibodies in endemic regions of fogo selvagem in Brazil, Hilario-Vargas [/bib_ref] [bib_ref] High levels of interleukin-1 in patiens with endemic pemphigus foliaceus, Rocha-Rodrigues [/bib_ref] [bib_ref] Glucocorticoid sensitivity and proinflammatory cytokines pattern in pemphigus, Chriguer [/bib_ref] [bib_ref] TNF-a end IL-6 are mediator in the blisterin process of pemphigus, Lopez-Robles [/bib_ref] 

## Clinical condition
The Pemphigus herpetiformis -This condition can be seen in PF and PV. It manifests as urticarial plaques and vesicles in a herpetiform or annular distribution, with pruritus. [bib_ref] Fogo Selvagem (Endemic Pemphigus Foliaceus), Hans-Filho [/bib_ref] Pemphigus erythematosus or Senear-Usher syndrome: Forme frustes, with lesions localizing predominantly to the malar regions, concomitant with laboratory findings of systemic lupus erythematosus. [bib_ref] Fogo Selvagem (Endemic Pemphigus Foliaceus), Hans-Filho [/bib_ref] Neonatal pemphigus foliaceus is rarer than neonatal PV, due to the predominance of Dsg-3 compared with Dsg-1 in the newborn's skin. Mothers of these newborns usually have disseminated disease and high titers of anti-Dsg1 autoantibodies. [bib_ref] Nikolsky's sign revisited, Juneja [/bib_ref] [bib_ref] Diagnosis and clinical features of pemphigus foliaceus, James [/bib_ref] [bib_ref] Transplacental passage of maternal pemphigus foliaceus autoantibodies induces neonatal pemphigus, Avalos-Diaz [/bib_ref] [bib_ref] Neonatal Autoimmune Blistering Disease: A Systematic Review, Zhao [/bib_ref] In the differential diagnosis, seborrheic dermatitis, impetigo, chronic cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, IgA pemphigus, and the pemphigus variant of non-IgA subcorneal pustular dermatosis should be considered. In the evaluation of patients with erythroderma that is to be clarified, immunological examinations are recommended to rule out PF. [bib_ref] Endemic pemphigus foliaceus (fogo selvagem). I. Clinical features and immunopathology, Diaz [/bib_ref] [bib_ref] Endemic pemphigus foliaceus (fogo selvagem) -1998. The Cooperative Group on Fogo Selvagem..., Hans-Filho [/bib_ref] 

## Laboratory diagnosis
To confirm the diagnosis of any autoimmune bullous disease, clinical, histopathological, and immunological criteria are required. [bib_ref] Anti-desmoglein-1 antibodies in onchocercia-sis, leishmaniasis and Chagas disease suggest a possible etiological..., Diaz [/bib_ref] [bib_ref] Pemphigus and pregnancy, Lin [/bib_ref] [bib_ref] Neonatal pemphigus foliaceus, Lorente Lavirgen [/bib_ref] Histopathology -In PF, cleavage below the stratum corneum is observed with the presence of acantholytic keratinocytes in or adjacent to the granulosa layer, and occasional neutrophils are seen. In the dermis, a mixed inflammatory infiltrate is observed with eosinophils and neutrophils; eosinophils are more prevalent in drug-induced PF. A biopsy for histopathology should be performed at the vesicle/blister or recent erosion edge, with a 4-mm punch. Indirect immunofluorescence (IIF) -More than 80% of patients have IIF-detectable IgG autoantibodies that correlate with disease activity and extent. Neither DIF nor IIF distinguishes PF from PV.
Enzyme-linked immunosorbent assay (ELISA) -Commercially available recombinant Dsg-1 is used as the antigen and has high sensitivity and specificity-higher than IIF. This technique can aid in monitoring disease activity and the response to treatment.
Other techniques include immunoblotting and immunoprecipitation, which are difficult to execute and are restricted to research services. it is suggested that the clinical condition be evaluated using the Karnofsky index-a 100% value refers to a normal person, with no evidence of disease; hospitalization is indicated when this index is 50% or less (50% refers to a patient requiring considerable help, often medical and/or specialized care, and 40% refers to a disabled patient who requires special and comprehensive care).
In deciding which regimen to prescribe for a patient with FS, the extent of pemphigus should be determined. A practical method would be to consider up to 1% involvement as a mild clinical form, up to 10% as moderate, and over 10% of compromised body area (FS active lesions) as severe, with 1% representing the sum of the area of FS lesions, corresponding approximately to the hand palmar area. In some departments, a protocol is included to verify extent and severity of the lesions using the PAAS (Pemphigus Area and Activity Score) and ABSIS (Autoimmune Bullous Skin Disorder Intensity Score) scores. [bib_ref] Severity score indexes for blistering diseases, Daniel [/bib_ref] [bib_ref] Objective scoring systems for disease activity in autoimmune bullous disease, Sebaratnam [/bib_ref] Prior to initiation of therapy, complete blood count, creatinine, sodium, potassium, transaminases, gamma-glutamyl transferase (gGT), alkaline phosphatase, total proteins and protein frac- Methotrexate is an interesting option, based on its low cost and wide availability. However, it is hepatotoxic. It is used at 7.5 to 25mg/week, administered over 1 or 2 consecutive days. After 24 hours, folic acid should be prescribed at a dose of 5mg. Alcohol, sulfamidic derivatives, and allopurinol are banned.
For less extensive forms, one can attempt dapsone 100mg/d or up to 1.5mg/kg/d, because it has also corticosteroid-sparing effects. However, glucose-6-phosphate dehydrogenase (G6PD) activity should be evaluated beforehand. Considering that pemphigus is an antibody-mediated disease, dapsone use is controversial.
Cyclophosphamide can also be used at 500mg IV as a bolus or 2mg/kg/d. It has corticosteroid-sparing effects, but the risk of sterility, hemorrhagic cystitis, and secondary malignant neoplasia should be considered.
The evidence indicates that the major benefit of adjuvant use is the corticoid-sparing effect-not in modifying the course of the disease. In addition, adjuvants reduce the risk of relapse without altering remission rates.

