Pemphigus

Overview

Pemphigus is a rare group of autoimmune blistering diseases that affect the skin and mucous membranes. In pemphigus, the immune system mistakenly produces antibodies against proteins in the skin called desmogleins, which normally help skin cells stick together. When these proteins are attacked, skin cells separate from each other, leading to the formation of painful blisters and erosions. Without treatment, pemphigus can be life-threatening due to fluid loss, infection, and other complications.

The condition affects approximately 0.75 to 5 people per million annually, with variations in incidence among different ethnic groups. Pemphigus is more common in people of Mediterranean, Middle Eastern, and South Asian descent. The disease typically appears in middle-aged or older adults, though it can occur at any age. Both men and women are affected equally, though some subtypes may show slight gender preferences.

There are several types of pemphigus, with pemphigus vulgaris being the most common form, accounting for about 70% of cases. Pemphigus foliaceus is the second most common type. Each type has distinct characteristics regarding the location and depth of blisters, severity, and prognosis. Modern treatments have dramatically improved outcomes, reducing mortality from over 90% to less than 10% with appropriate therapy.

Symptoms

The symptoms of pemphigus vary depending on the type and severity of the disease. The hallmark feature is the development of blisters and erosions on the skin and/or mucous membranes. These blisters are fragile and break easily, leaving painful raw areas that can become infected. The progression and location of symptoms help distinguish between different types of pemphigus.

Primary Symptoms

Pemphigus Vulgaris Symptoms

Pemphigus vulgaris typically begins with painful erosions in the mouth, which may precede skin involvement by weeks or months:

• Oral lesions: Painful erosions on the gums, inner cheeks, tongue, or throat
• Difficulty eating: Due to painful mouth sores
• Skin blisters: Flaccid (loose) blisters that rupture easily
• Nikolsky sign: Skin slips off with gentle rubbing
• Widespread involvement: Can affect any area of skin
• Nail changes: Paronychia or nail dystrophy may occur

Pemphigus Foliaceus Symptoms

This form typically doesn't involve mucous membranes and has more superficial blisters:

• Scaly, crusty erosions: Rather than intact blisters
• Seborrheic distribution: Face, scalp, chest, and back
• Itching or burning: More common than in pemphigus vulgaris
• No oral involvement: Key distinguishing feature
• Erythematous base: Red, inflamed skin beneath lesions

Other Forms and Their Characteristics

Systemic Symptoms

Beyond skin manifestations, pemphigus can cause:

• Fatigue and malaise
• Weight loss (due to painful oral lesions)
• Secondary infection signs
• Dehydration from fluid loss
• Protein loss through skin
• Psychological distress

Causes

Pemphigus is an autoimmune disease caused by the production of autoantibodies against specific proteins in the skin. Understanding the underlying mechanisms helps explain why blisters form and guides treatment approaches. While the exact trigger for autoantibody production remains unclear, several factors contribute to disease development.

Autoimmune Mechanism

The fundamental cause of pemphigus is the immune system's misdirected attack on the skin:

• Autoantibody production: IgG antibodies target desmoglein proteins
• Desmoglein 3: Primary target in pemphigus vulgaris (found in mucous membranes and deep skin)
• Desmoglein 1: Primary target in pemphigus foliaceus (found in superficial skin)
• Acantholysis: Loss of cell-to-cell adhesion leads to blister formation
• Complement activation: May contribute to tissue damage

Genetic Factors

Genetic predisposition plays a significant role:

• HLA associations: Certain HLA types increase susceptibility
  • HLA-DR4 and HLA-DQ in pemphigus vulgaris
  • HLA-DR14 in pemphigus foliaceus
• Ethnic clustering: Higher incidence in certain populations
• Familial cases: Rare but documented
• Genetic polymorphisms: In immune regulatory genes

Environmental Triggers

Various environmental factors may trigger pemphigus in genetically susceptible individuals:

Medications (Drug-Induced Pemphigus)

