Pemphigus: Symptoms, Types, Causes and Treatment

Pemphigus is a rare, chronic, and potentially life-threatening group of autoimmune diseases that cause blistering of the skin and mucous membranes. The disease can have a devastating impact on quality of life, with symptoms ranging from painful sores to widespread erosions. Understanding the symptoms, types, underlying causes, and treatment options for pemphigus is essential for patients, caregivers, and clinicians alike. This article offers a comprehensive, evidence-based overview of pemphigus, synthesizing current research and clinical guidelines.

Symptoms of Pemphigus

Pemphigus can present in a variety of ways, often making early recognition challenging. The hallmark features are blisters and erosions, but the clinical picture is broader and can involve several organ systems. Early and accurate identification of symptoms can significantly influence the prognosis and management of the disease.

Symptom	Description	Areas Affected	Source
Blisters	Flaccid, easily ruptured blisters	Skin, mucous membranes	1 5 7
Erosions	Painful, non-healing sores	Oral cavity, skin, eyes	1 6 8
Ulcers	Deeper lesions following blisters	Mouth, throat, nose	1 6
Pain	Often severe, especially with eating	Oral and mucosal lesions	1 6
Dysphagia	Difficulty swallowing	Oral/pharyngeal mucosa	1
Pruritus	Itching (less common)	Skin, especially PF*	2 4

*PF = Pemphigus foliaceus

Table 1: Key Symptoms

Blisters and Erosions: The Core Features

Pemphigus is primarily characterized by the formation of flaccid blisters that rupture easily, leading to painful erosions. These blisters can appear on the skin and mucous membranes, including the mouth, nose, eyes, throat, and even the genital area. In many cases, especially in pemphigus vulgaris, oral erosions are the first and sometimes only manifestation for a prolonged period, making diagnosis more difficult 1 5 6.

Ulcers and Secondary Symptoms

When blisters break, they leave behind raw, ulcerated areas that are slow to heal. These ulcers are particularly debilitating when located in the mouth or throat, as they can make eating and swallowing extremely painful (dysphagia). This can lead to malnutrition and dehydration if not managed appropriately 1 6.

Pain and Quality of Life

Pain is a consistent feature, especially in oral and mucosal lesions. The discomfort can be severe, often described as burning or stinging, and can impair speech and eating. Over time, persistent erosions and ulcers can significantly reduce a patient’s quality of life 1 6.

Pruritus (Itching)

While not as common as pain, some forms of pemphigus, particularly pemphigus foliaceus, can present with itching (pruritus), which may precede or accompany blister formation. This symptom can sometimes lead to misdiagnosis as other, more common dermatological conditions 2 4.

Types of Pemphigus

Pemphigus is not a single disease but rather a group of related disorders, each with its own set of clinical features, antigenic targets, and typical patient profiles. Understanding these distinctions is essential for accurate diagnosis and effective treatment.

Type	Main Features	Typical Presentation	Source
Pemphigus vulgaris	Most common, severe	Oral erosions, skin blisters	1 3 5 6
Pemphigus foliaceus	Superficial, less severe	Scaly skin blisters, rare mucosa	1 3 5
Paraneoplastic	Associated with malignancy	Polymorphous lesions, severe	1 4
IgA pemphigus	IgA autoantibodies	Pustules, annular plaques	1 4
Variants (vegetans, herpetiformis, brasiliensis)	Unusual forms	Vegetative plaques, herpetiform blisters	1 3

Table 2: Pemphigus Types and Features

Pemphigus Vulgaris

This is the most common and severe form, accounting for the majority of cases in Europe and North America. Pemphigus vulgaris typically begins with painful erosions in the mouth, which may precede skin involvement by months. Eventually, blisters and erosions appear on the skin, especially in areas subject to friction 1 5 6. Without treatment, pemphigus vulgaris can be fatal due to dehydration and infections 6.

Pemphigus Foliaceus

Pemphigus foliaceus is a superficial form of the disease. It generally affects only the skin, sparing the mucous membranes. The blisters are more superficial and fragile, resulting in scaly crusted lesions rather than deep erosions. It tends to have a milder course than pemphigus vulgaris 1 3 5.

Paraneoplastic Pemphigus

This rare variant is associated with underlying malignancies (most commonly lymphomas or leukemias). The presentation is highly variable but often includes severe mucosal involvement, polymorphic skin lesions, and resistance to standard therapies. Paraneoplastic pemphigus is frequently life-threatening and challenging to manage 1 4.

IgA Pemphigus

IgA pemphigus is characterized by autoantibodies of the IgA type rather than the more common IgG. It presents with pustules or annular plaques and may be mistaken for other pustular skin diseases. It has two main variants: intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis 1 4.

Other Variants

• Pemphigus vegetans: Presents with wart-like vegetative plaques, usually in skin folds 1 3.
• Pemphigus herpetiformis: Mimics the appearance of herpetic (clustered) blisters 1 3.
• Pemphigus brasiliensis: An endemic form of pemphigus foliaceus found in certain regions 3.

Causes of Pemphigus

Pemphigus is an autoimmune disease, meaning the body’s immune system mistakenly attacks its own tissues—in this case, the proteins that glue skin cells together. This process is complex and involves genetic, immunological, and potentially environmental factors.

