Pemphigus vulgaris

Pemphigus vulgaris is a rare potentially life-threatening autoimmune blistering skin disease that is characterized by painful blisters and erosions on your skin and/or mucous membranes most commonly inside your mouth and circulating antibodies (autoantibodies) directed against desmoglein-1 (Dsg1) and desmoglein-3 (Dsg3) ¹, ², ³, ⁴. Pemphigus vulgaris is considered the most severe form of pemphigus ⁵, ⁶. In pemphigus vulgaris, the circulating antibodies (autoantibodies) are directed against desmoglein-3 (anti-Dsg3) in the mucosa and against desmoglein-1 (anti-Dsg1) in the skin or against both proteins in the mucocutaneous areas ⁷, ⁸, ⁹. The binding of anti-desmoglein-3 (anti-Dsg3) and anti-desmoglein-1 (anti-Dsg1) antibodies to desmosomal components impairs intraepidermal adhesion, leading to the separation of keratinocytes (acantholysis) and the formation of vesicles, blisters, and erosions on the skin and mucous membranes ¹⁰, ¹¹, ¹².

The oral mucosa is affected primarily in approximately 70% of cases, causing difficulty swallowing for months after the blisters appear on the skin surface (trunk, buttocks, and feet) ³. The genitourinary tract may be particularly affected in women ³. Blisters can erupt and leave erosions and crusts, and if the skin lesions are extensive, then electrolyte abnormalities, fluid loss, and abnormally low levels of protein in the blood (hypoproteinemia) may be observed ³. The most common complication of pemphigus vulgaris is secondary bacterial, fungal or viral infection.

Pemphigus vulgaris is the most common form of pemphigus accounting for 70% of all pemphigus cases worldwide and affects men and women equally ¹³, ³, ⁴. Pemphigus vulgaris is a rare disease with an estimated incidence in central Europe of 2 new cases per million inhabitants per year that varies between 0.76 (Finland) and 16.1 (Israel) cases per million inhabitants ². Although pemphigus vulgaris occurs worldwide, it primarily affects adults, peaking in incidence between the fourth and sixth decades of life ². In Brazil, pemphigus vulgaris 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) ².

Normally your immune system makes antibodies to protect you against bacteria, viruses, fungi, parasites and cancer cells and these antibodies do not attack your own body. However, in pemphigus vulgaris, your immune system makes antibodies (autoantibodies) that attack the “glue” holding the outer layer of the skin (epidermis) together, making it fragile and prone to blistering. It is not clear why some people develop these autoantibodies. The autoantibodies in pemphigus vulgaris attack proteins called desmogleins. These proteins form the “glue” that holds the cells of the skin together. When the autoantibodies formed in pemphigus vulgaris attack the desmoglein proteins, the cells in the skin no longer hold together and separate. This causes blisters that are typical of pemphigus vulgaris. Histopathology demonstrates blisters above the basal cells, which form a layer resembling headstones. Eosinophilic infiltration can be detected.

Various subtypes of pemphigus vulgaris have been identified, based on their clinical and histopathological characteristics and the specific antigens against which autoantibodies are produced. Variants of pemphigus vulgaris include ⁴:

• Pemphigus vegetans
  • Pemphigus vegetans is a rare subtype of pemphigus vulgaris, accounting for 1% to 2% of all cases of pemphigus ¹⁴. Pemphigus vegetans is characterized by vegetative plaques composed of excessive granulating tissue and crusting. Pemphigus vegetans most commonly occurs at skin folds or intertriginous areas such as your armpits and groin, face and scalp ¹⁵. Oral involvement is extremely common; occasionally, the tongue may also undergo changes, presenting with cerebriform pattern ¹⁶. Verrucous plaques along the vermilion border of the lips or at the angles of the mouth are some presentations of pemphigus vegetans ¹⁴. Characteristic histological finding include hyperkeratosis, pseudoepitheliomatous hyperplasia and papillomatosis with acantholysis that creates a suprabasal cleft.
  • Pemphigus vegetans 2 clinical subtypes are described ¹⁵:
    1. Pemphigus vegetans of Neumann (vegetative plaques arising from pemphigus vulgaris lesions). Neumann type of pemphigus vegetans is considered severe and usually begins as pemphigus vulgaris with vesicles and blisters that rupture to form hypertrophic erosions, evolving into exudative vegetating masses.
    2. Pemphigus vegetans of Hallopeau (plaques not preceded by bullae). Hallopeau type of pemphigus vegetans is a milder form than begins with pustules that rupture and evolve into vegetating erosions.
• Neonatal pemphigus.
  • Neonatal pemphigus occurs in 30% to 45% of children of pemphigus vulgaris carriers, by the passage of maternal antibodies to the fetus through the placenta ¹⁷. Neonatal pemphigus is manifested by vesicles, blisters, and erosions from the moment of birth, and the involvement of mucous membranes is rare ¹⁸. Neonatal pemphigus is transient and tends to disappear spontaneously within three weeks, as it results from the transfer of antibodies that are progressively eliminated.
• Pemphigus herpetiformis
  • Pemphigus herpetiformis was previously described a rare subtype of pemphigus vulgaris (PV) or pemphigus foliceus (PF). Pemphigus herpetiformis is characterized by urticarial plaques and vesiculobullous eruption seen in herpetiform or annular pattern. Plaques are associated with severe itch and rarely involve the mucosa. Histologically, pemphigus herpetiformis is characterized by eosinophilic spongiosis, mostly without acantholysis (the separation of keratinocytes).

Regardless of the pemphigus 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 (a defense mechanism that protects the body from extracellular microbes and toxins by the production of antibodies by B lymphocytes) ¹⁹.

Pemphigus vulgaris diagnosis generally requires a skin biopsy. Whenever possible, an entire vesicle should be removed by skin biopsy. Pemphigus vulgaris 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 (DIF) is the most accurate method for the diagnosis of mucosal pemphigus ²⁰. Histopathological examination of the skin and mucosal lesions with direct immunofluorescence (DIF) staining of the skin sections to reveal antibodies. In some cases, circulating antibodies can be detected by a blood test using indirect immunofluorescence test (IIF) or enzyme-linked immunosorbent assay (ELISA).

The hallmark of pemphigus is the finding of immunoglobulin G (IgG) autoantibodies against the cell surface of keratinocytes with direct immunofluorescence (DIF). The diagnosis of pemphigus should be seriously questioned if the test result of direct immunofluorescence (DIF) is negative. It is important that the biopsy for direct immunofluorescence (DIF) be performed on the normal-appearing perilesional skin, as immune reactants can be difficult to detect in the blistered epidermis.

Pemphigus vulgaris treatment is to prevent new areas from developing bacterial infections and promote healing of affected areas. The treatment of autoimmune pemphigus vulgaris is usually based on systemic corticosteroids and immunosupresants, because pemphigus vulgaris is a severe group of mucosal and skin disease with significant morbidity and mortality. Corticosteroids represent the first-line treatment in all forms of pemphigus ²¹. Treatment should be started as early as possible, and its goal is to achieve and maintain disease remission. Prednisone at 0.5 to 1.5 mg/kg per day or prednisolone 20 to 40 mg per day may be used ²¹. If initial control is not reached within 2 weeks, a higher prednisone dose is advised ²¹. Considering the serious side effects of high and prolonged doses of systemic corticosteroid therapy, systemic 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 ². Oral antibiotics may be prescribed to treat secondary bacterial infection.

Work-up before corticosteroid or immunosuppressive therapy ²²:

• Weight, height, and blood pressure
• Complete blood count (CBC)
• Creatinine, blood electrolyte levels
• Transaminases, g-glutamyltransferase (GGT), alkaline phosphatase (ALP) levels
• Total serum protein, albumin level
• Fasting serum glucose level
• Lipids
• Vitamin D
• Hepatitis B, hepatitis C, syphilis and HIV
• Quantiferon gold or Purified Protein Derivative (PPD) test also known as a tuberculin skin test (TST) or Mantoux test is recommended
• Recommended, on indication or optional:
  • Serum IgA deficiency should be ruled out prior to IVIG treatment
  • Analysis of thiopurine methyltransferase activity is recommended when azathioprine is considered in countries where genetic polymorphisms for decreased thiopurine methyltransferase activity levels are more common
  • Chest radiograph if Quantiferon gold or tuberculin skin test (TST) is abnormal
  • Beta-hCG test is recommended to exclude pregnancy in women of childbearing potential
  • Bone densitometry is recommended prior to corticosteroid treatment (should be repeated after 6 months and then annually)
  • Eye examination (glaucoma, cataract) is recommended (initially and then annually)

Pemphigus vulgaris is an active disease and often requires dose adjustments and changes in medications according to the response to treatment. Follow-up and response to treatment of pemphigus vulgaris should be monitored closely. Septicemia (a life-threatening infection that occurs when bacteria, viruses, or fungi enter the bloodstream and spread throughout the body) is the leading cause of death in pemphigus vulgaris ²³. A retrospective cohort study by Kridin et al. in Israel found that survival rates were lower in patients with pemphigus vulgaris compared with the general population. Patients who were diagnosed with pemphigus vulgaris at an older age had a lower survival rate. The median overall survival from the point of diagnosis was 10.1 years (0.2 to 29.8 years). There was not a statistically significant survival difference between men and women.[78]

Figure 1. Pemphigus vulgaris

Footnotes: Pemphigus vulgaris showing blisters, erosions and crusts (A, B, C), positive anti-epithelial antibodies (D), and direct immunofluorescence (DIF) that show intraepidermal blister with acantholytic cells (E).

