Residency · Residency · Dermatology

Autoimmune Blistering Diseases: Pemphigus and Pemphigoid

Overview

Autoimmune blistering diseases arise when the immune system produces autoantibodies that target structural proteins responsible for cell-cell adhesion within the epidermis or for anchoring the epidermis to the underlying dermis at the basement membrane zone (BMZ). These diseases are broadly divided into two categories based on where the blister forms. In the pemphigus group, antibodies attack desmosomal proteins, causing loss of keratinocyte cohesion and intraepidermal blistering. In the pemphigoid group, antibodies target hemidesmosomal or BMZ components, producing subepidermal blistering with a thicker, more durable blister roof. Accurate diagnosis requires the integration of clinical findings, histopathology (H&E), direct immunofluorescence (DIF), and serologic testing.

Pemphigus Vulgaris (PV)

Epidemiology

Pemphigus vulgaris is the most common form of pemphigus, with an incidence of 0.5 to 3.2 per 100,000 per year. Peak onset occurs between ages 40 and 60. There is a higher incidence among Ashkenazi Jewish and Mediterranean populations, linked to the HLA-DRB1*04:02 allele, and no significant sex predilection.

Pathogenesis

The disease is driven by IgG autoantibodies against desmoglein 3 (Dsg3), with or without additional antibodies against desmoglein 1 (Dsg1). Desmogleins are transmembrane glycoproteins within desmosomes, the structures that mediate cell-cell adhesion between keratinocytes. The desmoglein compensation theory elegantly explains the clinical phenotype. In mucosal-dominant PV, only anti-Dsg3 antibodies are present; Dsg1 can compensate for the loss of Dsg3 function in the skin (where both are expressed), but in the mucosa, where Dsg3 is the sole desmoglein in the upper layers, compensation cannot occur, and blisters form. In mucocutaneous PV, both anti-Dsg3 and anti-Dsg1 antibodies are present, eliminating compensation in both skin and mucosa. The result of antibody binding is acantholysis, the loss of keratinocyte adhesion, with suprabasal cleft formation.

Clinical Features

Oral involvement occurs in over 90% of patients and is often the presenting complaint, manifesting as painful erosive stomatitis affecting the buccal mucosa, palate, gingiva, and tongue. Intact blisters are rarely seen in the mouth because the fragile blister roofs rupture almost immediately, and the condition may initially present as "desquamative gingivitis." Skin lesions appear as flaccid, fragile blisters on non-inflamed skin that rupture easily, leaving painful erosions with a predilection for the scalp, face, trunk, and intertriginous areas. These lesions heal without scarring in the absence of secondary infection. The Nikolsky sign is positive, meaning that lateral pressure on uninvolved skin adjacent to a blister causes the skin to shear and extend. The Asboe-Hansen sign (bulla spread sign) is also positive, with direct pressure on an intact blister causing lateral extension.

Histopathology

The hallmark histologic finding is suprabasal acantholysis, with cleft formation just above the basal layer. The basal keratinocytes remain attached to the basement membrane zone in a characteristic "tombstone" pattern. Early or pre-bullous lesions may show eosinophilic spongiosis. The blister roof remains intact with a suprabasal split, and the inflammatory infiltrate is typically sparse, containing eosinophils and neutrophils.

Immunology

Direct immunofluorescence performed on perilesional skin reveals intercellular IgG and C3 deposition in a "chicken-wire" or "fishnet" pattern throughout the epidermis, with a sensitivity exceeding 90%. Indirect immunofluorescence demonstrates circulating IgG against epithelial cell surfaces using monkey esophagus as a substrate. ELISA testing quantifies anti-Dsg3 and anti-Dsg1 antibody titers, which correlate with disease activity and are invaluable for monitoring treatment response. Anti-Dsg3 titers reflect mucosal disease activity, while anti-Dsg1 titers reflect cutaneous disease activity.

<image>Histopathology of pemphigus vulgaris showing suprabasal acantholysis with tombstone pattern of basal keratinocytes, alongside direct immunofluorescence showing intercellular IgG deposition in a chicken-wire pattern</image>

Pemphigus Foliaceus (PF)

Pathogenesis

Pemphigus foliaceus is caused by IgG autoantibodies targeting desmoglein 1 (Dsg1) only. Dsg1 is expressed throughout the epidermis but serves as the sole desmoglein in the superficial granular layer. In the deeper epidermis and mucosa, Dsg3 compensates for the loss of Dsg1 function. This explains why PF produces only superficial blisters and spares the mucosa entirely.

