Pemphigoid

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Immunobullous Skin Diseases Testing Algorithm

Clinical Background

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 or older, rarely in children
Sex - M:F, equal distribution

Pathophysiology

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
- BP230 is an intracellular hemidesmosomal plaque protein
Mucous membrane pemphigoid variant has antibodies to other basement membrane zone components including laminin-5, laminin-6, beta 4 integrin subunit; pemphigoid with laminin-5 antibodies has association with internal malignancy

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:
- Acral blisters in infants and vulvar lesions in prepubertal girls
- Drug-induced pemphigoid
- Dyshidrosiform pemphigoid resembling dyshidrotic eczema
- Eczematous pemphigoid
- Erythrodermic pemphigoid
- Lichen planus pemphigoides
- Localized pemphigoid
- Mucous membrane pemphigoid
- Noninflammatory pemphigoid
- Pemphigoid nodularis or nodular pemphigoid resembling prurigo nodularis
- Urticarial pemphigoid resembling chronic urticaria

Treatment

Prednisone, other immunosuppressives, and steroid-sparing agents such as azathioprine

See Also

Dermatitis Herpetiformis

Epidermolysis Bullosa Acquisita

Immunobullous Skin Diseases Screening

Linear IgA Disease

Paraneoplastic Pemphigus

Pemphigus

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Immunobullous Skin Diseases Testing Algorithm

Diagnosis

Indications for testing - presence of chronic blistering skin disease after other more common diseases ruled out or unexplained pruritus, erythroderma, eczema, urticaria or desquamative gingivitis, mucositis
Perilesional skin biopsy for direct immunofluorescence submitted in Michel’s (or Zeus) medium.
Immunohistology
- Perilesional skin biopsy - cutaneous direct immunofluorescence submitted in Michel’s (or Zeus) medium
  - Linear IgG basement membrane zone and C3 staining in 90% or more
  - Linear IgA or IgM may also be present
Initial serum screening - Pemphigus and Pemphigoid Panels and Endomysial antibodies (all 3 tests for initial testing) or Epithelial Skin Antibodies testing
- Broad screening recommended unless a specific immunobullous skin disease type is suspected because of overlap in clinical immunobullous disease presentations
Laboratory testing
- Serum basement membrane zone antibodies and IgG BP180 and BP230 antibodies testing
  - Testing is highly sensitive and specific for pemphigoid
  - Testing can distinguish pemphigoid from linear IgA disease and epidermolysis bullosa acquisita
  - Detection of IgG antibodies to both BP180 and BP230 increases sensitivity and specificity in diagnosing pemphigoid; levels of IgG antibodies to BP180 and/or BP230 may be useful in monitoring disease activity and response to therapy
- Serum epithelial skin antibodies demonstrating epidermal or combined epidermal and dermal localization on split human skin
- Epithelial basement zone membrane IgG antibodies (present in serum in 80% of bullous pemphigoid and 20% of mucous membrane pemphigoid patients)

Disease Monitoring

Basement membrane zone antibodies, particularly IgG BP180 and BP230 antibody levels by ELISA
Antibodies to either or both BP180 and BP230 antigens may be increased and levels correlated more closely to clinical activity than to titers of basement membrane zone antibodies

Differential Diagnosis

Dermatologic disease
- Bullous impetigo
- Contact dermatitis
- Dermatitis herpetiformis
- Drug-induced bullous disorder
- Epidermolysis bullosa acquisita
- Erythema multiforme
- Herpes gestationis
- Herpes infection
- Linear IgA bullous dermatosis
- Pemphigus
- Porphyria and pseudoporphyria
- Urticaria
Ocular disease
- Cicatrizing keratitis
- Moorhens ulcer
- Peripheral ulcerative keratitis

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Immunobullous Skin Diseases Testing Algorithm

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Cutaneous Direct Immunofluorescence, Biopsy

ARUP #: 0092572

Methodology: Direct Immunofluorescence

Use:

Determine presence and staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in perilesional skin or mucosal biopsy specimens from patients suspected of having pemphigoid

Limitations:

Test may be inaccurate if tissue not taken from correct location, type and age of lesion may also be important; specimen must have epidermis/epithelium and basement membrane zone

Tissue must be submitted in Michel’s or Zeus medium; this test cannot be performed on formalin-fixed tissue

Follow-up:

Concurrent serum testing for pemphigoid is most sensitive and specific for diagnosis and to subtype disease when circulating basement membrane zone antibodies are present

Test name: Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies

ARUP #: 0092001

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence

Use:

For diagnosis of most types of pemphigoid, epidermolysis bullosa acquisita, linear IgA disease (including linear IgA bullous dermatosis and childhood immunobullous disease)