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Figure 2. Pemphigus vulgaris in mouth

Footnote: Pemphigus vulgaris oral with an intact blister on the palate

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Figure 3. Pemphigus vulgaris oral

Footnotes: (A) Vesicles, blisters, and ulcerations on the lips. Ulcerations in the buccal and palate mucosa; (B) Serohematic ulcerations and crusts on the lips

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Figure 4. Pemphigus vulgaris disease

Footnotes: (A) Vesicles, blisters, and ulcerations on the torso; (B) Ulcerations and crusts on the back; (C) Ulcerations and crusts on the scalp

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Figure 5. Pemphigus vulgaris fingernail

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Figure 6. Diagnosis of pemphigus

Footnotes: Diagnosis of pemphigus requires clinical presentation and histopathology that are consistent with pemphigus and either a positive direct immunofluorescence (DIF) microscopy result or serologic detection of autoantibodies against epithelial cell surface antigens.

Abbreviations: ELISA = enzyme-linked immunosorbent assay; PF = pemphigus foliaceus; PV = pemphigus vulgaris; WOCBP = women of childbearing potential.

[Source ²² ]

Figure 7. Pemphigus vulgaris treatment algorithm

Footnotes:

Pemphigus vulgaris 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)

Pemphigus vulgaris mucocutaneous:

• Mild: Less than 1% of body surface area (BSA)
• Moderate: 1 – 10% of body surface area (BSA)
• Severe: Greater than 10% of body surface area (BSA)

Body surface area (BSA) 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

Abbreviations: PV = pemphigus vulgaris; AZA = azathioprine; MMF = mycophenolate mofetil; IVIG = intravenous immunoglobulin

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Who gets pemphigus vulgaris?

Pemphigus vulgaris affects people of all races, age, and sex. Pemphigus vulgaris most commonly appears between the ages of 30 and 60 years and is more common in Jews and Indians than in other races, presumably for genetic reasons, for example, HLA-DRB1*0402 is associated with over 90% of Ashkenazi Jews with pemphigus vulgaris and HLA-DQB1*0503 is associated with non-Jewish populations ³.

Drug-induced pemphigus is also recognized and is most often caused by penicillamine, penicillin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, propranolol, indomethacin, beta-blockers phenylbutazone, piroxicam, cephalosporins and tuberculostatic agents. Interestingly, drug-induced pemphigus may also occur after treatment with interferon-gamma and interleukin-2 ²⁵, ⁸. The clinical picture of drug-induced pemphigus resembles pemphigus foliaceous but can be similar to that of pemphigus vulgaris or pemphigus erythematosus (Senear-Usher syndrome); the autoantibodies are against Dsg3 and Dsg1 ³.

Pemphigus is sometimes triggered by cancers particularly lymphomas, lung cancer and Castelman disease (paraneoplastic pemphigus), infection, or trauma.

Pemphigus vulgaris causes

Pemphigus vulgaris is an autoimmune blistering disease, that means your immune systems starts reacting against your tissue. Possible triggering factors include environmental agents, infections, drugs, and tumors. Environmental factors such as diet, stress, viral infections, medications, ultraviolet radiation, ionizing radiation therapy, pesticides, and allergens may all induce immune dysregulation leading to a flare of pemphigus vulgaris ²⁶, ²⁷, ²⁸. Several studies have linked pemphigus vulgaris specific human leukocyte antigens (HLAs) class II alleles, such as HLA-DRB1*04:02 (in Ashkenazi Jews) and HLADQB1*05:03 and HLA-DRB1*1401:04 (in non-Jewish patients of European or Asian descent) ²⁹, ³⁰, ³¹., ³².

Exposure to certain medications like penicillamine and captopril can trigger pemphigus vulgaris ¹. Such a trigger can happen through the effects on binding to molecules involved in cell adhesion, influence on enzymes that mediate keratinocyte aggregation, and by stimulating neoantigen formation ³³. Furthermore, nonsteroidal antiinflammatory drugs (NSAIDs), penicillin, and cephalosporins have also been associated with drug-induced pemphigus vulgaris ³⁴,  ³³. Finally, controversial case reports associating pemphigus vulgaris with certain foods like red wine, garlic, leek, and peppers exist, though such an association is not supported by robust evidence ³⁵.

The building block cells of the skin epidermis are called keratinocytes. These cells are cemented together at special sticky spots called desmosomes. Pemphigus vulgaris is characterized by acantholysis (the separation of keratinocytes) and the formation of intraepidermal blisters, resulting from the presence of immunoglobulin G (IgG) autoantibodies against the transmembrane desmosomal glycoprotein called desmoglein-3 (Dsg3), a desmosomal cadherin, which is found in desmosomes in the keratinocytes near the bottom of the epidermis. About 50% of patients with pemphigus vulgaris also have anti-desmoglein-1 antibodies (anti-Dsg1) ³⁶. The result is the keratinocytes separate from each other, and are replaced by fluid or blister. Because the blister is very close to the surface of the skin, the blisters rupture easily.

Pemphigus vulgaris pathophysiology

In patients with pemphigus vulgaris, autoantibodies against desmoglein-1 (Dsg 1) and desmoglein-3 (Dsg 3) is the purported cause ³⁷. Desmogleins are transmembrane glycoproteins that are an integral part of desmosomes which, in part, are required for cell–cell adhesion via interaction with intermediate filaments. The most common targets of desmoglein for IgG antibodies are the extracellular cadherin domains, which can result in the loss of desmosome-adhesive properties. These signaling pathways trigger endocytosis, depletion, and direct inhibition of desmoglein-3 (Dsg 3) interactions ³⁸. It is generally believed that the amino portion of the cadherin proteins is most implicated in the pathogenesis of acantholysis leading to pemphigus vulgaris ³⁹.

Early lesions of pemphigus vulgaris show suprabasal epidermal acantholysis, clefting and blister formation ⁴⁰. The blister cavity may contain inflammatory cells including eosinophils and rounded acantholytic cells with intensely eosinophilic cytoplasm and a perinuclear halo. The floor of the blister may be lined with intact keratinocytes, the “tombstone pattern” ⁴⁰. Acantholysis can also affect adnexae. Dermal changes include perivascular inflammatory infiltrate particularly with eosinophils.

Many animal models have shown that enzymatic inactivation of desmoglein-1 (Dsg 1) and gene deletion of desmoglein-3 (Dsg 3) results in pathology similar to pemphigus vulgaris ⁴¹, ⁴². This phenomenon was observed to be dose-dependent and suggests that reducing the circulating levels of IgG against Dsg 1 and Dsg 3 can improve patient outcomes ⁴³. In patients with primarily skin disease, Dsg-1 likely plays a role more superficially, whereas Dsg-3 is more likely to be found in deeper cutaneous structures and mucous membranes ⁴⁴, ⁴⁵. The implication is that desmoglein-3 (Dsg 3) can compensate for the absence of desmoglein-1 (Dsg 1) in mucosal structures thus demonstrating pemphigus vulgaris in cutaneous lesions only. In contrast, Dsg 1 without Dsg 3 is insufficient to manage mucous membranes or cutaneous lesions alone, implying that Dsg 1 is in lower proportion in mucous membranes.

The binding of antibodies to desmogleins has been confirmed by epitope mapping and is presumed to disrupt desmoglein binding by affecting steric hindrance ⁴⁶. Another theory for the pathophysiology of pemphigus vulgaris is the desmoglein nonassembly depletion hypothesis. This theory suggests that autoantibodies not only bind desmoglein but that they also bind each other, leading to crosslinking and the inability of desmosomes to maintain cell–cell adhesion ⁴⁷, ⁴⁸.

Direct immunofluorescence (DIF) may be positive in perilesional skin with intercellular deposits of IgG and/or C3 in the epidermis ⁴⁰. Antigen deposition can be seen in hair follicles (follicular outer root sheath and germinal matrix), meaning direct immunofluorescence may be positive when performed on plucked hair follicles.

Pemphigus vulgaris signs and symptoms

Most patients with pemphigus vulgaris first present with lesions on the mucous membranes such as inside the mouth in 70% of cases and genitals in 20% of cases ². Blisters usually develop on the skin after a few weeks or months, although in some cases, mucosal lesions may be the only signs and symptoms of pemphigus vulgaris ². Skin lesions appear as thin-walled flaccid blisters filled with clear fluid that easily rupture causing itchy and painful erosions. Skin blisters most often arise on your upper chest, back, scalp, and face. The skin around the nails may be painful, red, and swollen.

The inside of your mouth is commonly involved in pemphigus vulgaris. Oral lesions are painful ulcers or eroded lesions that form in any area in the oral cavity. Involvement of the pharynx and larynx cause pain on swallowing, a hoarse voice and weight loss. Nose involvement causes nasal congestion and bleeding. Other mucous membranes can also be affected, such as the conjunctiva, esophagus, labia, vagina, cervix, penis, urethra and anal mucosa ⁴.

Features of oral mucosal pemphigus include ⁴:

• Oral lesions in 50–70% of patients
• Superficial blistering and erosions
• Widespread involvement within the mouth
• Painful, slow-to-heal ulcers
• Spread to the larynx causing hoarseness when talking
• Difficulty eating and drinking.

Vesicles and flaccid blisters develop on the skin, commonly affecting the scalp, face, and upper chest. These lesions rupture, giving rise to considerable areas of erosion that are painful. If the skin lesions are extensive, there might be disruptions in electrolyte balance, protein loss, and anemia. In addition, rupture of the skin-mucosal barrier facilitates secondary infections.

