Bullous Pemphigoid: Symptoms, Types, Causes and Treatment

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, primarily affecting the elderly. Known for its dramatic blisters and severe itching, BP can be both distressing and potentially life-threatening if left untreated. However, not all cases look the same—some people never develop blisters at all, making diagnosis and management challenging. In this article, we’ll explore the key symptoms, distinct types, underlying causes, and the latest in evidence-based treatment.

Symptoms of Bullous Pemphigoid

Bullous pemphigoid often makes itself known through an intensely itchy rash and characteristic blisters, but the range of symptoms can be surprisingly broad. Some people may endure weeks or months of non-specific skin irritation before classic blisters appear. Early recognition of these symptoms is crucial for timely diagnosis and effective management.

Symptom	Description	Typical Onset	Sources
Itching	Intense, persistent pruritus	Early, often precedes blisters	1 2 3 4 5 7 17
Blisters	Tense, fluid-filled, subepidermal	Acute/bullous phase	1 2 5 7 8 17
Eczematous/Urticarial Lesions	Red, inflamed, sometimes scaly patches	Prodromal/early phase	2 3 4 5 7 17
Excoriations	Scratch marks from persistent itching	Any stage	2 3 4 7 15 17
Mucosal involvement	Rare, may affect mouth or other linings	Occasionally, especially in severe/atypical cases	5 7 8

Table 1: Key Symptoms of Bullous Pemphigoid

The Evolution of Symptoms

Early/Non-Bullous Phase

• Itching is often the first and most prominent symptom. In some cases, itch may occur even without visible skin changes—a presentation known as “pruritus sine materia” 3 4 7 17.
• Non-specific skin lesions such as eczema-like patches, urticarial (hive-like) plaques, or papules may develop and persist for weeks to years before blisters become evident 2 3 4 5 7.
• Excoriations from scratching are common and can sometimes be mistaken for other skin conditions like eczema or prurigo 7 15 17.

Bullous (Blistering) Phase

• Tense blisters are the hallmark. These are typically large, filled with clear or blood-tinged fluid, and do not rupture easily. The blisters often arise on red or normal-appearing skin, commonly on the trunk, arms, and legs 1 2 5 7.
• Localized vs. generalized: The blisters may be scattered or widespread, and sometimes only appear in certain body regions 7 8.

Other Features

• Mucosal involvement is rare in BP but, when present, may indicate a more severe or atypical disease variant 5 7 8.
• Systemic symptoms such as fever or malaise are uncommon, but elderly patients may experience significant discomfort, sleep disturbance, or secondary infection due to the intense itch and open skin lesions 1 5 15.

Types of Bullous Pemphigoid

Bullous pemphigoid is not a single, uniform disease. It encompasses a spectrum of clinical presentations, from classic blistering to subtle, non-bullous forms, and even rare variants affecting children or confined to specific body sites.

Type	Key Features	Distinct Populations/Locations	Sources
Classic Bullous	Tense blisters, urticarial plaques	Elderly, trunk/limbs	1 5 7 8 17
Non-bullous/Pruritic	Itch, eczematous or urticarial lesions, no blisters	Elderly, may precede blisters or remain sole feature	3 4 7 15 17
Localized BP	Blisters confined to one area	Scalp, lower legs, surgical sites	7
Child/Infant BP	Blisters, often genital, facial, palm/sole	Children	7
Mucous Membrane-Involved BP	Blisters or erosions on mucosae	Oral, pharyngeal, sometimes severe cases	8

Table 2: Types of Bullous Pemphigoid

Classic Bullous Pemphigoid

• Most common presentation, especially among the elderly 1 5 7.
• Characterized by large, tense blisters on inflamed or normal-looking skin, often accompanied by intense itching.
• Blisters usually appear on the trunk, extremities, and flexural areas, sparing mucous membranes in most cases 1 5.

Non-Bullous/Pruritic Pemphigoid

• Accounts for up to 20% of cases 3 4 7 15 17.
• Presents with severe itching, excoriated or eczematous lesions, urticarial plaques, or papules—without blisters, sometimes for years.
• Termed “pruritic non-bullous pemphigoid,” this variant can be easily mistaken for eczema or prurigo, especially in elderly patients 3 4 7.
• Some patients never progress to the blistering phase 3.

Localized Bullous Pemphigoid

• Blisters are confined to a single area, such as the scalp, legs, or surgical scars 7.
• May arise in response to local trauma or as a result of lower disease activity.

Pediatric (Childhood) BP

• Rare, but when it occurs, about half of children present with exclusive genital lesions; others may have facial, palmar, or plantar involvement 7.

Mucosal-Involved and Other Atypical Forms

• Mucosal involvement is rare but can be seen in severe or atypical cases, sometimes closely resembling mucous membrane pemphigoid 5 7 8.
• Other rare presentations include erythroderma and vesicular or lichenoid eruptions 7.

Causes of Bullous Pemphigoid

BP is an autoimmune condition, meaning the body’s immune system mistakenly attacks its own skin. While the exact triggers remain unclear, both genetic and environmental factors contribute to disease development.

Cause/Factor	Mechanism/Description	Key Details or Triggers	Sources
Autoantibodies	Target BP180 (Collagen XVII) & BP230 at basement membrane	Main pathogenic event	1 5 9 10 12 17
Genetic Predisposition	HLA-DQβ1*0301 and other HLA genes	Strongest known genetic link	9
Immune Dysregulation	Th/Treg imbalance, Th17/IL-17 pathway activation	Promotes autoreactivity	9 10 11 12
Environmental Triggers	Drugs, physical agents, infections	15% of cases; drugs (diuretics, neuroleptics), radiation, viral infections	9 17
Aging/Comorbidities	Associated with neurological diseases, aging skin	Elderly, dementia, Parkinson’s	5 17

Table 3: Causes and Triggers of Bullous Pemphigoid

Autoimmune Mechanisms

• BP occurs when the immune system produces IgG and sometimes IgE autoantibodies directed against two hemidesmosomal proteins: BP180 (Collagen XVII) and BP230 1 5 9 10 17.
• The binding of these autoantibodies to their targets at the dermal-epidermal junction activates the complement system, recruits inflammatory cells (including eosinophils), and ultimately causes the skin layers to separate, forming blisters 1 10 11 12.
• Recent research highlights the role of eosinophils and IgE in promoting inflammation and itch 10 11 13.

