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Disease Categories > Autoimmune Disease > Immunobullous Disease

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Pemphigoid

Pemphigoid is a chronic autoimmune blistering disease of the skin and mucous membranes.

Epidemiology

Incidence – 7-10 per million
Age of onset – 60-80 years, rarely in children
Gender – M:F; equal

Pathology and Immunopathology

Subepidermal or subepithelial blister with inflammation including eosinophils
IgG and complement are found at the basement membrane zone in perilesional tissue; IgE basement membrane zone antibodies are difficult to detect but likely are important in pathophysiology
Two major molecular structures in hemidesmosomes to which pemphigoid antibodies bind have been identified and termed BP180 (BP Ag2) for a 180 kD bullous pemphigoid antigen and BP230 (BP Ag1) for a 230 kD bullous pemphigoid antigen; IgG antibodies to one or both target antigens are present (other basement membrane zone antigens may be targets as well)
- BP180 is a transmembrane component of the basement membrane zone with collagen-like domains
  - Serum levels of BP180 antibodies correlate with disease activity
- BP230 is an intracellular hemidesmosomal plaque protein
  - Serum levels of BP230 antibodies also correlate with disease activity
- Detection of antibodies to both BP180 and BP230 increases sensitivity and specificity in diagnosing pemphigoid
- Antibodies to either or both antigens may be increased and levels correlated more closely to clinical activity than to titers of basement membrane zone antibodies
Mucous membrane pemphigoid variant has antibodies to other basement membrane zone components including laminin-5, laminin-6, β4 integrin subunit

Clinical Presentation

Tense bullae with clear fluids or erosions develop on erythematous, urticarial or normal-appearing skin with predominant flexural distribution
Mucosal involvement occurs in 10-40%
Pruritus is common
Involvement of ocular conjunctivae may lead to scarring and blindness in ocular pemphigoid
Scarring alopecia may occur in mucous membrane (cicatricial) pemphigoid; when involving the scalp, is known as Brunsting-Perry pemphigoid.
Variants include:
- Mucous membrane pemphigoid
- Localized pemphigoid
- Urticarial pemphigoid
- Eczematous pemphigoid
- Dyshidrosiform pemphigoid
- Drug-induced pemphigoid
- Pemphigoid nodularis resembling prurigo nodularis
- Lichen planus pemphigoides
- Acral blisters in infants and vulvar lesions in prepubertal girls
- Erythrodermic pemphigoid
- Noninflammatory pemphigoid

Diagnosis

Laboratory testing
- Linear IgG basement membrane zone and C3 staining in 90% or more by direct immunofluorescence in perilesional tissue
- Serum epithelial skin antibodies demonstrating epidermal or combined epidermal and dermal localization on split human skin
- Epithelial basement zone membrane (BMZ) IgG antibodies (present in serum in 80% of bullous pemphigoid and 20% of mucous membrane pemphigoid patients)
- BP180 and BP230 antibodies
  - Testing for basement membrane zone antibodies and BP180 and BP230 antibodies is highly sensitive and specific for pemphigoid; it will distinguish pemphigoid from linear IgA disease and epidermolysis bullosa acquisita

Differential Diagnosis

Pemphigus
Epidermolysis bullosa acquisita
Linear IgA bullous dermatosis
Drug-induced bullous disorder
Herpes gestationis
Dermatitis herpetiformis
Porphyria and pseudoporphyria
Contact dermatitis
Erythema multiforme
Urticaria
Herpes infection
Bullous impetigo