Pemphigus vegetans is a rare clinical subtype of pemphigus vulgaris that is characterized by vegetative skin lesions in the skin folds or intertriginous areas such as your armpits and groin ¹³, ⁶, ⁴⁹, ⁵⁰. In addition to blisters and pustules, vegetations or papillomatous verruciform may be found and oral lesions may occur ²⁵, ⁸.

In comparison to white skin, people with darker skin may differ in their presentation which can cause diagnostic delay ⁴. Diagnostic features in people with darker skin may include flaccid blister which lack redness and and hyperpigmented plaques with superficial erosion and bleeding crusts ⁴. At later and more advanced stages, plaques with a pink base and surrounding hyperpigmentation are present.

Pemphigus vulgaris complications

Pemphigus vulgaris can cause very extensive with life-threatening erosions, especially if the diagnosis is delayed. Other potentially severe complications of pemphigus vulgaris may include:

• Secondary bacterial infection
• Fungal infection, especially candida
• Viral infection, especially herpes simplex
• Nutritional deficiencies due to difficulty eating
• Complications of systemic steroids especially infections and osteoporosis
• Complications of immune suppressive treatments
• The psychological effects of severe skin disease and its treatment (anxiety and depression)
• An elevated risk of cardiovascular disease (atherosclerosis, heart failure, arrhythmia, thromboembolism and cardiovascular death).

Pemphigus vulgaris diagnosis

It is advisable that your family doctor refers you to a skin specialist (dermatologist). A dermatologist can make a provisional diagnosis of pemphigus vulgaris by examining the affected area of your skin with a complete review of the medications you’re taking to exclude the possibility of drug-induced pemphigus.

Diagnosis of pemphigus vulgaris generally requires a biopsy of a blister and from the skin adjacent to a lesion. Histology typically shows rounded-up and separated keratinocytes (acantholytic cells) just above the basal layer of the epidermis. Suprabasal clefting may be reported.

Pemphigus is confirmed by direct immunofluorescence staining of perilesional skin biopsy sections to reveal immunoglobulin G (IgG) antibodies or complement on the cell surfaces of keratinocytes.

In most cases, circulating antibodies can be detected by a blood test called indirect immunofluorescence test (IIF). The level of antibodies fluctuates and may reflect the effectiveness of treatment. Specific anti-dsg1 and anti-dsg3 antibody titres can also be measured in blood or saliva by enzyme-linked immunosorbent assay (ELISA).

Pemphigus vulgaris may co-exist with or be confused with pemphigus foliaceus, cicatricial pemphigoid and lichen planus.

A skin biopsy specimen of a recent (less than 24 hour) small vesicle consisting of the peripheral portion of a blister (1/3 of the sample) and perilesional skin (placed in 4% formalin solution) (2/3 of the sample) should be obtained for routine histopathologic analysis: acantholysis at the granular layer in pemphigus foliaceus or intraepidermal suprabasal acantholysis in pemphigus vulgaris.

The hallmark of pemphigus is the finding of immunoglobulin G (IgG) autoantibodies against the cell surface of keratinocytes with direct immunofluorescence (DIF). The diagnosis of pemphigus should be seriously questioned if the test result of direct immunofluorescence (DIF) of skin biopsy is negative. It is important that the skin biopsy for direct immunofluorescence (DIF) be performed on the normal-appearing perilesional skin, as immune reactants can be difficult to detect in the blistered epidermis. Skin biopsy of perilesional skin (≤1 cm from a recent lesion), put into a cryotube for transportation in saline (delivery <36 hour) in a cylinder of liquid nitrogen or Michel’s fixative for direct immunofluorescence (DIF) microscopy analysis ²².

Direct immunofluorescence (DIF) and indirect immunofluorescent (IIF) findings are usually indistinguishable from pemphigus vulgaris, with intercellular immunoglobulin G (IgG) and C3 throughout the epidermis ²². Occasionally intercellular staining is restricted to the upper layers of the epidermis, both on direct and indirect immunofluorescence.

• Direct immunofluorescence (DIF) microscopy: IgG and/or C3 deposits at the surface of epidermal keratinocytes. The smooth and reticular staining pattern is also referred to as chicken wire, honeycomb, or fishnet-like ²²
• IgA deposits with an epithelial cell surface pattern in addition to IgG may be present in a subset of cases ²²
• Epithelial cell surface deposits may be associated with linear or granular deposits of IgG or C3 along the dermoepidermal junction, suggestive of other autoimmune blistering diseases (including paraneoplastic pemphigus or pemphigus erythematosus) or the coexistence of pemphigus and pemphigoid ²².

Cytological examination

Cytological examination (Tzanck smear) is useful for the rapid demonstration of acantholytic keratinocytes of the spinous layer (abundant eosinophilic cytoplasm and rounded central nucleus), stained preferably by hematoxylin and eosin (Figure 8) ¹⁶.

Figure 8. Pemphigus vulgaris cytological examination (Tzanck smear) 

Footnote: Grouping of acantholytic keratinocytes observed on cytological examination by the Tzanck method (Hematoxylin & eosin, x400)

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Laboratory diagnosis

• Histopathological examination: Whenever possible, an entire vesicle should be removed by skin biopsy. Pemphigus vulgaris 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 (DIF): Immunoglobulin G (IgG) and C3 autoantibodies can be detected in a perilesional skin fragment (lacy pattern in the stratum spinosum).
• Indirect immunofluorescence (IIF): 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 pemphigus vulgaris.

Recently, trichoscopy has been evaluated as a useful tool in the differential diagnosis of scalp pemphigus. Extravasations and yellow hemorrhagic crusts were the most frequent findings. The “fried egg sign” (yellow dots with a whitish halo) was identified as a new trichoscopic feature of pemphigus ⁵¹.

Figure 9. Pemphigus vulgaris histopathological examination

Footnotes: (A) Histopathological examination, showing a blister with suprabasal cleavage level affecting the epidermis and follicular epithelium (Hematoxylin & eosin, x40); (B) In detail, acantholytic keratinocytes in the blister content (Hematoxylin & eosin, x400)

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Figure 10. Pemphigus vulgaris indirect immunofluorescence

Footnotes: Pemphigus vulgaris indirect immunofluorescence with intercellular intraepithelial IgG.

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Pemphigus vulgaris differential diagnosis

Pemphigus vulgaris differential diagnosis includes other forms of pemphigus, bullous pemphigoid, paraneoplastic pemphigus, Stevens-Johnson syndrome, Darier’s disease, Hailey-Hailey disease, subacute cutaneous lupus erythematosus, and Grover’s disease.

• Oral erosions may mimic several diseases, such as aphthous stomatitis, acute herpetic stomatitis, erythema multiforme or Stevens-Johnson syndrome, lichen planus, systemic lupus erythematosus, paraneoplastic pemphigus, and mucous membrane pemphigoid ²⁰, ¹⁶, ⁵².
• Skin lesions of pemphigus vulgaris, the differential diagnosis includes other forms of pemphigus, bullous pemphigoid, linear IgA bullous dermatosis, bullous erythema multiforme, and dermatitis herpetiformis.
• Skin folds lesions of pemphigus vegetans should be differentiated from chronic infections and Hailey-Hailey disease. Vegetating plaques simulating pemphigus vegetans can also be seen in IgA pemphigus and in paraneoplastic pemphigus. The histologic differential diagnosis includes Hailey-Hailey disease, Darier’s disease and Grover’s disease, or transient acantholytic dermatosis ¹⁵.

The demonstration of immunoglobulin G (IgG) autoantibodies against epidermal surfaces is essential to determine if the disorder accounts for a form of pemphigus ²¹.

• Darier’s disease: Suprabasal clefting with dyskeratosis in the form of corps ronds and grains. Immunofluorescence is negative.
• Hailey-Hailey disease: Disruption of epithelium adjacent to bullae (intact in pemphigus vulgaris) with sparing of adnexal structures. Immunofluorescence is negative.
• Pemphigus foliaceus: Acantholysis more superficial within the granular layer. Lacks mucous membrane involvement.
• Grover’s disease: There is a pemphigus-like form of this disease. Negative immunofluorescence and lack of adnexal involvement are helpful features.

Pemphigus vulgaris treatment

The primary aim of treatment of pemphigus vulgaris is to decrease blister formation, prevent infections and promote healing of blisters and erosions ²², ⁵³, ⁵⁴. Corticosteroids represent the first-line treatment in all forms of pemphigus ²¹. Systemic corticosteroids in the form of moderate to high doses of oral prednisone or prednisolone, or as pulsed intravenous methylprednisolone are the mainstay of medical treatment for controlling pemphigus vulgaris disease. Prednisone is the most commonly used oral corticosteroid, followed by prednisolone and deflazacort. Since the introduction of  steroid therapy in the 1950s, many deaths from pemphigus vulgaris have been prevented (the mortality rate dropped from 99% to 5–15%) ², ²¹. Although several groups prefer to administer a prednisone dosage of 40 to 60mg/day for patients with mild pemphigus vulgaris and 60 to 100mg/day for more severe conditions, most supply a full dose (1 to 2mg/kg/day oral) for all patients from the outset. However, extremely high prednisone dosages, as used previously (3 to 4mg/kg/day), have been shown to be disadvantageous due to their frequent and severe side effects. Moreover, corticosteroids are not a cure for pemphigus vulgaris but improve your quality of life by reducing the disease activity. The doses of corticosteroids needed to control pemphigus vulgaris and the length of time on treatment may result in serious side effects and risks.

