Bullae are elevated, fluid-filled blisters ≥ 10 mm in diameter.
Bullous pemphigoid occurs more often in patients > age 60 but can occur in children. IgG autoantibodies bind to certain hemidesmosomal antigens (BPAg1 [BP230], BPAg2 [BP180]), resulting in the activation of complement to form a subepidermal blister (see figure Skin cleavage levels in pemphigus and bullous pemphigoid Skin cleavage levels in pemphigus and bullous pemphigoid ).
Skin cleavage levels in pemphigus and bullous pemphigoid
Pemphigus foliaceus blisters form in the superficial layers of the epidermis. Pemphigus vulgaris blisters can form at any epidermal level but typically form in the lower aspects of the epidermis. Bullous pemphigoid blisters form subepidermally (lamina lucida of the basement membrane zone). In this figure, the basement membrane zone is disproportionately enlarged to display its layers.
Etiology of Bullous Pemphigoid
No cause of bullous pemphigoid has been proved; however, the following triggers have been suggested:
Drugs (including furosemide, spironolactone, omeprazole, PD-1 and PD-L1 monoclonal antibodies [eg, durvalumab, nivolumab, pembrolizumab], sulfasalazine, penicillin, penicillamine, etanercept, antipsychotics, and dipeptidyl peptidase-4 inhibitors)
Physical triggers (including trauma, radiation therapy for breast cancer, UV radiation, and anthralin)
Skin disorders (including psoriasis Psoriasis Psoriasis is an inflammatory disease that manifests most commonly as well-circumscribed, erythematous papules and plaques covered with silvery scales. Multiple factors contribute, including... read more , lichen planus Lichen Planus Lichen planus is a recurrent, pruritic, inflammatory eruption characterized by small, discrete, polygonal, flat-topped, violaceous papules that may coalesce into rough scaly plaques, often accompanied... read more , and some infections)
Disorders (diabetes mellitus Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more , rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily involves the joints. RA causes damage mediated by cytokines, chemokines, and metalloproteases. Characteristically... read more , ulcerative colitis Ulcerative Colitis Ulcerative colitis is a chronic inflammatory and ulcerative disease arising in the colonic mucosa, characterized most often by bloody diarrhea. Extraintestinal symptoms, particularly arthritis... read more , and multiple sclerosis Multiple Sclerosis (MS) Multiple sclerosis (MS) is characterized by disseminated patches of demyelination in the brain and spinal cord. Common symptoms include visual and oculomotor abnormalities, paresthesias, weakness... read more )
Genetic and environmental factors may play a role.
Triggers may induce an autoimmune reaction by mimicking molecular sequences in the epidermal basement membrane (molecular mimicry, as with drugs and possibly infections), by exposing or altering normally tolerated host antigens (as with physical triggers and certain disorders), or by other mechanisms. Epitope spreading refers to the recruitment of autoreactive lymphocytes against normally tolerated host antigens, which contributes to disease chronicity and course.
Certain central nervous system (CNS) and psychiatric disorders may precede bullous pemphigoid, especially multiple sclerosis and schizophrenia, but also dementias, intracranial bleeds, stroke, delusional and personality disorders, and Parkinson disease. To a lesser degree, these disorders may be preceded by bullous pemphigoid. Hypothesized shared causes include a cross-reactive immune response between neural and cutaneous antigens (BPAg1 is expressed in the CNS), as well as triggering by certain drugs used to treat the disorders (eg, phenothiazine antipsychotics, spironolactone); however, a mechanism of triggering by drugs is not understood.
Symptoms and Signs of Bullous Pemphigoid
Pruritus is the first symptom of bullous pemphigoid. Skin lesions may not develop for several years. Often, characteristic tense bullae develop on skin of the trunk and in the flexural and intertriginous areas. Bullae may develop on normal-appearing skin or may be preceded by erythematous or urticarial-appearing plaques. Localized disease may occur at trauma sites, stomas, and anogenital and lower leg areas. Dyshidrotic pemphigoid is a rare form of bullous pemphigoid that affects the hands and feet and can look like dyshidrotic dermatitis (a form of hand and foot dermatitis Hand and Foot Dermatitis Hand and foot dermatitis is a dermatitis affecting the hands and/or feet. It can be due to a contact dermatitis (allergic or irritant) or atopic dermatitis. Manifestations are erythema, scaling... read more ) on the palms. Bullae usually do not rupture, but those that do often rapidly heal.
Polymorphic, annular, dusky-red, edematous lesions, with or without peripheral vesicles, can occur. Rarely, small blisters develop on the mucosa. Leukocytosis and eosinophilia are common, but fever is rare. The Nikolsky sign, where upper layers of epidermis move laterally with slight pressure or rubbing of skin adjacent to a blister, is negative.