Cause	Mechanism/Target	Contribution	Source
Autoantibodies	Against desmoglein 1/3	Disrupt cell adhesion	1 5 7 8
Genetic factors	HLA class II alleles	Increased susceptibility	1 6 8
Cell-mediated immunity	T and B cell interaction	Autoantibody production	1 8 15
Environmental	Drugs, infections	Possible triggers	11

Table 3: Key Causes and Mechanisms

Autoantibodies and Desmosome Dysfunction

The central event in pemphigus is the production of autoantibodies—most commonly IgG—against desmosomal proteins, especially desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3). These proteins are critical for cell-to-cell adhesion in the skin and mucosa. When antibodies bind to these targets, they disrupt the desmosomes, leading to loss of cohesion between keratinocytes (acantholysis) and blister formation 1 5 7 8.

Genetic Susceptibility

Genetics play a significant role. Specific human leukocyte antigen (HLA) class II alleles, such as HLA-DRB104:02 and HLA-DQB105:03, are strongly linked to increased risk, especially for pemphigus vulgaris. Certain ethnic groups, like Ashkenazi Jews and people of Mediterranean or Indian descent, are more commonly affected, highlighting the importance of a genetic predisposition 1 6 8.

Role of T Cells and B Cells

Pemphigus pathogenesis is not solely antibody-driven; it also involves complex interactions between T and B lymphocytes. T helper cells, particularly of the Th2 subtype, help activate B cells that then produce the pathogenic autoantibodies. Research suggests that both cell-mediated and humoral immunity are involved, particularly in severe or refractory cases 8 15.

Environmental and Triggering Factors

Although the precise triggers are not always clear, several environmental factors have been implicated:

• Certain medications (e.g., penicillamine, ACE inhibitors)
• Viral or other infections
• UV exposure

These factors may provoke disease onset or exacerbate existing disease in genetically predisposed individuals 11.

Treatment of Pemphigus

Treating pemphigus is challenging due to its chronic nature and potential for severe complications. The primary goal is to control disease activity, promote healing of lesions, and minimize treatment-related side effects.

Therapy	Mode of Action	Indication/Outcome	Source
Corticosteroids	Immunosuppression	First-line, rapid control	1 5 6 7 14
Steroid-sparing agents	Azathioprine, MMF, etc.	Reduce steroid side effects	1 6 14 15
Rituximab	Anti-CD20 B-cell depletion	Moderate-severe, first-line	5 12 13 15
IVIG/Plasmapheresis	Remove pathogenic antibodies	Refractory/adjunctive	7 14 16
Other	Dapsone, methotrexate, cyclophosphamide	Alternative/adjuvant	14 16

Table 4: Key Treatments and Strategies

Corticosteroids: The Mainstay

Systemic corticosteroids remain the cornerstone of pemphigus treatment. They are effective in rapidly reducing inflammation and suppressing the autoimmune attack, but long-term use carries significant risks, including infections, diabetes, osteoporosis, and other complications 1 5 6 7 14.

Steroid-Sparing Immunosuppressants

To minimize steroid exposure, additional immunosuppressive agents are often used. These include:

• Azathioprine
• Mycophenolate mofetil (MMF)
• Methotrexate
• Cyclophosphamide
• Dapsone

These agents act by suppressing the immune system through various mechanisms and are used in combination with steroids to achieve disease control with lower steroid doses 1 6 14 15.

Rituximab and Biologic Therapies

Recent years have seen the emergence of biologic therapies, most notably rituximab, an anti-CD20 monoclonal antibody that depletes B cells, the source of autoantibodies. Rituximab has demonstrated high efficacy, with many patients achieving complete remission and reduced reliance on corticosteroids. It is now considered a first-line therapy for moderate-to-severe pemphigus in international guidelines 5 12 13 15.

IVIG, Plasmapheresis, and Other Modalities

For patients who are refractory to standard therapies, additional options include:

• Intravenous immunoglobulin (IVIG): Helps neutralize pathogenic antibodies and modulate immune response 7 14 16.
• Plasmapheresis or immunoadsorption: Physically removes circulating autoantibodies 7 14.
• Other agents: Dapsone, methotrexate, and novel biologics are considered in refractory cases 14 16.

Multidisciplinary Approach and Monitoring

Due to the chronic nature and risks associated with treatment, management of pemphigus requires a multidisciplinary approach, involving dermatologists, oral medicine specialists, and sometimes other specialists. Regular monitoring for treatment efficacy and adverse effects is crucial 1 12 15.

Conclusion

Pemphigus is a complex and rare autoimmune disease that can be life-threatening if not properly managed. Recent advances in understanding its pathogenesis have enabled the development of more targeted and effective therapies. However, early recognition, accurate diagnosis, and a personalized, multidisciplinary approach remain essential.

Key takeaways:

• Pemphigus presents with painful blisters and erosions on the skin and mucous membranes, most often starting in the mouth.
• There are several types, with pemphigus vulgaris and foliaceus being the most common. Paraneoplastic and IgA pemphigus are less common but clinically significant.
• The disease is driven by autoantibodies (mainly against desmoglein 1 and 3) in genetically predisposed individuals, with both humoral and cell-mediated immune responses involved.
• Treatment has evolved from reliance on corticosteroids to include steroid-sparing agents and biologics such as rituximab, which can induce long-term remission.
• Ongoing research and a multidisciplinary approach are critical to improving outcomes and quality of life for patients living with pemphigus.

By staying informed and working closely with healthcare providers, patients with pemphigus can achieve better disease control and maintain a higher quality of life.