Prior to initiation of therapy, weight, height, and blood pressure, complete blood count (CBC), creatinine, sodium, potassium, transaminases, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total proteins and protein fractions, fasting blood glucose, vitamin D, serology for hepatitis B and C, human immunodeficiency virus (HIV) and syphilis, and chest x-ray should be examined ². Optional recommendations include: ruling out IgA deficiency prior to intravenous immunoglobulin (IVIG); measuring thiopurine methyltransferase activity before azathioprine; abdominal ultrasonography (optional), purified protein derivative (PPD) test also known as a tuberculin skin test (TST) or Mantoux test, or Quantiferon if the risk for tuberculosis is high; measuring activity of glucose-6-phosphate dehydrogenase (G6PD), bilirubins, and reticulocytes prior to dapsone; beta-HCG (human chorionic gonadotrophin) to exclude pregnancy; bone densitometry before corticosteroid therapy (should be repeated after 6 months and then annually); and an ophthalmological evaluation to rule out glaucoma and cataract (initially and then annually). Regardless of the parasitological stool examination, preventive treatment of strongyloidiasis is recommended, as is systemic antibiotic therapy if pyoderma is present ².

Other immunosuppressive drugs (mostly off-label) used to reduce the dose of steroids and may be required by patients with pemphigus vulgaris for years. These are most often:

• Azathioprine
• Mycophenolate mofetil
• Cyclophosphamide
• Rituximab, which is now approved by the Food and Drug Administration (FDA) in the US.

Other medications that are sometimes used in pemphigus (often in combination) include:

• Dapsone
• Methotrexate
• Tetracyclines
• Nicotinamide
• Plasmapheresis
• Intravenous immunoglobulin
• Extracorporeal photopheresis
• Immunoadsorption
• The TNFα inhibitor, infliximab.

At optimal therapy, patients may continue to experience mild disease activity.

Other considerations include bone prophylaxis, baseline eye assessment by eye specialist and psychological support if needed.

Systemic Corticosteroids

Corticosteroids act rapidly in pemphigus vulgaris with 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 pemphigus vulgaris 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 corticosteroid dosage decrease should decline toward the end, which can sometimes take years, due to the lack of uniform protocols for this practice. Certain expert 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 corticosteroid 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 ⁵⁵, ⁵⁶.

Although corticosteroids are effective in controlling pemphigus vulgaris in most patients, they have frequent and potentially severe side effects, the most significant of which are high blood pressure, 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 ⁵⁷.

To minimize the side effects, morbidity, and mortality of pemphigus vulgaris, contrary to what was advocated several decades ago, it is recommended that the daily dosage of prednisone does not exceed 1.5 mg/kg/day above this value, the likelihood of skin infection and evolution to septicemia (the main death cause in these patients) increases progressively. Therefore, other drugs are recommended, in association with corticosteroids-termed adjuvant drugs (corticosteroid-sparing agents) ⁵⁸.

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 ⁵⁹, ⁶⁰.

Maintenance after consolidation phase

Corticosteroid should be reduced progressively, after disease control or the end of the consolidation phase, reducing the corticosteroid dose by approximately 25% every 2 weeks until 20 mg/day and then slowly. If more than 3 lesions appear, return to the previous dose. If the disease recurs, return to the dose of the 2 previous phases. If it does not stabilize within 2 weeks, return to the starting dose. If the treatment is combined with an immunosuppressant, replace it or use rituximab, IVIG, or immunoadsorption. High levels of anti-Dsg-1 by ELISA indicate cutaneous relapses ².

Corticosteroid-sparing agents (adjuvant drugs)

People affected by pemphigus vulgaris often require an additional immunosuppressant agent. When pemphigus vulgaris is not controlled solely with corticosteroids or when the patient has clinical contraindications to high-dose corticosteroids (e.g., high blood pressure, diabetes mellitus, glaucoma, osteoporosis-all of which are frequent in the age group in which the prevalence of pemphigus vulgaris peaks), other drugs, called adjuvants or corticosteroid-sparing agents, should be incorporated. Adjuvant drugs also prevent relapses in previously controlled patients ⁶¹. Adjuvant drugs (immunosuppressants) work by dampening down the immune system and are given under the close supervision of a dermatology consultant. Options include ²²:

• Azathioprine
• Mycophenolate mofetil
• Methotrexate
• Rituximab (anti-CD20 monoclonal antibodies)

These medications can have side effects, so people who take them must be monitored carefully including regular blood tests. More information can be found in the individual patient information leaflets for the corresponding drug.

Azathioprine

Azathioprine is a cytotoxic drug (a substance that kills cells, especially cancer cells, by preventing them from growing and dividing) that is used in most autoimmune diseases. Azathioprine is an imidazole derivative of mercaptopurine, which antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. Azathioprine can also interfere with cellular metabolism and impede mitosis. Azathioprine affects several aspects of the immune system. Azathioprine 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 ⁶².

Azathioprine is currently the first-line corticosteroid-sparing agents ²². The efficacy of azathioprine as a corticosteroid-sparing agent in autoimmune bullous diseases, particularly in pemphigus vulgaris, is well documented and is the oldest and most prescribed immunosuppressive medication in this context ⁵⁶, ⁶³, ⁶⁴.

The recommended dosage of azathioprine in pemphigus vulgaris is 100 to 200 mg/day (1 to 3 mg/kg/day), orally, divided into 2 doses. Start azathioprine at 50 mg/day the first week to detect idiosyncratic reactions such as sudden-onset fevers, oral ulcers, elevated liver function test results and/or drug reaction with eosinophilia and systemic symptoms (and in that case stop immediately), and then raise to desired dose ²². Azathioprine therapeutic effect begins after 4 to 6 weeks, which restricts its use as monotherapy. Three months of azathioprine use should elapse before replacing it with another adjuvant when there is no satisfactory clinical response ⁵⁵, ⁶⁵.

Although not predictive for idiosyncratic reactions, thiopurine methyltransferase (TPMT) activity should be evaluated in countries/ethnicities where there is a higher incidence of polymorphisms before commencing therapy because recommended azathioprine doses vary depending on thiopurine methyltransferase activity. In general, adults with pemphigus and high thiopurine methyltransferase activity are treated with normal doses of azathioprine (≥2.5 mg/kg/day) ²². Patients with intermediate or low thiopurine methyltransferase activity should receive a lower maintenance dose (≥0.5 to 1.5 mg/kg/day) depending on level of enzyme activity. Patients who lack thiopurine methyltransferase activity should avoid treatment with azathioprine ²².

Azathioprine main side effects are leukopenia, thrombocytopenia, anemia, pancytopenia, and hepatotoxicity. Long-term immunosuppression can increase the risk of infections and cancers. Azathioprine is contraindicated in pregnant women and breastfeeding mothers ⁶⁶.

Mycophenolate mofetil (MMF)

After oral administration, mycophenolate mofetil 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 ⁶⁷.

Mycophenolate mofetil (MMF) has been used as an adjuvant to corticosteroids in patients with pemphigus vulgaris as first-line treatment and in non-responders to azathioprine. Several groups prefer mycophenolate mofetil to azathioprine as the first-line adjuvant therapy in pemphigus vulgaris, due to its lower hepatotoxicity and comparable efficacy. Compared with azathioprine, mycophenolate mofetil is a poorer corticosteroid-sparing agent but is more effective in controlling pemphigus vulgaris ⁵⁵, ⁶⁸, ⁶⁹, ⁷⁰.

The recommended dosage of mycophenolate mofetil in pemphigus vulgaris is 2-3 g/day, divided into 2 doses. Mycophenolate mofetil main side effects are altered bowel habits, neutropenia, lymphopenia, and myalgia. It should be noted that the onset of action with mycophenolate mofetil is slow and evidence of response occurs between 2 and 12 months of continued use ²¹. Therapeutic failure should be considered only after 3 months of use at a dosage of 3 g/day ⁶⁸, ⁷¹.

Methotrexate

Methotrexate is an interesting option, based on its low cost and wide availability. However, it is liver toxic. Based on methotrexate anti-inflammatory activity and inhibition of cell proliferation through the suppression of dihydrofolate reductase, methotrexate can be added as an adjuvant in pemphigus vulgaris at 10 to 20 mg/week administered over 1 or 2 consecutive days in cases of therapeutic failure to other adjuvants. After 24 hours, folic acid should be prescribed at a dose of 5 mg. Alcohol, sulfamidic derivatives, and allopurinol are all banned ². The most frequent methotrexate side effects are gastrointestinal intolerance, hematological toxicity, and infection ⁷², ⁷³, ⁷⁴.

Rituximab (anti-CD20 monoclonal antibodies)

Currently there are 2 intravenous CD20 inhibitors available, rituximab and ofatumumab. All the published trials so far have used rituximab ²². There are many prospective and retrospective studies that have proven rituximab efficacy, leading to complete and sustained remission in most patients in 3 to 4 months ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹. A recent systematic review that included 114 studies and 1085 patients concluded that rituximab is an excellent treatment for refractory cases ⁸⁰. Certain authors and expert groups recomend rituximab as a first-line treatment option for pemphigus vulgaris ⁷⁶, ⁵⁵, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴.

Rituximab (anti-CD20 monoclonal antibody), which depletes normal and pathogenic B lymphocytes, has been used for cases of severe and refractory pemphigus vulgaris since 2006 ⁷⁵. 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 rituximab also affects T lymphocytes ⁸⁵. In June 2018, the US FDA approved rituximab for pemphigus vulgaris.

Rituximab is the first-line treatment in new-onset moderate-to-severe pemphigus and/or for patients who do not achieve clinical remission with systemic corticosteroids and/or immunosuppressive adjuvants ⁸⁶.