Disease Monitoring

BMZ antibodies, particularly IgG BP180 and BP230 antibody levels by ELISA

Treatment

Prednisone and steroid-sparing agents such as azathioprine

Indications for Ordering

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies 0092001 Method: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence	Establish diagnosis of pemphigoid or epidermolysis bullosa acquisita in patients suspected of having or known to have any type of subepidermal immunobullous disease Distinguish these diseases from each other and other immunobullous disease, such as pemphigus and dermatitis herpetiformis Panel includes epithelial basement membrane zone IgG & IgA, BP 180 & BP 230 IgG antibodies	Clinical correlation necessary since incidence of false-positives, although rare, increases with age	Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of pemphigoid and epidermolysis bullosa acquisita cases are positive)
Epithelial Basement Membrane Zone IgG Antibodies 0092056 Method: Indirect Immunofluorescence (IFA)	Establish diagnosis of pemphigoid or epidermolysis bullosa acquisita in patients suspected of having or known to have any type of pemphigoid or epidermolysis bullosa acquisita Distinguish these diseases from each other and other immunobullous disease, such as pemphigus and dermatitis herpetiformis	Clinical correlation necessary since incidence of false-positives, although rare, increases with age Note that this test does NOT include IgA basement membrane zone antibody determination; linear IgA disease may be missed IgG BP180 and BP230 antibody levels are NOT included in this test.	Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of pemphigoid and epidermolysis bullosa acquisita cases are positive)
Bullous Pemphigoid (180 kDa & 230 kDa) Antigens, IgG 0092566 Method: Enzyme Linked Immunosorbent Assay	Test for IgG BP180 (BPAG2) and BP230 (BPAG1) antibodies in patients suspected of having or known to have any type of pemphigoid, including bullous pemphigoid and variant forms, mucous membrane (cicatricial) pemphigoid and herpes gestationis Detect relative levels of BP180 and BP230 IgG antibodies to diagnose pemphigoid and monitor disease activity including response to therapy	Patients with pemphigoid may show reactivity to multiple basement membrane zone components; therefore, negative/normal IgG BP180 and BP230 antibody levels do not rule out pemphigoid or other subepidermal immunobullous diseases Correlations with indirect and direct immunofluorescence results and clinical presentation are important for initial diagnosis	A perilesional skin biopsy for direct immunofluorescence is very helpful for diagnosis because of increased sensitivity (>90% of pemphigoid cases are positive); however, specificity is lower due to similar direct immunofluorescence findings in both pemphigoid and epidermolysis bullosa acquisita

General References

Allen J, Wojnarowska F. Linear IgA disease: the IgA and IgG response to the epidermal antigens demonstrates that intermolecular epitope spreading is associated with IgA rather than IgG antibodies, and is more common in adults. Br J Dermatol. 2003;149(5):977-985. (Link to PubMed)

Amo Y, Ohkawa T, Tatsuta M, Hamada Y, Fujimura T, Katsuoka K, Hashimoto T. Clinical significance of enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid. J Dermatol Sci. 2001;26(1):14-18. (Link to PubMed)

Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, Fine JD, Foster CS, Ghohestani R, Hashimoto T, Hoang-Xuan T, Kirtschig G, Korman NJ, Lightman S, Lozada-Nur F, Marinkovich MP, Mondino BJ, Prost-Squarcioni C, Rogers RS III, Setterfield JF, West DP, Wojnarowska F, Woodley DT, Yancey KB, Zillikens D, Zone JJ. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. 2002;138(3):370-379. (Link to PubMed)

Harman KE. New laboratory techniques for the assessment of acquired immunobullous disorders. Clin Exp Dermatol. 2002;27(1):40-46. (Link to PubMed)

Korman NJ. Bullous pemphigoid. The latest in diagnosis, prognosis, and therapy. Arch Dermatol. 1998;134(9):1137-1141. (Link to PubMed)

Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen. Arch Dermatol Res. 1996;288(9):507-509. (Link to PubMed)

Mutasim DF, Adams BB. Immunofluorescence in dermatology. J Am Acad Dermatol. 2001;45(6):803-822. (Link to PubMed)

Tsuji-Abe Y, Akiyama M, Yamanaka Y, Kikuchi T, Sato-Matsumura KC, Shimizu H. Correlation of clinical severity and ELISA indices for the NC16A domain of BP180 measured using BP180 ELISA kit in bullous pemphigoid. J Dermatol Sci. 2005;37(3):145-149. (Link to PubMed)

Yancey KB. The pathophysiology of autoimmune blistering diseases. J Clin Invest. 2005;115(4):825-828. (Link to PubMed)

Yoshida M, Hamada T, Amagai M, Hashimoto K, Uehara R, Yamaguchi K, Imamura K, Okamoto E, Yasumoto S, Hashimoto T. Enzyme-linked immunosorbent assay using bacterial recombinant proteins of human BP230 as a diagnostic tool for bullous pemphigoid. J Dermatol Sci. 2006;41(1):21-30. (Link to PubMed)

Zone JJ, Taylor T, Hull C, Schmidt L, Meyer L. IgE basement membrane zone antibodies induce eosinophil infiltration and histological blisters in engrafted human skin on SCID mice. J Invest Dermatol. 2007;127(5):1167-1174. (Link to PubMed)

Reviewed by

Leiferman, Kristin M., M.D. Co-Director, Immunodermatology Laboratory at ARUP Laboratories; Professor, Dermatology, University of Utah

Zone, John J., M.D. Co-Director, Immunodermatology Laboratory at ARUP Laboratories; Professor and Chairman, Dermatology, University of Utah

Comprehensive Review: September 2007
Last Update: September 2007