• Thiol drugs: Penicillamine, captopril, enalapril
• Phenol drugs: Aspirin, rifampin, phenobarbital
• Others: NSAIDs, antibiotics, antihypertensives
• Mechanism: May unmask subclinical disease or directly damage desmogleins

Other Environmental Factors

• Infections: Viral infections may trigger onset
• UV radiation: May exacerbate pemphigus foliaceus
• Dietary factors: Garlic, leeks, and other alliums in certain populations
• Physical trauma: May precipitate lesions (Koebner phenomenon)
• Stress: Psychological stress may trigger flares

Special Forms

Endemic Pemphigus (Fogo Selvagem)

A form of pemphigus foliaceus endemic to certain regions:

• Found in rural Brazil, Colombia, and Tunisia
• Possibly triggered by insect bites (sandfly)
• Environmental factors play major role
• Affects younger individuals and families

Paraneoplastic Pemphigus

Associated with underlying malignancy:

• Lymphoproliferative disorders most common
• Antibodies against multiple antigens
• More severe prognosis
• Treatment of cancer may improve skin disease

Risk Factors

While pemphigus can affect anyone, certain factors increase the likelihood of developing the disease. Understanding these risk factors helps identify high-risk individuals and may guide screening in certain populations. Most people with risk factors never develop pemphigus, highlighting the complex interplay between genetics and environment.

Demographic Risk Factors

• Age: Most common between 40-60 years, though can occur at any age
• Ethnicity: Higher incidence in:
  • Ashkenazi Jews (up to 10 times higher risk)
  • Mediterranean populations
  • Middle Eastern populations
  • South Asian populations
• Gender: Generally equal, slight female predominance in some studies
• Geographic location: Endemic areas for fogo selvagem

Genetic Risk Factors

• HLA types: Specific alleles confer increased susceptibility
• Family history: Rare familial cases reported
• Other autoimmune diseases: May indicate immune dysregulation

Medical Risk Factors

• Medications: Certain drugs can trigger pemphigus
  • ACE inhibitors
  • Penicillamine
  • Rifampin
  • Phenobarbital
• Malignancy: Associated with paraneoplastic pemphigus
• Pregnancy: May trigger or exacerbate pemphigus
• Myasthenia gravis: May coexist with pemphigus

Environmental Risk Factors

• Sun exposure: May worsen pemphigus foliaceus
• Dietary factors: Thiols in certain foods
• Occupational exposures: Pesticides, industrial chemicals
• Stress: May precipitate disease onset or flares

Diagnosis

Diagnosing pemphigus requires a combination of clinical evaluation, histopathology, and immunological testing. Early and accurate diagnosis is crucial for initiating appropriate treatment and preventing complications. The diagnostic process has become more sophisticated with advances in immunofluorescence and serological testing.

Clinical Evaluation

The diagnostic process begins with thorough assessment:

• Medical history: Onset, progression, medications, family history
• Physical examination: Distribution and characteristics of lesions
• Nikolsky sign: Lateral pressure causes skin separation
• Asboe-Hansen sign: Pressure on blister extends it laterally
• Mucosal examination: Essential for all patients

Histopathological Examination

Skin Biopsy

A fresh blister edge provides optimal diagnostic yield:

• Suprabasal acantholysis: In pemphigus vulgaris
• Subcorneal acantholysis: In pemphigus foliaceus
• Row of tombstones: Basal cells remain attached
• Eosinophilic spongiosis: May be present early

Immunofluorescence Studies

Direct Immunofluorescence (DIF)

Gold standard for diagnosis - performed on perilesional skin:

• IgG deposition: Intercellular pattern (chicken wire)
• C3 complement: Often present
• Location: Throughout epidermis in vulgaris, superficial in foliaceus
• Sensitivity: 90-95% in active disease

Indirect Immunofluorescence (IIF)

Detects circulating antibodies in serum:

• Substrate: Monkey esophagus or human skin
• Pattern: Intercellular IgG binding
• Titer: May correlate with disease activity
• Sensitivity: 80-90% in active disease