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 (375 mg/m², 1 week apart for 4 weeks) and that for rheumatoid arthritis (2 × 1000 mg with an interval of 2 weeks apart; can be repeated after 6 months) ⁷⁶, ⁸⁷, ⁸⁸, ⁸⁹. 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 intravenous immunoglobulin (IVIG), plasmapheresis, or immunoadsorption (the latter appears to prolong the response time with respect to rituximab alone). Rituximab 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 ⁸⁰, ⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴, ⁷⁵.

Rituximab treatment can be repeated in cases of clinical relapse or as early as 6 months after treatment. Lower doses are sometimes used for retreatment. Combine with short-term (<4 months) systemic corticosteroids and long-term (>12 months) immunosuppressive treatment, although the need for immunosuppressive adjuvants in rituximab therapy remains unclear.

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, low blood pressure, chills, headache, nausea, itch, and skin rash. In addition, neutropenia, hypogammaglobulinemia, and infections, including sepsis, are rarely reported.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that selectively affects B lymphocytes and antibody production. Cyclophosphamide can be administered orally in pemphigus vulgaris (1 to 3 mg/kg/day) or intravenously, with or without dexamethasone IV, in the form of pulse therapy ⁹⁵. In such cases, dexamethasone is administered at 100 mg/day IV for 3 days, with cyclophosphamide 500 mg/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 50 mg/day and prednisone 1 mg/kg/day is maintained. Treatment failure should be considered after 3 months of use at 2mg/kg/day ⁵⁶, ⁷⁶, ⁹⁶.

Cyclophosphamide main toxic effects are infertility, secondary cancer, hemorrhagic cystitis, lymphopenia, and sepsis ². Due to its greater toxicity, it can be considered as an adjuvant only in cases that are refractory to azathioprine and mycophenolate mofetil ⁵⁶, ⁶³, ⁹⁷, ⁹⁸, ⁹⁹, ¹⁰⁰, ¹⁰¹.

Cyclophosphamide is used in cases of limited resources or in severe cases that have not responded to other treatments. Cyclophosphamide is used as a drug of last resort on account of long-term side effects.

Dapsone

Dapsone has anti-inflammatory and anti-TNF activity that can be attempted as adjuvant medication in pemphigus vulgaris at 50 to 200 mg/day orally, but there are conflicting reports in the literature. Dapsone side effects are usually dose-dependent and reversible ⁵⁶, ¹⁰², ¹⁰³.

Cyclosporine

Cyclosporine is a calcineurin inhibitor with potent immunosuppressive activity against B and T lymphocytes. Cyclosporine is effective as an adjuvant in the treatment of pemphigus vulgaris in rare cases at dosages of 3 to 5 mg/kg/day, oral or IV ¹⁰⁴.

Anti-TNF drugs

TNF-alpha is one of the cytokines that are involved in acantholysis. Anti-TNF drugs also known as tumor necrosis factor (TNF) inhibitors, are biologic agents used to treat inflammatory conditions. Tumor necrosis factor (TNF)-alpha inhibitors, including etanercept, infliximab, adalimumab, certolizumab pegol and golimumab. Case reports with the use of infliximab and etanercept have suggested its efficacy in pemphigus vulgaris, but other studies contradict these findings ⁶⁶, ¹⁰⁵.

Intravenous immunoglobulin (IVIG)

Intravenous immunoglobulin (IVIG) is a concentrate of the pooled immunoglobulins (Ig) derived from 1000 to 100,000 healthy donors depending upon the manufacturer ¹⁰⁶. The mode of action of intravenous immunoglobulin (IVIG) in pemphigus vulgaris is complex, with several mechanisms acting synergistically such as selectively removing pathogenic IgG autoantibodies; 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. Intravenous immunoglobulin (IVIG) advantage is its safety profile, with few side effects (headache, dyspnea, tachycardia, abdominal discomfort and aseptic meningitis). IgA deficiency should be excluded before starting this treatment ². Patients with IgA deficiency should receive IgA-depleted IVIG treatment ²².

Intravenous immunoglobulin (IVIG) is used in cases of pemphigus vulgaris 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 0.4 g/kg/day for 5 days, always as an adjunct to corticosteroid therapy once per month. Intravenous immunoglobulin (IVIG) is expensive and takes 3 to 6 cycles on average. It can be used in pregnant women ⁶⁹, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹.

Systemic corticosteroid and adjuvant drugs are maintained and have been used in combination with rituximab.

Immunoadsorption (immunoapheresis) and Plasmapheresis

Plasmapheresis was first used in 1978 for pemphigus vulgaris to remove pathogenic autoantibodies from circulation. However, plasmapheresis 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., pulse therapy with methylprednisolone and cyclophosphamide) be used in monthly cycles for up to 1 year ⁵⁵, ¹⁰⁵. Intravenous immunoglobulin (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 pemphigus vulgaris that are unresponsive to other therapeutic modalities ⁶⁶. Plasmapheresis is available in few hospitals and is expensive. Its main side effect is septicemia.

Immunoadsorption also known as immunoapheresis introduced in 1984 is a more selective extracorporeal clearance technique that removes immunoglobulins, especially IgG1, IgG2, and IgG4, from the plasma and does not remove other antibodies or plasma components from circulation, unlike plasmapheresis ¹¹⁰. Immunoapheresis is a first-line treatment option in emergency situations or second-line corticosteroid-sparing agent where available. With immunoapheresis, circulating levels of immunoglobulins can be decreased by over 80%. It is another option for refractory or very severe patients and is available in advanced centers for autoimmune diseases. Immunoadsorption is performed in cycles of 4 consecutive days every 4 weeks and it has fewer side effects than plasmapheresis ¹¹¹, ¹¹².

Immunoapheresis contraindications include severe systemic infection, severe cardiovascular disease, extensive hemorrhagic diathesis, hypersensitivity against components of the immunoadsorption column, and the use of angiotensin-converting enzyme inhibitors (ACE inhibitors) ².

Topical therapy

Always used as an adjuvant to systemic therapies, topical treatment of pemphigus vulgaris lesions aims to reduce pain and prevent secondary infections. Topical therapy is usually applied as corticosteroid creams and antibiotics. There are reports on the use of tacrolimus, particularly in facial lesions ¹¹³. 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), topical tacrolimus, or topical ciclosporin 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) ⁶⁶, ⁵⁵.

Systemic antibiotic therapy

Systemic antibiotic therapy is indicated only in cases with clinical or laboratory evidence of a secondary infection and never prophylactically. Preferably, antibiotic therapy should be guided by a blood or skin fragment culture and its antibiogram.

General management

In pemphigus vulgaris disease, appropriate wound care is particularly important as this should promote healing of blisters and erosions.

• Handle skin very gently to avoid causing new blisters and erosions.
• Wear surgical gloves and use aseptic technique when changing dressings.
• Analgesics may be needed especially for dressing changes.
• Gently cleanse with an antiseptic solution or take a bleach bath.
• Drain intact blisters, but leave the blister roof in place.
• Apply a bland emollient ointment, such as 50% white soft paraffin + 50% liquid paraffin, directly to the skin, or apply the ointment to a dressing.
• Use non-adherent dressings (such as petrolatum-soaked gauze or silicone mesh). These may incorporate an antiseptic.
• An absorbent dressing may be applied over the primary dressing if the erosions are oozing.
• Be vigilant in identifying and treating any infection.

During active phases of the disease, people with pemphigus vulgaris should minimize activities that may traumatize the skin and mucous membranes. These include activities such as contact sports and eating or drinking food that may irritate or damage the inside of your mouth (spicy, acidic, hard and crunchy foods).

Oral hygiene and proper dental care are also essential:

• Use a soft toothbrush and mint-free toothpaste to gently and thoroughly brush teeth twice daily.
• Rinse your mouth using an antiseptic or anti-inflammatory mouthwash.
• Treat oral candidiasis, if present.

Pemphigus vulgaris treatment plan

Pemphigus vulgaris treatment should comprise 2 phases ⁵⁶, ¹¹⁴, ¹¹⁵, ¹¹⁶, ¹¹⁷, ¹¹⁸:

1. Induction of remission
2. Maintenance of remission.

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 pemphigus vulgaris, 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 pemphigus vulgaris 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. pemphigus vulgaris 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 pemphigus vulgaris, 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 pemphigus vulgaris 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.

Pemphigus vulgaris prognosis

Before the advent of corticosteroids and immunosuppressants, pemphigus vulgaris had a 2-year mortality rate of 50% ². With steroid and immunosuppressive therapy, the mortality due to pemphigus vulgaris has decreased in the past 50 years from 75% to 10% ², ¹¹⁹, ⁹⁵, ⁶⁶. The mortality due to pemphigus vulgaris stems mainly from the side effects of medications ¹²⁰, ¹²¹, ¹²², ¹¹⁹. The main cause of death in patients with pemphigus vulgaris is septicemia (a life-threatening infection that occurs when bacteria, viruses, or fungi enter the bloodstream and spread throughout the body) ²³. Patients often present as people with large burns, experiencing loss of the skin-mucosal barrier, which promotes infections and electrolytic and metabolic disorders. Oral lesions are usually more resistant to treatment and can persist for years, significantly impairing patients’ quality of life. Generally, it is possible to obtain total disease control, which allows the medication to be suspended, but the patient should be kept under observation, because relapses are frequent ⁵, ³², ⁴⁹, ⁶⁵. The corticosteroids and immunosupressants needed to control pemphigus vulgaris and the length of time on treatment (average 5 to 10 years) may also result in serious side effects and risks.