Panel includes epithelial basement membrane zone IgG & IgA on human split skin and monkey esophagus substrates by IFA, BP 180 & BP 230 IgG antibodies by ELISAs

Distinguish these diseases from each other and other immunobullous disease, such as pemphigus and dermatitis herpetiformis

Use along with Pemphigus Panel and endomysial antibody, IgA, testing to differentiate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

IgG BP180 and BP230 antibody levels may be useful in monitoring disease activity and response to therapy

Limitations:

Because of clinical overlap among immunobullous diseases and similar names, testing for pemphigoid may be confused with testing for pemphigus and misordered

Clinical correlation necessary since incidence of false-positives, although rare, increases with age

Follow-up:

Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of pemphigoid, linear IgA disease, epidermolysis bullosa acquisita and dermatitis herpetiformis cases are positive)

Test name: Pemphigus Panel - IgG Epithelial Cell Surface Antibodies and Levels of IgG Desmoglein 1 and Desmoglein 3 Antibodies, Serum

ARUP #: 0090650

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence

Use:

For diagnosis of most types of pemphigus and for monitoring disease activity and response to therapy.

Panel tests for IgG epithelial cell surface antibodies on intact human skin and monkey esophagus substrates by IFA and IgG desmoglein 1 and desmoglein 3 antibodies by ELISAs

Use along with Pemphigoid Panel and endomysial IgA antibody testing, or Epithelial Skin Antibody testing to differentiate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

Limitations:

Clinical correlation is necessary since cell surface antibodies by IFA, usually in low titers, may be found in normal individuals because of blood group reactivity or in patients with fungal infections, burns, drug reactions and other dermatoses

Because of clinical overlap among immunobullous diseases and similar names, testing for pemphigus may be confused with testing for pemphigoid and misordered; testing for IgG pemphigus antibody types (most common) also may be confused with IgA pemphigus testing (rare)

Follow-up:

A concurrent perilesional skin biopsy for direct immunofluorescence is helpful for diagnosis because of increased sensitivity (>90% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive); although it is not possible to reliably distinguish pemphigus subtypes based on direct immunofluorescence

Monitor disease activity and response to therapy with Pemphigus Panel

Test name: Tissue Transglutaminase Antibody, IgA with Reflex to Endomysial Antibody, IgA Titer by IFA

ARUP #: 0050734

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Use:

Use along with pemphigoid and pemphigus panel tests, and epithelial skin antibody testing to differentiate among the immunobullous skin diseases in patients suspected of having or known to have any type of subepidermal immunobullous disease

Limitations:

This test alone is insufficient to diagnose immunobullous diseases

Follow-up:

Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of pemphigoid, pemphigus, linear IgA disease, dermatitis herpetiformis and epidermolysis bullosa acquisita cases are positive)

Test name: Epithelial Skin Antibody

ARUP #: 0090299

Methodology: Indirect Immunofluorescence

Use:

Use along with endomysial antibody, IgA, test to differentiate among the immunobullous skin diseases in patients suspected or known to have any type of these disorders

Panel includes epithelial basement membrane zone IgG & IgA antibodies by IFA and IgG & IgA cell surface antibodies by IFA on split human skin, intact human skin and monkey esophagus substrates

Limitations:

Does not include testing for antibodies to target antigens, BP180 & BP230 for pemphigoid and desmoglein 1 & 3 for pemphigus that may be more sensitive and the levels of which correlate with disease activity and response to therapy

Follow-up:

Test name: Epithelial Basement Membrane Zone IgG Antibodies

ARUP #: 0092056

Methodology: Indirect Immunofluorescence (IFA)

Use:

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

Limitations:

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, which may increase sensitivity in diagnosing pemphigoid

Follow-up:

Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of pemphigoid and epidermolysis bullosa acquisita cases are positive)

Test name: Bullous Pemphigoid (180 kDa & 230 kDa) Antigens, IgG

ARUP #: 0092566

Methodology: Enzyme Linked Immunosorbent Assay

Use:

Test for IgG BP180 (BP Ag2) and BP230 (BP Ag1) antibodies in patients suspected 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

Limitations:

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

Follow-up:

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

References

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.

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.

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.

Di Zenzo G, Marazza G, Borradori L. Bullous pemphigoid: physiopathology, clinical features and management. Adv Dermatol. 2007;23:257-288.

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

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

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.

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

Rashid S, Dana MR. Cicatrizing and autoimmune diseases. Chem Immunol Allergy. 2007;92:195-202.

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.

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

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.

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.

Medical Reviewers

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 2008
Last Update: September 2008