Genetic and Immune Factors

• Genetic susceptibility is primarily linked to certain HLA genes, especially HLA-DQβ1*0301, which may predispose individuals to autoimmunity 9.
• An imbalance between regulatory T cells and autoreactive helper T cells, as well as activation of Th17/IL-17 pathways, further drives the autoimmune response 9 12.

Environmental and Triggering Factors

• Drugs: Certain medications, such as loop diuretics, spironolactone, and neuroleptics, can trigger BP in genetically predisposed individuals 9 17.
• Physical agents: Radiation therapy, ultraviolet exposure, burns, and even surgical procedures have been reported as rare triggers 9.
• Infections: Viruses (including hepatitis B/C, human herpesviruses, and H. pylori) may play a role in some cases 9.
• In about 15% of patients, an identifiable trigger can be found 9.

Aging and Comorbidities

• BP is strongly associated with aging and often coexists with neurological disorders like dementia or Parkinson’s disease 5 17.
• Age-related changes in the immune system and skin barrier may increase vulnerability to autoimmune attack.

Treatment of Bullous Pemphigoid

Managing BP requires a tailored approach, balancing disease control with the risks of therapy, especially in elderly patients with comorbidities. Recent advances have expanded the therapeutic toolkit, offering safer and more effective options.

Treatment	Main Use/Indication	Key Benefits/Risks	Sources
Topical corticosteroids	First-line for localized/mild-moderate BP	Effective, safe, reduced mortality	1 5 15 16 17
Systemic corticosteroids	Severe or widespread cases	Rapid control, but higher risk of side effects	1 5 15 16 17
Tetracyclines (doxycycline)	Mild-moderate BP, steroid-sparing	Non-inferior to steroids for short-term control, safer long-term	5 14
Immunosuppressants (azathioprine, methotrexate, mycophenolate)	Adjunct in resistant/severe cases	Steroid-sparing, various risks	1 5 15 16 17
Anti-inflammatory antibiotics (dapsone, erythromycin)	Alternative/steroid-sparing	For select patients	1 5 15
Biologics/Future therapies	Refractory cases, research stage	Target inflammatory pathways	5 17

Table 4: Treatments for Bullous Pemphigoid

Topical Corticosteroids

• Very potent topical steroids (e.g., clobetasol propionate) are now considered first-line treatment for localized or moderate BP 1 5 15 16 17.
• Studies show they are as effective as, or superior to, oral steroids for extensive BP, offering better disease control and lower mortality 16.
• Side effects include risk of skin thinning and, with large-area use, systemic absorption 16.

Systemic Corticosteroids

• Oral corticosteroids (e.g., prednisolone) are used for severe or widespread BP or when topical therapy is impractical 1 5 15 16 17.
• While highly effective, they carry increased risks of infections, diabetes, osteoporosis, and cardiovascular complications—especially in elderly patients 15 16.
• Lower doses are now preferred, as higher doses do not provide additional benefit and may increase side effects 16.

Tetracyclines and Anti-inflammatory Antibiotics

• Doxycycline and related tetracyclines have emerged as effective, safer alternatives to steroids, particularly for mild to moderate BP 5 14.
• A major randomized trial found doxycycline to be “non-inferior” to steroids for short-term blister control, with significantly fewer severe treatment-related adverse events long-term 14.
• Dapsone and erythromycin may also be used in select patients 1 5 15.

Immunosuppressants

• Immunosuppressive agents like azathioprine, methotrexate, and mycophenolate mofetil serve as steroid-sparing agents or for refractory cases 1 5 15 16 17.
• Their use should be individualized, weighing the benefits of reduced steroid exposure against the risks of immunosuppression 15 16.

Biologics and Emerging Therapies

• Biologic drugs targeting specific immune pathways (e.g., rituximab, anti-IL-5 agents) are under investigation for refractory cases 5 17.
• Future therapies may focus on modulating the inflammatory cascade more precisely, aiming for effective disease control with fewer side effects 17.

Supportive and Adjunctive Care

• Wound care, infection prevention, and management of comorbidities are vital components of comprehensive BP management 1 5 15.
• Prompt identification and discontinuation of potential triggering drugs or environmental factors can sometimes lead to rapid improvement 9.

Conclusion

Bullous pemphigoid is a complex, often debilitating autoimmune disease that requires timely recognition and a nuanced approach to management. Here’s what we covered:

• BP most often affects the elderly, presenting with severe itch and tense blisters, but it can also appear as non-bullous, eczematous, or urticarial lesions.
• There are several distinct types—including classic, non-bullous, localized, pediatric, and mucous membrane-involved variants.
• BP arises from an autoimmune attack on hemidesmosomal proteins, with both genetic predisposition and environmental triggers playing roles.
• Treatment is tailored to severity, with topical corticosteroids and doxycycline now favored for many patients, and systemic steroids or immunosuppressants reserved for more severe or recalcitrant cases.
• Prompt diagnosis and individualized care can dramatically improve outcomes and quality of life for those affected by this challenging disease.

By staying alert to the broad range of presentations and leveraging the growing array of treatment options, clinicians and patients alike can work towards effective, safe, and compassionate care for bullous pemphigoid.