1. Ingold CJ, Sathe NC, Khan MAB. Pemphigus Vulgaris. [Updated 2024 Mar 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560860[↩][↩]
2. Porro AM, Hans Filho G, Santi CG. Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology. An Bras Dermatol. 2019 Apr;94(2 Suppl 1):20-32. doi: 10.1590/abd1806-4841.2019940206[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
3. Ávalos-Díaz E, Herrera Esparza R. Dermatological autoimmune diseases. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 34. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459479[↩][↩][↩][↩][↩][↩][↩][↩]
4. Pemphigus vulgaris. https://dermnetnz.org/topics/pemphigus-vulgaris[↩][↩][↩][↩][↩][↩][↩]
5. Kridin K. Pemphigus group: overview, epidemiology, mortality, and comorbidities. Immunol Res. 2018;66:255–270. doi: 10.1007/s12026-018-8986-7[↩][↩]
6. Bystryn JC, Rudolph JL. Pemphigus. Lancet. 2005;366:61–73. doi: 10.1016/S0140-6736(05)66829-8[↩][↩]
7. Shimizu H, editor. Shimizu’s Textbook of Dermatology. Nakayama Shoten Publishers. Hokkaido University Press; Japan: Oct 1, 2007.[↩]
8. Sánchez-Pérez J, García-Díez A. Pénfigo [Pemphigus]. Actas Dermosifiliogr. 2005 Jul-Aug;96(6):329-56. Spanish. doi: 10.1016/s0001-7310(05)73090-8[↩][↩][↩]
9. Sticherling M, Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev. 2012 Jan;11(3):226-30. doi: 10.1016/j.autrev.2011.05.017[↩]
10. Di Zenzo G, Amber KT, Sayar BS, Müller EJ, Borradori L. Immune response in pemphigus and beyond: progresses and emerging concepts. Semin Immunopathol. 2016;38:57–74. doi: 10.1007/s00281-015-0541-1[↩]
11. Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest. 1999;103:461–468. doi: 10.1172/JCI5252[↩]
12. Pan M, Liu X, Zheng J. The pathogenic role of autoantibodies in pemphigus vulgaris. Clin Exp Dermatol. 2011;36:703–707. doi: 10.1111/j.1365-2230.2011.04092.x[↩]
13. Joly P, Litrowski N. Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis, brasiliensis) Clin Dermatol. 2011;29(4):432–436. doi: 10.1016/j.clindermatol.2011.01.013[↩][↩]
14. Caetano Lde V, Enokihara MM, Porro AM. Recurrent angular cheilitis in a patient with mucocutaneous pemphigus vulgaris. Clin Exp Dermatol. 2015;40:819–821. doi: 10.1111/ced.12629[↩][↩]
15. Ruocco V, Ruocco E, Caccavale S, Gambardella A, Lo Schiavo A. Pemphigus vegetans of the folds (intertriginous areas) Clin Dermatol. 2015;33:471–476. doi: 10.1016/j.clindermatol.2015.04.011[↩][↩][↩]
16. Amagai M. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. 3rd ed. Vol. 1. Philadelphia: Elsevier; 2012. Pemphigus; pp. 469–471.[↩][↩][↩]
17. Carvalho AA, Santos Neto DAD, Carvalho MADR, Eleutério SJP, Xavier AREO. Neonatal pemphigus in an infant born to a mother with pemphigus vulgaris: a case report. Rev Paul Pediatr. 2019;37:130–134. doi: 10.1590/1984-0462/;2019;37;1;00004[↩]
18. Gushi M, Yamamoto Y, Mine Y, Awazawa R, Nonaka K, Taira K, et al. Neonatal pemphigus vulgaris. J Dermatol. 2008;35:529–535. doi: 10.1111/j.1346-8138.2008.00515.x[↩]
19. Amber KT, Staropoli P, Shiman MI, Elgart GW, Hertl M. Autoreactive T cells in the immune pathogenesis of pemphigus vulgaris. Exp Dermatol. 2013;22:699–704. doi: 10.1111/exd.12229[↩]
20. Wojnarowska F, Venning VA. Burns T, Breathnach S, Cox N, Griffiths C. Rook’s Textbook of Dermatology. 8th ed. Vol. 2. New York: Ed Blackwell Science; 2010. Immunobullous Diseases; pp. 40.1–40.1.[↩][↩]
21. Lepe K, Yarrarapu SNS, Zito PM. Pemphigus Foliaceus. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499829[↩][↩][↩][↩][↩][↩][↩]
22. Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: Recommendations of an international panel of experts. J Am Acad Dermatol. 2020 Mar;82(3):575-585.e1. doi: 10.1016/j.jaad.2018.02.021[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
23. Porro AM, Seque CA, Ferreira MCC, Enokihara MMSES. Pemphigus vulgaris. An Bras Dermatol. 2019 Jul 29;94(3):264-278. doi: 10.1590/abd1806-4841.20199011[↩][↩][↩][↩][↩][↩][↩][↩]
24. Pemphigus vulgaris images. https://dermnetnz.org/images/pemphigus-vulgaris-images[↩]
25. Hertl MD. Autoimmune Bullous Skin Disorders. Pemphigus. In: Hertl MD, editor. Autoimmune diseases of the skin pathogenesis, diagnosis, management. 2nd ed. Springer Wien; New York: 2005. pp. 45–69.[↩][↩]
26. Patel F, Wilken R, Patel FB, Sultani H, Bustos I, Duong C, Zone JJ, Raychaudhuri SP, Maverakis E. Pathophysiology of Autoimmune Bullous Diseases: Nature Versus Nurture. Indian J Dermatol. 2017 May-Jun;62(3):262-267. doi: 10.4103/0019-5154.159620[↩]
27. Tavakolpour S. Pemphigus trigger factors: special focus on pemphigus vulgaris and pemphigus foliaceus. Arch Dermatol Res. 2018 Mar;310(2):95-106. doi: 10.1007/s00403-017-1790-8[↩]
28. Crocker C. Radiation-induced pemphigus in a patient with an invasive ductal carcinoma of the breast: a case report. Oxf Med Case Reports. 2020 Jan 31;2020(1):omaa001. doi: 10.1093/omcr/omaa001[↩]
29. Firooz A, Mazhar A, Ahmed AR. Prevalence of autoimmune diseases in the family members of patients with pemphigus vulgaris. J Am Acad Dermatol. 1994 Sep;31(3 Pt 1):434-7. doi: 10.1016/s0190-9622(94)70206-3[↩]
30. Szafer F, Brautbar C, Tzfoni E, Frankel G, Sherman L, Cohen I, Hacham-Zadeh S, Aberer W, Tappeiner G, Holubar K, et al. Detection of disease-specific restriction fragment length polymorphisms in pemphigus vulgaris linked to the DQw1 and DQw3 alleles of the HLA-D region. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6542-5. doi: 10.1073/pnas.84.18.6542[↩]
31. Lombardi ML, Mercuro O, Ruocco V, Lo Schiavo A, Lombari V, Guerrera V, Pirozzi G, Manzo C. Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients. J Invest Dermatol. 1999 Jul;113(1):107-10. doi: 10.1046/j.1523-1747.1999.00626.x[↩]
32. Pollmann R, Schmidt T, Eming R, Hertl M. Pemphigus: a Comprehensive Review on Pathogenesis, Clinical Presentation and Novel Therapeutic Approaches. Clin Rev Allergy Immunol. 2018;54:1–25. doi: 10.1007/s12016-017-8662-z[↩][↩]
33. Brenner S, Goldberg I. Drug-induced pemphigus. Clin Dermatol. 2011 Jul-Aug;29(4):455-7. doi: 10.1016/j.clindermatol.2011.01.016[↩][↩]
34. Feng S, Zhou W, Zhang J, Jin P. Analysis of 6 cases of drug-induced pemphigus. Eur J Dermatol. 2011 Sep-Oct;21(5):696-9. doi: 10.1684/ejd.2011.1428[↩]
35. Ruocco V, Ruocco E, Lo Schiavo A, Brunetti G, Guerrera LP, Wolf R. Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. Clin Dermatol. 2013 Jul-Aug;31(4):374-381. doi: 10.1016/j.clindermatol.2013.01.004[↩]
36. Hammers CM, Stanley JR. Mechanisms of disease: pemphigus and bullous pemphigoid. Annu Rev Pathol. 2016 May 23;11:175–197. doi: 10.1146/annurev-pathol-012615-044313[↩]
37. Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol. 1999 Feb;40(2 Pt 1):167-70. doi: 10.1016/s0190-9622(99)70183-0[↩]
38. Didona D, Maglie R, Eming R, Hertl M. Pemphigus: Current and Future Therapeutic Strategies. Front Immunol. 2019 Jun 25;10:1418. doi: 10.3389/fimmu.2019.01418[↩]
39. Amagai M, Karpati S, Prussick R, Klaus-Kovtun V, Stanley JR. Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic. J Clin Invest. 1992 Sep;90(3):919-26. https://pmc.ncbi.nlm.nih.gov/articles/instance/329947/pdf/jcinvest00488-0243.pdf[↩]
40. Pemphigus vulgaris pathology. https://dermnetnz.org/topics/pemphigus-vulgaris-pathology[↩][↩][↩]
41. Hartmann V, Hariton WV, Rahimi S, Hammers CM, Ludwig RJ, Müller EJ, Hundt JE. The human skin organ culture model as an optimal complementary tool for murine pemphigus models. Lab Anim. 2023 Aug;57(4):381-395. doi: 10.1177/00236772221145647[↩]
42. Boch K, Dräger S, Zillikens D, Hudemann C, Hammers CM, Patzelt S, Schmidt E, Langan EA, Eming R, Ludwig RJ, Bieber K. Immunization with desmoglein 3 induces non-pathogenic autoantibodies in mice. PLoS One. 2021 Nov 3;16(11):e0259586. doi: 10.1371/journal.pone.0259586[↩]
43. Egu DT, Schmitt T, Waschke J. Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin. Front Immunol. 2022 May 20;13:884067. doi: 10.3389/fimmu.2022.884067[↩]