Diagnosis of Bullous Pemphigoid
Skin biopsy and IgG titers
If blisters develop, bullous pemphigoid needs to be differentiated from pemphigus vulgaris Pemphigus Vulgaris Pemphigus vulgaris is an uncommon, potentially fatal, autoimmune disorder characterized by intraepidermal blisters and extensive erosions on apparently healthy skin and mucous membranes. Diagnosis... read more , a blistering disorder with a worse prognosis; differentiation is usually possible using clinical criteria (see Table: Distinguishing Bullous Pemphigoid From Pemphigus Vulgaris Distinguishing Bullous Pemphigoid From Pemphigus Vulgaris ).
Test results help differentiate bullous pemphigoid from pemphigus vulgaris Pemphigus Vulgaris Pemphigus vulgaris is an uncommon, potentially fatal, autoimmune disorder characterized by intraepidermal blisters and extensive erosions on apparently healthy skin and mucous membranes. Diagnosis... read more , linear IgA disease Linear Immunoglobulin A (IgA) Disease Linear immunoglobulin A (IgA) disease is an uncommon bullous disease distinguished from bullous pemphigoid and dermatitis herpetiformis by linear deposits of IgA in the basement membrane zone... read more , erythema multiforme Erythema Multiforme Erythema multiforme is an inflammatory reaction, characterized by target or iris skin lesions. Oral mucosa may be involved. Diagnosis is clinical. Lesions spontaneously resolve but frequently... read more , drug-induced eruptions Drug Eruptions and Reactions Drugs can cause multiple skin eruptions and reactions. The most serious of these are discussed elsewhere in THE MANUAL and include Stevens-Johnson syndrome and toxic epidermal necrolysis, hypersensitivity... read more , mucous membrane pemphigoid Mucous Membrane Pemphigoid Mucous membrane pemphigoid is the designation given to a heterogeneous group of rare chronic autoimmune disorders that tend to cause waxing and waning bullous lesions of the mucous membranes... read more , paraneoplastic pemphigoid, dermatitis herpetiformis Dermatitis Herpetiformis Dermatitis herpetiformis is an intensely pruritic, chronic, autoimmune, papulovesicular cutaneous eruption strongly associated with celiac disease. Typical findings are clusters of intensely... read more , and epidermolysis bullosa acquisita Epidermolysis Bullosa Acquisita Epidermolysis bullosa acquisita is a rare, acquired, chronic condition characterized by subepidermal blistering. Diagnosis is by skin biopsy and direct immunofluorescence. Treatment is with... read more .
If bullous pemphigoid is suspected, skin biopsy is done for histology and direct immunofluorescence testing. Samples from in and around the lesion itself are often used for histology, but samples of uninvolved skin (often about 3 mm from the edge of a lesion) are used for direct immunofluorescence. The blister in bullous pemphigoid is subepidermal, often containing many neutrophils and eosinophils. Direct immunofluorescence shows linear IgG and complement deposits along the basement membrane zone (dermal–epidermal junction). Indirect immunofluorescence shows circulating IgG deposits on the epidermal side of a salt-split preparation of normal (ie, test substrate) skin.
Serum is tested for IgG antibodies to BPAg1 and BPAg2 using an enzyme-linked immunosorbent assay (ELISA). Circulating IgG autoantibodies are present in about three fourths of patients.
Prognosis for Bullous Pemphigoid
Bullous pemphigoid is a chronic, potentially fatal disease, particularly without treatment. Although topical and systemic therapies are helpful, they may cause adverse effects.
Remission is typical within months, but treatment is sometimes needed for several years.
Treatment of Bullous Pemphigoid
Corticosteroids, topical or oral
Immunosuppressant drugs or biologics
High-potency topical corticosteroids (eg, clobetasol 0.05% cream) should be used for localized disease and may reduce the required dose of systemic drugs.
Patients with generalized disease often require systemic treatment with prednisone 60 to 80 mg orally once a day, which can be tapered to a maintenance level of ≤ 10 to 20 mg/day after several weeks. Most patients achieve remission after 2 to 10 months, but treatment may need to continue for several years before the disease process remits enough to allow discontinuation. If long-term therapy is necessary, a new blister every few weeks does not require increasing the prednisone dose.
Bullous pemphigoid occasionally responds to the anti-inflammatory activity of certain drugs, such as the combination of tetracycline or minocycline and nicotinamide. Other treatment options include monotherapy with dapsone, sulfapyridine, or erythromycin. IV immune globulin has been used occasionally.
For patients with generalized and recalcitrant disease, and sometimes to decrease corticosteroid dose in chronic disease, immunosuppressants such as methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, and cyclosporine may be used. Among the biologics, rituximab and omalizumab may be used.
Bullous pemphigoid usually affects patients > age 60 and is autoimmune and idiopathic.
Pruritus may precede development of a rash by years, and mucous membrane involvement is rare.
Biopsy the skin for histology and immunofluorescence testing and measure circulating autoantibodies.
Treat patients with high-potency topical corticosteroids when possible to avoid or minimize use of systemic corticosteroids.
Anti-inflammatory, immunosuppressant, and biologic therapy may be used to decrease corticosteroid dose.
Symptoms usually lessen within months, but treatment is sometimes needed for several years.