Serological Testing

ELISA (Enzyme-Linked Immunosorbent Assay)

Quantitative measurement of specific antibodies:

• Anti-desmoglein 1: Pemphigus foliaceus and mucosal-sparing vulgaris
• Anti-desmoglein 3: Pemphigus vulgaris with mucosal involvement
• Both antibodies: Mucocutaneous pemphigus vulgaris
• Monitoring: Levels correlate with disease activity

Differential Diagnosis

Several conditions can mimic pemphigus:

• Bullous pemphigoid - Tense blisters, older patients
• Mucous membrane pemphigoid - Scarring tendency
• Dermatitis herpetiformis - Grouped vesicles, gluten sensitivity
• Linear IgA disease - Different immunofluorescence pattern
• Stevens-Johnson syndrome - Drug-induced, targetoid lesions
• Herpes simplex - Grouped vesicles on erythematous base

Diagnostic Algorithm

1. Clinical suspicion based on history and examination
2. Skin biopsy for histopathology
3. Direct immunofluorescence on perilesional skin
4. Serum for indirect immunofluorescence and/or ELISA
5. Additional tests if paraneoplastic pemphigus suspected

Treatment Options

Treatment of pemphigus aims to control disease activity, induce remission, and minimize side effects from therapy. The introduction of systemic corticosteroids revolutionized pemphigus treatment, reducing mortality from over 90% to less than 10%. Modern treatment strategies emphasize early aggressive therapy followed by gradual tapering and the use of steroid-sparing agents.

First-Line Therapy

Systemic Corticosteroids

Remain the cornerstone of initial treatment:

• Prednisone: 1-2 mg/kg/day for pemphigus vulgaris
• Lower doses: 0.5-1 mg/kg/day may suffice for foliaceus
• Pulse therapy: IV methylprednisolone for severe cases
• Response time: New blister formation stops within days to weeks
• Tapering: Gradual reduction once control achieved

Rituximab

Now considered first-line therapy in combination with corticosteroids:

• Mechanism: Anti-CD20 monoclonal antibody depleting B cells
• Dosing: Various protocols (rheumatoid arthritis or lymphoma protocol)
• Efficacy: Complete remission in 70-90% of patients
• Duration: Effects last 6-12 months or longer
• Safety: Generally well-tolerated, monitor for infections

Adjuvant Immunosuppressants

Used to reduce corticosteroid doses and maintain remission:

Azathioprine

• Dose: 1-3 mg/kg/day
• Check TPMT levels before starting
• Monitor blood counts and liver function
• May take 4-8 weeks for effect

Mycophenolate Mofetil

• Dose: 2-3 g/day in divided doses
• Generally well-tolerated
• GI side effects common
• Contraindicated in pregnancy

Other Options

• Cyclophosphamide: For refractory cases
• Methotrexate: Weekly dosing
• Cyclosporine: Rapid onset but nephrotoxic
• Dapsone: Particularly for IgA pemphigus

Additional Therapies

Intravenous Immunoglobulin (IVIG)

• For refractory cases or contraindications to other therapies
• Dose: 2 g/kg over 3-5 days monthly
• Expensive but generally safe
• May allow steroid reduction

Plasmapheresis

• Removes pathogenic antibodies
• Rapid but temporary effect
• Used with immunosuppression to prevent rebound
• Reserved for life-threatening cases

Immunoadsorption

• Selective removal of IgG antibodies
• Fewer side effects than plasmapheresis
• Not widely available

Supportive Care

Wound Care

• Gentle cleansing: Saline or antiseptic solutions
• Non-adherent dressings: Prevent trauma
• Topical antibiotics: For secondary infection
• Pain management: Oral analgesics, topical anesthetics

Oral Care

• Soft diet: Avoid spicy, acidic foods
• Oral rinses: Saline, anesthetic mouthwashes
• Topical steroids: Clobetasol gel for oral lesions
• Dental hygiene: Soft toothbrush, regular dental care