44. Kawamura T, Muramatsu K, Orita A, Mai Y, Sugai T, Haga N, Fujimura Y, Miyauchi T, Izumi K, Koga H, Ishii N, Ujiie H. Two cases of Hallopeau-type pemphigus vegetans with anti-desmoglein 1 and anti-desmocollin 3 antibodies without mucosal involvement. J Eur Acad Dermatol Venereol. 2023 Apr;37(4):e508-e510. doi: 10.1111/jdv.18704[↩]
45. Jindal A, Rao C, Pai SB, Rao R. Utility of oral mucosa as a substrate for the serodiagnosis of pemphigus: A descriptive analysis. Indian J Dermatol Venereol Leprol. 2022 Mar-Apr;88(2):156-161. doi: 10.25259/IJDVL_469_20[↩]
46. Ishii K, Yoshida K, Stanley JR, Yamagami J, Amagai M, Ishiko A. Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin. J Invest Dermatol. 2020 Oct;140(10):1919-1926.e7. doi: 10.1016/j.jid.2020.02.010[↩]
47. Schmitt T, Waschke J. Autoantibody-Specific Signalling in Pemphigus. Front Med (Lausanne). 2021 Aug 9;8:701809. doi: 10.3389/fmed.2021.701809[↩]
48. Oktarina DA, van der Wier G, Diercks GF, Jonkman MF, Pas HH. IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis. Br J Dermatol. 2011 Sep;165(3):552-62. doi: 10.1111/j.1365-2133.2011.10463.x[↩]
49. Broussard KC, Leung TG, Moradi A, Thorne JE, Fine JD. Autoimmune bullous diseases with skin and eye involvement: Cicatricial pemphigoid, pemphigus vulgaris, and pemphigus paraneoplastica. Clin Dermatol. 2016;34:205–213. doi: 10.1016/j.clindermatol.2015.11.006[↩][↩]
50. Becker BA, Gaspari AA. Pemphigus vulgaris and vegetans. Dermatol Clin. 1993 Jul;11(3):429-52.[↩]
51. Sar-Pomian M, Kurzeja M, Rudnicka L, Olszewska M. The value of trichoscopy in the differential diagnosis of scalp lesions in pemphigus vulgaris and pemphigus foliaceus. An Bras Dermatol. 2014 Nov-Dec;89(6):1007-12. doi: 10.1590/abd1806-4841.20143830[↩]
52. Venugopal SS, Murrell DF. Diagnosis and clinical features of pemphigus vulgaris. Dermatol Clin. 2011;29:373–380. doi: 10.1016/j.det.2011.03.004[↩]
53. Kridin K. Emerging treatment options for the management of pemphigus vulgaris. Ther Clin Risk Manag. 2018 Apr 27;14:757-778. doi: 10.2147/TCRM.S142471[↩]
54. Joly P, Horvath B, Patsatsi Α, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1900-1913. doi: 10.1111/jdv.16752[↩]
55. Ruocco E, Wolf R, Ruocco V, Brunetti G, Romano F, Lo Schiavo A. Pemphigus: Associations and management guidelines: Facts and controversies. Clin Dermatol. 2013;31:382–390. doi: 10.1016/j.clindermatol.2013.01.005[↩][↩][↩][↩][↩][↩]
56. Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, et al. British Association of Dermatologists’ guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol. 2017;177:1170–1201. doi: 10.1111/bjd.15930[↩][↩][↩][↩][↩][↩]
57. Ahmed AR, Moy R. Death in pemphigus. J Am Acad Dermatol. 1982;7:221–228. doi: 10.1016/s0190-9622(82)70111-2[↩]
58. Frew JW, Martin LK, Murrell DF. Evidence-based treatments in pemphigus vulgaris and pemphigus foliaceus. Dermatol Clin. 2011;29:599–606. doi: 10.1016/j.det.2011.07.001[↩]
59. Chams-Davatchi C, Esmaili N, Daneshpazhooh M, Valikhani M, Balighi K, Hallaji Z, et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol. 2007;57:622–628. doi: 10.1016/j.jaad.2007.05.024[↩]
60. Rao PN, Lakshmi TS. Pulse therapy and its modifications in pemphigus: a six year study. Indian J Dermatol Venereol Leprol. 2003 Sep-Oct;69(5):329-33.[↩]
61. Atzmony L, Hodak E, Leshem YA, Rosenbaum O, Gdalevich M, Anhalt GJ, et al. The role of adjuvant therapy in pemphigus: A systematic review and meta- analysis. J Am Acad Dermatol. 2015;73:264–271. doi: 10.1016/j.jaad.2015.04.038[↩]
62. Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest. 2003;111:1122–1124. doi: 10.1172/JCI18384[↩]
63. Chams-Davatchi C, Mortazavizadeh A, Daneshpazhooh M, Davatchi F, Balighi K, Esmaili N, et al. Randomized double blind trial of prednisolone and azathioprine, vs. prednisolone and placebo, in the treatment of pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2013;27:1285–1292. doi: 10.1111/j.1468-3083.2012.04717.x[↩][↩]
64. Chaidemenos G, Apalla Z, Koussidou T, Papagarifallou I, Ioannides D. High dose oral prednisone vs. prednisone plus azathioprine for the treatment of oral pemphigus: a retrospective, bi-centre, comparative study. J Eur Acad Dermatol Venereol. 2011;25:206–210. doi: 10.1111/j.1468-3083.2010.03753.x[↩]
65. Committee for Guidelines for the Management of Pemphigus Disease. Amagai M, Tanikawa A, Shimizu T, Hashimoto T, Ikeda S, et al. Japanese guidelines for the management of pemphigus. J Dermatol. 2014;41:471–486. doi: 10.1111/1346-8138.12486[↩][↩]
66. Tavakolpour S. Current and future treatment options for pemphigus: Is it time to move towards more effective treatments? Int Immunopharmacol. 2017;53:133–142. doi: 10.1016/j.intimp.2017.10.027[↩][↩][↩][↩][↩]
67. Olejarz W, Bryk D, Zapolska-Downar D. Mycophenolate mofetil–a new atheropreventive drug? Acta Pol Pharm. 2014 May-Jun;71(3):353-61. https://www.ptfarm.pl/pub/File/Acta_Poloniae/2014/3/353.pdf[↩]
68. Cholera M, Chainani-Wu N. Management of Pemphigus Vulgaris. Adv Ther. 2016;33:910–958. doi: 10.1007/s12325-016-0343-4[↩][↩]
69. Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol. 2011;64:903–908. doi: 10.1016/j.jaad.2010.04.039[↩][↩]
70. Vyas N, Patel NS, Cohen GF. Mycophenolate mofetil as a first-line steroid-sparing agent in the treatment of pemphigus vulgaris. J Drugs Dermatol. 2013 Feb;12(2):210-6. https://jddonline.com/articles/mycophenolate-mofetil-as-a-first-line-steroid-sparing-agent-in-the-treatment-of-pemphigus-vulgaris-S1545961613P0210X[↩]
71. Beissert S, Mimouni D, Kanwar AJ, Solomons N, Kalia V, Anhalt GJ. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo controlled trial. J Invest Dermatol. 2010;130:2041–2048. doi: 10.1038/jid.2010.91[↩]
72. Gürcan HM, Ahmed AR. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. Br J Dermatol. 2009;161:723–731. doi: 10.1111/j.1365-2133.2009.09246.x[↩]
73. Baum S, Greenberger S, Samuelov L, Solomon M, Lyakhovitsky A, Trau H, et al. Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris. Eur J Dermatol. 2012;22:83–87. doi: 10.1684/ejd.2011.1611[↩]
74. Tran KD, Wolverton JE, Soter NA. Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients. Br J Dermatol. 2013;169:916–921. doi: 10.1111/bjd.12474[↩]
75. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immuneglobulin. N Engl J Med. 2006;355:1772–1779. doi: 10.1056/NEJMoa062930[↩][↩][↩]
76. Huang A, Madan RK, Levitt J. Future therapies for pemphigus vulgaris:Rituximab and beyond. J Am Acad Dermatol. 2016;74:746–753. doi: 10.1016/j.jaad.2015.11.008[↩][↩][↩][↩]
77. Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol. 2015;95:928–932. doi: 10.2340/00015555-2116[↩]
78. Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389:2031–2040. doi: 10.1016/S0140-6736(17)30070-3[↩][↩]
79. Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, Ortonne N, Hüe S, Paul M, et al. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol. 2015;151:200–203. doi: 10.1001/jamadermatol.2014.2421[↩][↩]
80. Tavakolpour S, Mahmoudi H, Balighi K, Abedini R, Daneshpazhooh M. Sixteen-year history of rituximab therapy for 1085 pemphigus vulgaris patients: A systematic review. Int Immunopharmacol. 2018;54:131–138. doi: 10.1016/j.intimp.2017.11.005[↩][↩][↩]
81. Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2) J Am Acad Dermatol. 2007;56:e55–e79. doi: 10.1016/j.jaad.2006.07.019[↩]
82. Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR, Werth VP, et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012;148:1031–1036. doi: 10.1001/archdermatol.2012.1522[↩]
83. Murrell DF, Peña S, Joly P, et al. Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts. J Am Acad Dermatol. 2018 doi: 10.1016/j.jaad.2018.02.021[↩]
84. Leshem YA, Hodak E, David M, Anhalt GJ, Mimouni D. Successful treatment of pemphigus with biweekly 1-g infusions of rituximab: a retrospective study of 47 patients. J Am Acad Dermatol. 2013;68:404–411. doi: 10.1016/j.jaad.2012.08.010[↩]
