Pemphigus Foliaceus and Other Rare Forms: Symptoms, Diagnosis and Treatment

What is Pemphigus Foliaceus?

The pemphigus group comprises a spectrum of rare, serious autoimmune blistering diseases of the skin and mucous membranes. They are classified according to the depth of the skin layer affected:

Deep pemphigus (suprabasal cleavage, which occurs deeper in the epidermis):

• Pemphigus vulgaris
• Pemphigus vegetans

Superficial pemphigus (subcorneal or granular layer cleavage, which occurs near the skin surface):

• Pemphigus foliaceus
• Pemphigus erythematosus (sebaceous pemphigus)
• Brazilian endemic pemphigus (Fogo Selvagem)
• IgA pemphigus
• Paraneoplastic pemphigus

All forms share a common hallmark: the formation of fluid-filled blisters (bullae) within the epidermis. These blisters are characteristically:

• Flaccid (not tense), reflecting the superficial or mid-epidermal location of the split
• Fragile: it ruptures easily, leaving raw and painful erosions
• Clear in content, initially containing serous fluid

General Course and Prognosis

All pemphigus variants follow a chronic course characterized by alternating periods of remission and relapse. The introduction of systemic corticosteroids decades ago dramatically improved the prognosis of all forms. Some variants (particularly pemphigus foliaceus and erythematosus) tend to worsen during the summer months, likely due to ultraviolet light exposure.

The main complications across all forms include:

• Superimposed infections: The open erosions act as portals of entry for bacteria and fungi
• Fluid and electrolyte loss, which occurs through extensive erosions
• Malnutrition, particularly when it involves severe oral mucosa damage, can have serious consequences

There are no known preventive measures for any of the pemphigus variants.

For an in-depth discussion of the most common form, pemphigus vulgaris, please refer to the dedicated article.

---

Cause

All forms of pemphigus are caused by a pathological autoimmune reaction. The immune system produces autoantibodies that, instead of defending the body against external pathogens (bacteria, viruses), attack the body’s own skin structures.

Molecular Mechanism: Acantholysis

The characteristic blisters of pemphigus result from the loss of adhesion between keratinocytes, which are the primary cells that make up the epidermis. This occurs through the following mechanism:

1. Autoantibodies (primarily of the IgG class in most variants, IgA in IgA pemphigus) bind to specific proteins on the surface of keratinocytes
2. Their primary targets are the desmogleins, which are structural proteins of the desmosomes. These desmosomes are the intercellular adhesion structures that hold keratinocytes together
   • Desmoglein 3 (Dsg3): Predominantly targeted in deep pemphigus (vulgaris, vegetans)
   • Desmoglein 1 (Dsg1): The primary target in superficial pemphigus (foliaceus, erythematosus, endemic)
3. Autoantibody binding disrupts desmosome function, causing the intercellular bonds to break down
4. The resulting loss of cell-to-cell cohesion within the epidermis, known as acantholysis, creates the intraepidermal cavities that appear clinically as blisters

What Triggers Autoantibody Production?

The precise trigger for autoantibody production in most pemphigus variants remains unknown. Genetic predisposition (particularly certain HLA alleles), environmental factors, and in some cases drugs or underlying malignancies may all play a role.

Risk Factors

No universally recognized environmental risk factors exist for most pemphigus variants. The one notable exception is:

• Brazilian endemic pemphigus (Fogo Selvagem): An infectious agent, which has not yet been identified, transmitted by the black fly Simulium pruinosum is considered a probable environmental trigger. The geographic distribution of the disease closely mirrors the habitat of this insect, and case numbers peak during periods of maximal insect density.

Transmission and Contagiousness

Pemphigus diseases are not contagious. They cannot be transmitted from person to person. The autoimmune process is entirely internal to the individual.

---

Symptoms by Variant

Pemphigus Vegetans

Pemphigus vegetans is a rare variant of pemphigus vulgaris, distinguished by its distinctive lesion morphology.