General Measures

• Nutritional support: High protein diet, supplements
• Fluid management: Monitor for dehydration
• Infection prevention: Monitor for signs of sepsis
• Psychological support: Chronic disease counseling

Monitoring and Follow-up

• Clinical assessment: Regular evaluation of disease activity
• Laboratory monitoring: Based on medications used
• ELISA titers: May guide treatment decisions
• Bone density: For long-term steroid use
• Infection screening: Before and during immunosuppression

Prevention

While pemphigus cannot be completely prevented due to its autoimmune nature and genetic predisposition, several strategies can help reduce the risk of disease onset in susceptible individuals and prevent flares in those already diagnosed. Understanding and avoiding triggers is key to management.

Primary Prevention

For individuals at higher risk (family history, high-risk ethnicity):

Medication Awareness

• Inform healthcare providers about pemphigus risk
• Avoid known triggering medications when possible
• Monitor closely if high-risk drugs are necessary
• Consider alternative medications when available

Lifestyle Modifications

• Stress management: Regular exercise, meditation, counseling
• Sun protection: Especially important for pemphigus foliaceus
• Dietary considerations: Limit thiol-containing foods if sensitive
• Infection prevention: Good hygiene, prompt treatment of infections

Secondary Prevention - Preventing Flares

For diagnosed patients in remission:

Maintenance Therapy

• Continue prescribed medications as directed
• Don't stop treatment without medical supervision
• Regular monitoring of antibody levels
• Gradual, supervised medication tapering

Trigger Avoidance

• Known drug triggers: Maintain list of medications to avoid
• Physical trauma: Gentle skin care, avoid friction
• Emotional stress: Develop coping strategies
• Infections: Prompt treatment, vaccination when appropriate
• Surgery: Inform surgeons about pemphigus

Preventing Complications

Infection Prevention

• Proper wound care for all lesions
• Early recognition of infection signs
• Prophylactic antibiotics when indicated
• Avoid contact with sick individuals during immunosuppression

Preventing Treatment Side Effects

• Osteoporosis prevention: Calcium, vitamin D, bisphosphonates
• Gastric protection: PPIs during steroid therapy
• Blood sugar monitoring: Screen for steroid-induced diabetes
• Eye exams: Monitor for cataracts, glaucoma
• Vaccination: Complete before starting immunosuppression

Special Situations

Pregnancy Planning

• Achieve disease control before conception
• Adjust medications to pregnancy-safe options
• Close monitoring throughout pregnancy
• Plan delivery with dermatology input

Surgical Procedures

• Inform surgical team about pemphigus
• Consider perioperative steroid coverage
• Gentle tissue handling
• Monitor for postoperative flares

Long-term Management

• Regular follow-up: Even during remission
• Patient education: Recognize early signs of relapse
• Support groups: Connect with other patients
• Medical alert: Wear identification about condition
• Emergency plan: Know when and where to seek help

When to See a Doctor

Early recognition and treatment of pemphigus significantly improve outcomes. Knowing when to seek medical attention can prevent complications and reduce disease severity. Both undiagnosed individuals with suspicious symptoms and diagnosed patients need clear guidelines for medical consultation.

Seek Emergency Care For:

• Widespread blistering affecting large body surface area
• Signs of severe infection (high fever, chills, confusion)
• Difficulty swallowing or breathing due to throat involvement
• Signs of dehydration (dizziness, dry mouth, decreased urination)
• Severe eye pain or vision changes
• Rapid spread of blisters despite treatment

Schedule Urgent Appointment If:

• Persistent mouth sores lasting more than 2 weeks
• Blisters that break easily and don't heal
• Painful blisters on previously normal skin
• Skin that sloughs off with gentle rubbing
• Recurrent blisters in the same locations
• Blisters accompanied by flu-like symptoms

For Diagnosed Patients - Contact Your Doctor If:

• New blisters appear after period of remission
• Increase in number or size of lesions
• Side effects from medications
• Signs of infection in existing lesions
• Difficulty eating due to oral lesions
• Emotional distress or depression

Regular Monitoring Needed For:

• Medication adjustments and tapering
• Laboratory monitoring while on treatment
• Preventive care (bone density, eye exams)
• Antibody level monitoring
• Assessment of treatment response

When to See a Specialist

Referral to a dermatologist is essential for:

• Suspected pemphigus based on symptoms
• Chronic blistering disorders
• Failed response to initial treatments
• Need for specialized testing (immunofluorescence)
• Complex medication management

Related Conditions

Understanding conditions related to pemphigus helps with differential diagnosis and recognizing associated disorders. Some conditions share similar mechanisms or clinical features, while others may occur concurrently with pemphigus.