85. Eming R, Nagel A, Wolff-Franke S, Podstawa E, Debus D, Hertl M. Rituximab exerts a dual effect in pemphigus vulgaris. J Invest Dermatol. 2008;128:2850–2858. doi: 10.1038/jid.2008.172[↩]
86. Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. French study group on autoimmune bullous skin diseases. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017 May 20;389(10083):2031-2040. doi: 10.1016/S0140-6736(17)30070-3[↩]
87. Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pità O. Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term follow-up. J Am Acad Dermatol. 2012;67:617–622. doi: 10.1016/j.jaad.2011.11.007[↩]
88. Heelan K, Al-Mohammedi F, Smith MJ, Knowles S, Lansang P, Walsh S, et al. Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703–708. doi: 10.1001/jamadermatol.2013.6739[↩]
89. Kanwar AJ, Vinay K, Sawatkar GU, Dogra S, Minz RW, Shear NH, et al. Clinical and immunological outcomes of high and low dose rituximab treatments in pemphigus patients:a randomized comparative observer blinded study. Br J Dermatol. 2014;170:1341–1349. doi: 10.1111/bjd.12972[↩]
90. Amber KT, Hertl M. An assessment of treatment history and its association with clinical outcomes and relapse in 155 pemphigus patients with response to a single cycle of rituximab. J Eur Acad Dermatol Venereol. 2015;29:777–782. doi: 10.1111/jdv.12678[↩]
91. Joly P, Mouquet H, Roujeau JC, D’Incan M, Gilbert D, Jacquot S, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med. 2007;357:545–552. doi: 10.1056/NEJMoa067752[↩]
92. Londhe PJ, Kalyanpad Y, Khopkar US. Intermediate doses of rituximab used as adjuvant therapy in refractory pemphigus. Indian J Dermatol Venereol Leprol. 2014;80:300–305. doi: 10.4103/0378-6323.136832[↩]
93. Ahmed AR, Nguyen T, Kaveri S, Spigelman ZS. First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic corticosteroids and immunosuppressive agents: preliminary retrospective study with a seven year follow-up. Int Immunopharmacol. 2016;34:25–31. doi: 10.1016/j.intimp.2016.02.013[↩]
94. Behzad M, Möbs C, Kneisel A, Möller M, Hoyer J, Hertl M, et al. Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical remission in difficult-to-treat pemphigus vulgaris. Br J Dermatol. 2012;166:844–852. doi: 10.1111/j.1365-2133.2011.10732.x[↩]
95. Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, Yayli S, et al. Pemphigus. S2 guideline for diagnosis and treatment-guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV) J Eur Acad Dermatol Venereol. 2015;29:405–414. doi: 10.1111/jdv.12772[↩][↩]
96. Shaik F, Botha J, Aboobaker J, Mosam A. Corticosteroid /cyclophosphamide pulse treatment in south African patients with pemphigus. Clin Exp Dermatol. 2010;35:245–250. doi: 10.1111/j.1365-2230.2009.03450.x[↩]
97. Zhao CY, Murrell DF. Pemphigus Vulgaris: An Evidence-Based Treatment Update. Drugs. 2015;75:271–284. doi: 10.1007/s40265-015-0353-6[↩]
98. Sharma VK, Khandpur S. Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroid in the management of pemphigus vulgaris. Clin Exp Dermatol. 2013;38:659–664. doi: 10.1111/ced.12073[↩]
99. Rose E, Wever S, Zilliken D, Linse R, Haustein UF, Bröcker EB, et al. Intravenous dexamethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: results of a multicenter prospectively randomized study. J Dtsch Dermatol Ges. 2005;3:200–206. doi: 10.1111/j.1610-0378.2005.04747.x[↩]
100. Sethy PK, Khandpur S, Sharma VK. Randomized open comparative trial of dexamethasone-cyclophosphamide pulse and daily oral cyclophosphamide versus cyclophosphamide pulse and daily oral prednisolone in pemphigus vulgaris. Indian J Dermatol Venereol Leprol. 2009;75:476–482. doi: 10.4103/0378-6323.55390[↩]
101. Parmar NV, Kanwar AJ, Minz RW, Parsad D, Vinay K, Tsuruta D, et al. Assessment of the therapeutic benefit of dexamethasone cyclophosphamide pulse versus only oral cyclophosphamide in phase II of the dexamethasone cyclophosphamide pulse therapy: a preliminary prospective randomized controlled study. Indian J Dermatol Venereol Leprol. 2013;79:70–76. doi: 10.4103/0378-6323.104672[↩]
102. Gürcan HM, Ahmed AR. Efficacy of dapsone in the treatment of pemphigus and pemphigoid: analysis of current data. Am J Clin Dermatol. 2009;10:383–396. doi: 10.2165/11310740-000000000-00000[↩]
103. Baum S, Debby A, Gilboa S, Trau H, Barzilai A. Efficacy of Dapsone in the treatment of pemphigus vulgaris: a single-center case study. Dermatology. 2016;232:578–585. doi: 10.1159/000448028[↩]
104. Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, et al. Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Am J Clin Dermatol. 2007;8:85–92. doi: 10.2165/00128071-200708020-00004[↩]
105. Sinha AA, Hoffman MB, Janicke EC. Pemphigus vulgaris: approach to treatment. Eur J Dermatol. 2015;25:103–113. doi: 10.1684/ejd.2014.2483[↩][↩]
106. Arumugham VB, Rayi A. Intravenous Immunoglobulin (IVIG) [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554446[↩]
107. Chaigne B, Mouthon L. Mechanisms of action of intravenous immunoglobulin. Transfus Apher Sci. 2017;56:45–49. doi: 10.1016/j.transci.2016.12.017[↩]
108. Svecova D. IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects. Australas J Dermatol. 2016;57:141–144. doi: 10.1111/ajd.12422[↩]
109. Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. 2009;60:595–603. doi: 10.1016/j.jaad.2008.09.052[↩]
110. Fuchs K, Rummler S, Ries W, Helmschrott M, Selbach J, Ernst F, Morath C, Gauly A, Atiye S, Stauss-Grabo M, Giefer M. Performance, clinical effectiveness, and safety of immunoadsorption in a wide range of indications. Ther Apher Dial. 2022 Feb;26(1):229-241. doi: 10.1111/1744-9987.13663[↩]
111. Eming R, Rech J, Barth S, Kalden JR, Schuler G, Harrer T, et al. Prolonged clinical remission of patients with severe pemphigus upon rapid removal of desmoglein- reactive autoantibodies by immunoadsorption. Dermatology. 2006;212:177–187. doi: 10.1159/000090659[↩]
112. Meyersburg D, Schmidt E, Kasperkiewicz M, Zillikens D. Immunoadsorption in dermatology. Ther Apher Dial. 2012;16:311–320. doi: 10.1111/j.1744-9987.2012.01075.x[↩]
113. Gach JE, Ilchyshyn A. Beneficial effects of topical tacrolimus on recalcitrant erosions of pemphigus vulgaris. Clin Exp Dermatol. 2004;29:271–272. doi: 10.1111/j.1365-2230.2004.01499.x[↩]
114. Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58:1043–1046. doi: 10.1016/j.jaad.2008.01.012[↩]
115. Czernik A, Bystryn JC. Kinetics of response to conventional treatment in patients with pemphigus vulgaris. Arch Dermatol. 2008;144:682–683. doi: 10.1001/archderm.144.5.682[↩]
116. Martin LK, Werth V, Villanueva E, Segall J, Murrell DF. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev. 2009:CD006263. doi: 10.1002/14651858.CD006263.pub2[↩]
117. Herbst A, Bystryn JC. Patterns of remission in pemphigus vulgaris. J Am Acad Dermatol. 2000;42:422–427. doi: 10.1016/s0190-9622(00)90213-5[↩]
118. Almugairen N, Hospital V, Bedane C, Duvert-Lehembre S, Picard D, Tronquoy AF, et al. Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids. J Am Acad Dermatol. 2013;69:583–588. doi: 10.1016/j.jaad.2013.05.016[↩]
119. Bystryn J, Steinman NM. The Adjuvant Therapy of Pemphigus: An Update. Arch Dermatol. 1996;132(2):203–212. doi:10.1001/archderm.1996.03890260105016[↩][↩]
120. Kridin K, Sagi SZ, Bergman R. Mortality and cause of death in Israeli patients with pemphigus. Acta Derm Venereol. 2017;97:607–611. doi: 10.2340/00015555-2611[↩]
121. Hsu DY, Brieva J, Sinha AA, Langan SM, Silverberg JI. Comorbidities and inpatient mortality for pemphigus in the USA. Br J Dermatol. 2016;174:1290–1298. doi: 10.1111/bjd.14463[↩]
122. Meurer M. Immunosuppressive therapy for autoimmune bullous diseases. Clin Dermatol. 2012;30:78–83. doi: 10.1016/j.clindermatol.2011.03.013[↩]