Clinical Features

Because the blisters are so superficial, they rupture immediately and are rarely seen intact. Instead, PF presents as crusted erosions and scaly plaques with a characteristic "corn flake-like" crusting concentrated on seborrheic areas such as the scalp, face, chest, and upper back. No mucosal involvement occurs, which is the key clinical distinction from PV. The eruption may resemble seborrheic dermatitis, impetigo, or eczema. The Nikolsky sign is positive. Endemic pemphigus foliaceus (fogo selvagem) is clinically identical to PF but occurs in endemic areas of Brazil, where an insect vector (the Simulium blackfly) is suspected.

Histopathology

PF shows subcorneal or granular layer acantholysis with a superficial split. Acantholytic cells are found in the superficial epidermis, and tombstoning is less prominent than in PV because the split is superficial rather than suprabasal.

Immunology

DIF demonstrates intercellular IgG deposition that predominates in the upper epidermis. ELISA confirms anti-Dsg1 antibodies with anti-Dsg3 negativity.

Drug-Induced Pemphigus

Thiol-containing drugs such as penicillamine, captopril, and gold can induce true pemphigus through direct biochemical interaction with desmogleins. Non-thiol drugs including penicillins, cephalosporins, and phenobarbital are also implicated. Drug-induced pemphigus usually presents with a PF phenotype and may resolve with drug discontinuation, although some cases persist and require immunosuppressive treatment.

Paraneoplastic Pemphigus (PNP) / Paraneoplastic Autoimmune Multiorgan Syndrome (PAMS)

Paraneoplastic pemphigus is associated with lymphoproliferative neoplasms, most commonly non-Hodgkin lymphoma, CLL, Castleman disease, and thymoma. It involves multi-antigen antibodies targeting envoplakin, periplakin, desmoplakin, Dsg3, and Dsg1. Clinically, severe, painful stomatitis is present in nearly 100% of cases, and skin lesions are polymorphous, including lichenoid, pemphigus-like, erythema multiforme-like, and bullous morphologies. Bronchiolitis obliterans is a life-threatening pulmonary complication and the leading cause of death. DIF shows both intercellular and BMZ staining. IIF is uniquely positive on rat bladder epithelium, which lacks desmogleins but contains plakin proteins, making this substrate specific for PNP. The prognosis is poor, and treatment of the underlying malignancy is essential.

Bullous Pemphigoid (BP)

Epidemiology

Bullous pemphigoid is the most common autoimmune blistering disease overall, primarily affecting the elderly with a median age of 75 to 80. Its incidence is increasing and has been linked to neurologic diseases including dementia, Parkinson disease, stroke, and multiple sclerosis. Drug-induced BP is recognized with DPP-4 inhibitors (gliptins), PD-1/PD-L1 inhibitors, and diuretics.

Pathogenesis

BP is driven by IgG autoantibodies against BP180 (also called collagen XVII or BPAG2) and/or BP230 (BPAG1). BP180 is a transmembrane hemidesmosomal protein, while BP230 is an intracellular hemidesmosomal plaque protein. Antibody binding activates complement, recruits eosinophils, and triggers protease release that causes separation at the BMZ, resulting in subepidermal blister formation.

Clinical Features

BP often begins with a prodromal phase of urticarial plaques and intense pruritus that may persist for weeks to months before blisters appear. In the bullous phase, large, tense blisters develop on an erythematous or urticarial base. These blisters are tense because the subepidermal location provides a thick roof, in contrast to the flaccid blisters of pemphigus. They favor the trunk, proximal extremities, and flexural areas. The Nikolsky sign is usually negative. Oral involvement is present in only 10 to 30% of cases, unlike PV where it is nearly universal. Non-bullous (urticarial) BP presents with eczematous or urticarial pruritic plaques without visible blisters and is actually more common than the classic bullous presentation in elderly patients. It is frequently misdiagnosed as eczema or a drug reaction.

Histopathology

BP shows a subepidermal blister with an eosinophil-rich infiltrate. Eosinophils are found at the BMZ and within the blister cavity, accompanied by papillary dermal edema. There is no acantholysis, and the dermis shows a perivascular eosinophilic infiltrate.

Immunology

DIF of perilesional skin reveals linear IgG and C3 at the BMZ with a sensitivity exceeding 90%. IIF on salt-split skin shows IgG binding to the epidermal side, which distinguishes BP from epidermolysis bullosa acquisita (EBA), where binding occurs on the dermal side. ELISA for anti-BP180 NC16A antibodies correlates with disease activity and is the most useful serologic test for monitoring. Anti-BP230 ELISA is less specific.