Target antigens: Desmoglein 1 and Desmoglein 3

Clinical features:

• Vegetating lesions: warty, exophytic (growing outward) papillomatous growths with a moist, weeping surface that often exudes fluid
• Typically located in intertriginous areas, which include the large body folds: the groin, axillae, inframammary region, and umbilicus
• Oral mucosa involvement is common
• The vegetating plaques may represent either:
  • A form of abnormal re-epithelialization (healing response) of prior bullous or erosive lesions
  • The sequelae of pustular (pus-containing) skin lesions

Diagnosis: Clinical examination alone is insufficient. Skin biopsy with histopathology, direct immunofluorescence (DIF), and indirect immunofluorescence (IIF) are required for definitive diagnosis.

Pemphigus Foliaceus

Pemphigus foliaceus is a very rare superficial form of pemphigus, primarily affecting adults. It is characterized by acantholysis at the granular layer, which is a very superficial level of the epidermis.

Target antigen: Desmoglein 1 exclusively

Clinical features:

• Onset in the upper body: Scalp, face, upper trunk, and upper limbs
• Large, fragile bullae that rupture easily and rapidly transform into crusty scales, classically compared to “puff pastry” or “corn flakes” in texture and appearance
• After rupture, leaves extensive erosions covered by yellowish-brown crusts
• Exudation (continuous oozing of inflammatory fluid) keeps the skin persistently moist
• Mucous membranes are spared, a critical distinguishing feature from pemphigus vulgaris
• In severe cases, lesions spread and coalesce to produce erythroderma, which involves generalized redness and scaling affecting the majority of the body surface

Important: The superficiality of the blistering means that intact bullae are rarely seen clinically; the predominant finding is crusted erosions.

Pemphigus Erythematosus

Pemphigus erythematosus, also known as Senear-Usher syndrome or sebaceous pemphigus, is a variant of pemphigus foliaceus. It shares clinical and laboratory features with systemic lupus erythematosus (SLE), including positive ANA titers.

Target antigen: Desmoglein 1

Clinical features:

• Lesions are almost always asymptomatic, a distinctive characteristic
• Predominantly involves photoexposed areas: face, scalp, décolleté (sun-exposed neckline)
• Facial lesions may closely resemble:
  • Lupus erythematosus: Indurated erythematous plaques in a butterfly distribution
  • Seborrheic dermatitis: Erythematous, scaly patches on the nose and cheeks
• Trunk lesions show erosions (which help confirm the correct diagnosis over lupus)
• Mucous membranes are spared
• Tends to worsen with sun exposure, so sunscreen use is important in management

Brazilian Endemic Pemphigus (Fogo Selvagem)

Fogo Selvagem (Portuguese for “wild fire”) is a geographically restricted, endemic form of pemphigus foliaceus found predominantly in South America, particularly:

• Brazil (where it was first described)
• Argentina, Paraguay, Bolivia, Peru, Venezuela

It is endemic in border zones between civilized areas and tropical forests, where the black fly Simulium pruinosum is prevalent.

Target antigen: Desmoglein 1

Epidemiology:

• Predominantly affects men who work outdoors in endemic regions
• Case numbers peak seasonally when black fly populations are at their maximum density
• The putative infectious agent transmitted by the fly remains unidentified

Clinical features:

• Blistering erosions predominantly affecting the upper body: scalp, face, upper trunk
• Lesions are intensely burning and painful, and the name “wild fire” reflects this characteristic
• Mucous membranes are spared
• Clinically and histologically identical to pemphigus foliaceus

This endemic form demonstrates that environmental triggers (likely infectious) can initiate pathological autoimmune responses against skin desmoglein proteins in genetically susceptible individuals.

IgA Pemphigus

IgA pemphigus is a distinct and uncommon variant characterized by the presence of IgA-class autoantibodies (rather than the IgG class found in all other pemphigus forms) targeting desmosomal proteins.

Special population: Described particularly in patients with HIV/AIDS

Clinical features:

• Vesicles (clear fluid-filled) or pustules (pus-filled) predominantly on the trunk
• Can be clinically indistinguishable from Sneddon-Wilkinson subcorneal pustular dermatosis. The distinction requires immunofluorescence studies
• Associated with IgA monoclonal gammopathy in some patients

Key distinguishing feature: Immunofluorescence studies reveal IgA deposits on keratinocyte surfaces, rather than IgG, which is why the condition is named as such.