Other Autoimmune Blistering Diseases

• Bullous pemphigoid - Most common autoimmune blistering disease
• Mucous membrane pemphigoid - Primarily affects mucous membranes
• Epidermolysis bullosa acquisita - Mechanobullous disease
• Dermatitis herpetiformis - Associated with celiac disease
• Linear IgA disease - Different antibody type

Conditions That May Coexist

• Myasthenia gravis - May occur with pemphigus
• Thyroid disease - Autoimmune thyroiditis
• Rheumatoid arthritis - Shared autoimmune mechanisms
• Lupus - May have similar skin manifestations

Differential Diagnoses

• Stevens-Johnson syndrome - Drug-induced, acute onset
• Erythema multiforme - Target lesions
• Herpes simplex - Grouped vesicles
• Impetigo - Superficial bacterial infection
• Contact dermatitis - History of exposure

Paraneoplastic Associations

• Non-Hodgkin lymphoma - Most common with paraneoplastic pemphigus
• Chronic lymphocytic leukemia
• Castleman disease
• Thymoma

Frequently Asked Questions

Is pemphigus contagious?

No, pemphigus is not contagious. It's an autoimmune disease where your own immune system attacks your skin. You cannot catch it from someone else or spread it to others through contact.

Can pemphigus be cured?

While there's no permanent cure, pemphigus can go into complete remission with proper treatment. Many patients achieve long-term remission and can eventually stop or minimize medications. Early treatment improves the chances of achieving remission.

How long does treatment take?

Initial control usually occurs within weeks to months, but complete treatment often takes 2-5 years or longer. The duration varies based on disease severity, response to treatment, and individual factors. Some patients require long-term maintenance therapy.

Can I have children if I have pemphigus?

Yes, many people with pemphigus have successful pregnancies. However, careful planning is essential. The disease should be well-controlled before conception, and medications may need adjustment. Close monitoring during pregnancy is important as pemphigus can flare.

Will pemphigus affect my life expectancy?

With modern treatment, most people with pemphigus have a normal life expectancy. Before corticosteroids, mortality was over 90%, but now it's less than 10% with proper treatment. Early diagnosis and adherence to treatment are key factors.

Can diet affect pemphigus?

Some patients report flares with certain foods, particularly those high in thiols (garlic, onions, leeks). While not proven for all patients, keeping a food diary may help identify personal triggers. A balanced, nutritious diet supports healing and overall health.

Is pemphigus hereditary?

Pemphigus has a genetic component but isn't directly inherited. Having a family member with pemphigus slightly increases your risk, but most people with genetic susceptibility never develop the disease. Environmental factors play an important role in triggering the condition.

Can stress cause pemphigus flares?

Many patients report that emotional stress triggers or worsens their pemphigus. While the exact mechanism isn't fully understood, stress management through relaxation techniques, counseling, or support groups may help reduce flare frequency and severity.

References

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2. 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;82(3):575-585.e1.
3. Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026.
4. Amber KT, Murrell DF, Schmidt E, Joly P, Borradori L. Autoimmune Subepidermal Bullous Diseases of the Skin and Mucosae: Clinical Features, Diagnosis, and Management. Clin Rev Allergy Immunol. 2018;54(1):26-51.
5. Didona D, Maglie R, Eming R, Hertl M. Pemphigus: Current and Future Therapeutic Strategies. Front Immunol. 2019;10:1418.
6. Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019;394(10201):882-894.