<image>Clinical comparison of pemphigus vulgaris (flaccid blisters and erosions on non-inflamed skin) versus bullous pemphigoid (tense blisters on erythematous/urticarial base) with corresponding histopathology and DIF patterns</image>

Other Subepidermal Blistering Diseases

Mucous Membrane Pemphigoid (Cicatricial Pemphigoid)

Mucous membrane pemphigoid predominantly involves mucosal surfaces including the oral cavity, eyes (with risk of symblepharon and blindness), nose, larynx, and genitalia. Scarring is a hallmark, hence the name "cicatricial." The target antigens include BP180, laminin-332, and integrin alpha6-beta4. DIF shows linear IgG, IgA, or C3 at the BMZ. Ophthalmology referral is mandatory for any patient with ocular involvement.

Epidermolysis Bullosa Acquisita (EBA)

EBA is caused by antibodies against type VII collagen, the major component of anchoring fibrils. It presents in two forms: the mechanobullous (classic) form features skin fragility, blisters at trauma-prone sites, scarring, and milia formation, while the inflammatory form mimics BP clinically. DIF shows linear IgG at the BMZ, and salt-split skin demonstrates binding on the dermal side. EBA is notoriously difficult to treat, with options including dapsone, colchicine, and rituximab.

Linear IgA Bullous Dermatosis

This condition is discussed in Topic 39.

Treatment of Pemphigus

Rituximab as First-Line Therapy

The RITUX 3 trial demonstrated that rituximab combined with short-course prednisone is superior to prednisone alone as first-line therapy for PV, achieving complete remission off therapy in 89% of patients versus 34% with prednisone alone at 24 months. Rituximab is now considered first-line therapy for moderate-to-severe pemphigus. It is administered at 1000 mg IV for two doses (days 0 and 14), with maintenance infusions at 6 and 12 months. The drug works through B-cell depletion, which reduces autoantibody production.

Systemic Corticosteroids

Previously first-line, systemic corticosteroids now serve as bridge therapy alongside rituximab. Prednisone at 0.5 to 1.5 mg/kg/day is tapered over months as rituximab takes effect. Long-term high-dose corticosteroid use carries significant morbidity including osteoporosis, diabetes, infection, and adrenal insufficiency.

Other Immunosuppressive Agents

Mycophenolate mofetil is commonly used as a steroid-sparing adjunct. Azathioprine is an alternative to mycophenolate. IVIG provides rapid reduction in antibody titers and is used for severe or refractory disease. Dapsone can be useful for PF and mild PV. Cyclophosphamide is reserved for life-threatening, refractory cases.

Treatment of Bullous Pemphigoid

Mild-Moderate BP

Super-potent topical corticosteroids (clobetasol) are first-line for localized and moderate BP. A landmark trial by Joly et al. published in the New England Journal of Medicine in 2002 demonstrated that whole-body topical clobetasol is as effective as systemic prednisone with fewer side effects. The protocol involves 20 to 40 g/day applied to the entire body surface for 1 to 4 weeks, followed by a taper.

Moderate-Severe BP

Systemic prednisone at 0.5 mg/kg/day (a lower dose than used in pemphigus) is tapered over months. Doxycycline is a non-immunosuppressive alternative; the BLISTER trial showed non-inferiority to prednisone for BP with fewer adverse events. Dapsone and methotrexate are effective steroid-sparing options, with methotrexate being particularly useful in the elderly. Mycophenolate or azathioprine are used for steroid-dependent disease. Rituximab is reserved for refractory BP. Omalizumab (anti-IgE) and dupilumab have emerging evidence for refractory cases, though use remains off-label.

Clinical Pearls

The desmoglein compensation theory elegantly explains why PV affects mucosa and PF does not: Dsg3 is the only desmoglein in superficial oral mucosa, so anti-Dsg3 antibodies cause mucosal blisters, while Dsg1 compensates in skin unless anti-Dsg1 is also present. Rituximab has transformed pemphigus management from a disease requiring prolonged high-dose corticosteroids to one achievable with short-course steroids plus targeted B-cell depletion. Non-bullous (urticarial) BP is more common than the classic bullous presentation in elderly patients, and any pruritic eruption in an elderly patient unresponsive to standard treatment should prompt DIF. Salt-split skin DIF distinguishes BP (antibodies on the epidermal side) from EBA (antibodies on the dermal side), as both show linear IgG at the BMZ on standard DIF. ELISA titers for anti-Dsg1, anti-Dsg3 (pemphigus) and anti-BP180 (BP) are invaluable for monitoring disease activity and guiding treatment intensity.

References

• Joly P, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002;346(5):321-327
• Joly P, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (RITUX 3). Lancet. 2017;389(10083):2031-2040
• Williams HC, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid (BLISTER). BMJ. 2017;357:j1768
• Murrell DF, et al. Diagnosis and management of pemphigus: recommendations of an international panel of experts. J Am Acad Dermatol. 2020;82(3):575-585
• Schmidt E, et al. Pemphigoid diseases. Lancet. 2013;381(9863):320-332

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