Paraneoplastic Pemphigus

Paraneoplastic pemphigus (PNP) is the rarest and most severe form of pemphigus. It is characterized by its necessary association with an underlying neoplasm, typically of hematological origin.

• Non-Hodgkin lymphoma (most common)
• Chronic lymphocytic leukemia (CLL)
• Thymoma
• Castleman disease
• Less commonly: sarcomas, carcinomas

Pathogenesis: The tumor is thought to stimulate the production of autoantibodies directed not only against desmoglein 1 and 3 but also against a broader array of epidermal structural proteins, including:

• Desmoplakins 1 and 2
• Periplakin
• Plectin
• Envoplakin
• BP230 (bullous pemphigoid antigen)

This broader antigenic target explains the more severe, widespread, and treatment-resistant nature of PNP.

Clinical features:

• Severe, painful oral erosions are the most clinically prominent feature. These include extensive ulcerations of the oral mucosa, lips (which are often covered with thick hemorrhagic crusts), and throat. As a result, eating becomes extremely difficult or impossible
• Conjunctival, anogenital, and other mucosal surfaces may also be severely involved (unlike other superficial pemphigus forms)
• Cutaneous lesions are highly polymorphic; multiple different morphologies may coexist, creating significant diagnostic confusion
  • Intact blisters
  • Erythematous targetoid (concentric ring) lesions resembling erythema multiforme
  • Papular erythematous lesions
  • Lichenoid lesions
• Lesions predominantly involve the trunk and extremities
• Pulmonary involvement (bronchiolitis obliterans) is a devastating complication unique to PNP

---

Diagnosis

Diagnosis is based on a combination of clinical skin and mucosal examination and laboratory confirmation. At least one of the following laboratory methods is required in all cases:

1. Indirect Immunofluorescence (IIF)

IIF detects circulating anti-skin antibodies in the patient’s blood:

The patient’s serum, which is presumed to contain autoantibodies against epidermal components, is incubated with a substrate tissue containing the target antigens. This tissue typically includes:

• Sections of normal human skin
• Monkey esophagus sections
• Rat bladder sections
• If the serum contains anti-epidermal autoantibodies, they bind to the substrate
• Fluorescent-labeled anti-human immunoglobulin antibodies are then applied, which bind to the autoantibody-antigen complexes, making them visible under fluorescence microscopy
• Positive in approximately 80% of pemphigus cases
• Allows titration of antibody levels, which correlates with disease activity

2. Direct Immunofluorescence (DIF)

DIF detects autoantibody deposits directly within the patient’s skin:

• Performed on a biopsy of perilesional (clinically normal) skin taken from adjacent to a blister
• The biopsy is incubated with fluorescent-labeled anti-human immunoglobulin antibodies
• In pemphigus, this reveals a characteristic “fishnet” or “honeycomb” pattern of IgG (and/or IgA in IgA pemphigus) and complement (C3) deposits on the surface of keratinocytes throughout the epidermis
• DIF is considered the gold standard for pemphigus diagnosis, as it is positive in nearly 100% of active cases

3. Western Blot / ELISA

• Western blot and enzyme-linked immunosorbent assay (ELISA) can specifically identify the target antigens, confirming whether autoantibodies are directed against desmoglein 3 (deep pemphigus), desmoglein 1 (superficial pemphigus), or both
• ELISA for anti-Dsg1 and anti-Dsg3 antibodies is now widely used for initial diagnosis and monitoring of disease activity during treatment

4. Skin Biopsy and Histopathology

A biopsy of a fresh blister or lesional skin examined under light microscopy reveals:

• Intraepidermal cleavage (the blister cavity forming within the epidermis)
  • Suprabasal in deep pemphigus (vegetans, vulgaris)
  • Subcorneal (superficial) in superficial pemphigus (foliaceus, erythematosus, endemic)
• Acantholytic cells, rounded and detached keratinocytes, float within the blister cavity
• Modest inflammatory infiltrate in the dermis, predominantly lymphocytes