## Newer and more relevant therapies
Rituximab (monoclonal anti-CD20) is indicated when the patient is refractory to conventional therapy or if prednisone is required at dosages of higher than 10mg/d in combination with an immunosuppressant for more than 6 months. It is administered as pulse therapy, preferably at a dose of 1 g IV, repeated after 15 days Historically, monoclonal anti-CD20 has been used for treatment-refractory pemphigus and for patients with severe side effects to conventional immunosuppressive treatments. However, recent data indicate that the combination of rituximab and prednisone may be effective as an initial treatment for pemphigus, allowing the doses of prednisone to be reduced. It is associated with lower rates of side effects compared with high and prolonged doses of corticoid monotherapy.
In certain centers that specialize in the treatment of pemphigus (PV and PF), for moderate and severe clinical forms, rituximab, in combination with systemic corticosteroid therapy, has been used as initial and maintenance treatment in all patients. We present an algorithm for the treatment of fogo selvagem (see [fig_ref] FIgure 2: Pemphigus foliaceus -treatment algorithm FS -fogo selvagem [/fig_ref] Maintenance after consolidation phase: CE should be reduced progressively, after disease control or the end of the conso- Serological monitoring: Serology (IIF and/or ELISA) should be performed at the outset of treatment, after 3 months, and then according to disease progression.
Treatment discontinuation: Discontinuation is based primarily on clinical signs and may be accompanied by anti-Dsg ELISA and IIF. In some centers, negativity by IIF is recommended. Discontinue CS in patients with complete remission and minimal therapy, and discontinue adjuvants 6 to 12 months later.

## Evolution and prognosis
Until the 1950s, the prognosis was poor, with a significant
[fig] , 18 Future: therapies New anti-B cell immunobiologicals are being examined in clinical research regarding their efficacy, safety, and cost in patients with PV, including veltuzumab (anti-CD 20 antibody, SC administration), obinutuzumab, ofatumumab, ocaratuzumab, PRO 121921, anti-BAFF, and anti-BAFF-R. 36 Systemic antibiotic therapy Systemic antibiotic therapy is indicated only in cases with clinical or laboratory evidence of a secondary infection-never prophylactically. Preferably, its choice should be guided by a blood or skin fragment culture and an antibiogram. [/fig]
[fig] FIgure 1: Treatment algorithm for pemphigus vulgaris PV: pemphigus vulgaris; AZA: azathioprine; MMF: mycophenolate mofetil; IVIG: intravenous immunoglobulin PV only in mucous membrane: Mild: only in oral mucosa / Moderate: extensive lesions in oral mucosa / Severe: lesions in oral mucosa and others (for example, esophagus, larynx) PV mucocutaneous: Mild: < 1% de BSA / Moderate: 1 -10% of BSA / Severe: > 10% of BSA: BSA: body surface area (1% means the sum of injured areas corresponding to the palmar surface of the hand with the five digits) * This severity rating is not definitive and aims to provide initial guidance. Each case should be evaluated individually, including considering the speed of onset and progression of the lesions, comorbidities, contraindications to the use of corticosteroids and response to the treatment applied. ** Prednisone can be replaced by oral prednisolone chronic disease, and in one study, 36% of patients received treatment for over 10 years. At this stage, the role of adjuvant medications becomes more significant, although there are no prospective controlled studies that have clearly demonstrated the benefits of these drugs. For this reason, many groups do not use them routinely in PV, unless there are contraindications or notable side effects with corticosteroids or if the disease recurs on dose reduction. One exception is rituximab, for which, in 2017, the first randomized controlled trial to demonstrate the superiority of its combination with prednisolone over prednisolone alone for controlling PV after 2 years (89% versus 28% in complete remission) was published. [/fig]
[fig] TREATMENT: Treatment is indicated from the outset of symptoms in PF, even if the clinical manifestation is mild. The goal is to induce rapid control of the disease and complete remission, minimizing treatment-related adverse effects. 101,128-134 Considering the serious side effects of high and prolonged doses of systemic corticosteroid therapy, systemic non-steroidal immunomodulatory medication is recommended, especially with azathioprine, mycophenolate mofetil, or methotrexate, the most important of which is azathioprine. For severe and refractory cases, rituximab, intravenous immunoglobulin (IVIG), and eventually cyclophosphamide can be indicated. Risk factors and comorbidities should always be investigated, in addition to the recent use of drugs with the potential to induce pemphigus. Regarding indications for hospital admission, [/fig]
[fig] FIgure 2: Pemphigus foliaceus -treatment algorithm FS -fogo selvagem; BSAbody surface area (1% means the sum of injured areas corresponding to the palm area); CS -corticosteroid; DDS -diamino-diphenil-sulfone or dapsone; AZA -azathioprine; MMF -mycophenolate mofetil; MTX -methotrexate; IVIg -intravenous immunoglobulin. [/fig]