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Anais Brasileiros de Dermatologia

versão impressa ISSN 0365-0596versão On-line ISSN 1806-4841

An. Bras. Dermatol. vol.94 no.2 supl.1 Rio de Janeiro mar./abr. 2019  Epub 03-Jun-2019

http://dx.doi.org/10.1590/abd1806-4841.2019940206 

Bullous dermatoses

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

1Department of Dermatology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo (SP), Brazil.

2Dermatology Service, Hospital Universitário Maria Aparecida Pedrossian, Universidade Federal de Mato Grosso do Sul, Campo Grande (MS), Brazil.

3Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP), Brazil.


Abstract:

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.

Keywords: Autoimmunity; Pemphigus; Treatment

PEMPHIGUS VULGARIS

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.1,2 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. 3-5

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. 6

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.6 It is a rare disease, with an annual incidence that varies between 0.76 (Finland) and 16.1 (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. 8,9

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*05:03.10

PV is characterized by acantholysis and the formation of intraepidermal blisters, resulting from the presence of IgG autoantibodies against the transmembrane desmosomal glycoprotein Dsg3 (130 kD) 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 cavity, 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. 6,9,12,13

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). Due to the rarity of PV, there are few randomized controlled clinical trials. However, several observational studies, case reports, and case series have been published and support the clinical practice of specialists in PV cases. The mortality due to PV has decreased in the past 50 years and stems primarily from the side effects of medications. 14,15

Evaluation before starting treatment

Clinical evaluation: Weight, height, and blood pressure

Laboratory tests: Blood count; electrolytes; hepatic and renal function; blood glucose and glycated hemoglobin; vitamin D; lipids; serologies for hepatitis B and C, syphilis, and HIV; urine I; pregnancy test if applicable; chest x-ray; and bone densitometry (should be repeated after 6 months and then annually).

Ophthalmological evaluation: Initial and then annually.

Systemic treatment

Corticosteroids

Systemic corticosteroids are the basis of the treatment for PV. They have potent anti-inflammatory and immunosuppressive activities. The introduction of these drugs in the 1950s was followed by a reduction in mortality from 75% to 30%. 15-17

- Oral administration: Prednisone is the most commonly used oral corticosteroid, followed by prednisolone and deflazacort. Although several groups prefer to administer a dosage of 40 to 60mg/day (prednisone) for patients with mild PV and 60 to 100mg/day for more severe conditions, most supply a full dose (1 to 2mg/kg/day po) for all patients from the outset, avoiding a progressive increase in dose. However, extremely high dosages, as used previously (3 to 4mg/kg/day), have been shown to be disadvantageous due to their frequent and severe side effects.

Corticosteroids act rapidly in PV, effecting improvement in several days and impeding the emergence of new lesions after 2 to 3 weeks. Complete re-epithelization can take up to 2 months. After the condition is controlled, defined as the disruption of the emergence of new lesions and total re-epithelialization of existing lesions, the corticosteroid dose is slowly reduced. The rate of this decrease should decline toward the end, which can sometimes take years, due to the lack of uniform protocols for this practice. Certain groups recommend that starting from a specific daily dose (usually 40mg/day prednisone), the drug should be administered every other day, which would minimize the side effects. Similarly, there is no consensus on how to 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.18,19

- 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.20,21

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.22

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. 25 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. 19,26,27

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.18,28

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.29

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.18,30-32

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.30,33

Rituximab

Chimeric anti-CD20 monoclonal antibody (which depletes normal and pathogenic B lymphocytes) has been used for cases of severe and refractory PV since 2006.34 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.35 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.40

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/m2, 1x/week for 4 weeks) and that for rheumatoid arthritis (1000mg with an interval of 2 weeks; can be repeated after 6 months).36,41-43 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.40,44-48,34

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.18,36,38-40,49-52

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.16 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. 19,36,53

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. 19,26,54-58

Methotrexate

Based on its anti-inflammatory activity and inhibition of cell proliferation through the suppression of dihydrofolate reductase, 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.59-61

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. 19,62,63

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.32,65-67

Anti-TNF drugs

TNF-α 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.17,68

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.17 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. 69,70

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.71 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).17,18

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.

Treatment plan

PV treatment should comprise 2 phases: the induction of remission and the maintenance of remission. 19,72-76

Induction of remission

The objective is to control the disease, interrupting the emergence of new bullous lesions and the re-epithelialization of lesions that are already present. Corticosteroids are the most effective and fastest-acting therapeutic option for controlling PV, rendering them important at this stage. Disease control may take several weeks (on average 3 weeks), and dose escalation might be required for it to occur.

Adjuvant medications can be initiated at this stage, but their benefit is limited, because their onset of activity is slow. For this reason, its isolated use for the initial control of PV is not recommended.

Medication doses should be maintained until the condition is controlled, defined as re-epithelization of approximately 80% of skin and mucosal lesions and no emergence of new lesions for at least 2 weeks. Oral mucosal lesions usually resolve more slowly than skin lesions. At this stage, the corticosteroid dose can be reduced slowly.

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 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.

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 (Figure 1).

Figure 1 Treatment algorithm for pemphigus vulgarisPV: pemphigus vulgaris; AZA: azathioprine; MMF: mycophenolate mofetil; IVIG: intravenous immunoglobulinPV 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 

EVOLU