---

Pemphigus and Pregnancy

All forms of pemphigus can cause complications during pregnancy and carry risks for the fetus, including:

• Disease flares: Pregnancy can trigger or worsen autoimmune activity
• Neonatal pemphigus: maternal IgG autoantibodies cross the placenta and can cause transient blistering in the newborn. This condition is usually self-limited, resolving as maternal antibodies are cleared from the infant’s circulation
• Risks associated with systemic immunosuppressive therapy to mother and fetus

The authors of a major systematic review on the management of pemphigus in pregnancy (Tavakolpour et al., 2017) conclude that planning conception during disease remission and when systemic therapy has been minimized significantly reduces the risk of disease flares during pregnancy.

It is well documented that low-dose oral corticosteroids and topical corticosteroid creams can be used during pregnancy with an acceptable safety profile, particularly when the benefits of disease control outweigh the risks. All treatment decisions during pregnancy must be made in close collaboration between the dermatologist and the obstetrician.

---

Treatment

Corticosteroids: First-Line Treatment

As with pemphigus vulgaris, the cornerstone of treatment for all pemphigus variants is oral corticosteroids. The most commonly used agent is prednisone, initiated at:

• Full induction dose: 1 mg/kg of body weight per day
• Once clinical remission is achieved (cessation of new blister formation, beginning of healing), the dose is gradually tapered over months

Steroid-Sparing Immunosuppressants

To minimize the significant long-term side effects of chronic corticosteroid use, adjuvant immunosuppressants are added once remission is established:

• Azathioprine: the most commonly used steroid-sparing agent
• Mycophenolate mofetil: increasingly preferred due to a favorable efficacy/tolerability profile
• Methotrexate
• Cyclophosphamide reserved for severe, refractory cases

Biological Therapies

For severe or treatment-resistant cases, targeted biologic agents are now available:

• Rituximab (anti-CD20 monoclonal antibody) depletes B lymphocytes responsible for autoantibody production. It is now considered a first-line treatment in severe pemphigus in many guidelines and is sometimes combined with corticosteroids from the outset

Topical Treatments

• High-potency topical corticosteroids: Used for localized or mild disease, or as adjuncts to systemic therapy
• Topical antiseptics: For wound care and prevention of secondary infection of erosions
• Oral care: Regular antiseptic mouthwashes and careful oral hygiene for mucosal involvement

Special Considerations: Paraneoplastic Pemphigus

Paraneoplastic pemphigus is the most challenging form to treat:

• If the underlying neoplasm is benign (e.g., benign thymoma, Castleman disease), its surgical removal may lead to significant improvement or even remission of the skin disease
• When the underlying malignancy is malignant (e.g., non-Hodgkin lymphoma, CLL), the blistering disease tends to be more severe and resistant to therapy
• In particular, oral mucosal lesions are notoriously treatment-resistant and severely impair the patient’s ability to eat and drink
• The same immunosuppressants used in other forms of pemphigus are employed, but with generally less favorable responses
• Pulmonary involvement (bronchiolitis obliterans), when present, worsens the prognosis significantly

---

Sources and Bibliography

• Tavakolpour S, Mirsafaei H, Delshad S. Management of pemphigus disease in pregnancy. Am J Reprod Immunol. 2017;77. doi: 10.1111/aji.12601.
• Cainelli T., Giannetti A., Rebora A. Manuale di dermatologia medica e chirurgica. McGraw-Hill, 4th edition.
• Saurat J, Grosshans E., Laugier P, Lachapelle J. Dermatologia e malattie sessualmente trasmesse. Italian edition edited by Girolomoni G. and Giannetti A. Third edition, 2006. Masson.
• Amagai M. “Pemphigus”. In: Goldsmith LA, et al., eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. McGraw-Hill; 2012.
• Murrell DF, et al. “Definitions and outcome measures for pemphigus: recommendations by an international panel of experts”. Journal of the American Academy of Dermatology. 2008;58(6):1043–1046.
• Joly P, 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”. The Lancet. 2017;389(10083):2031–2040.
• DermNet NZ: Pemphigus
• National Organization for Rare Disorders (NORD) Pemphigus