Diagnostic Criteria for Epidermolysis Bullosa Acquisita

Abstract and Introduction

Abstract

Background: Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests, making an international consensus on the diagnosis of EBA essential.

Objectives: To obtain an international consensus on the clinical and diagnostic criteria for EBA.

Methods: The International Bullous Diseases Group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When > 30% disagreed with a proposal, a discussion was held and re–voting carried out.

Results: In total, 48 of 50 proposals achieved consensus after discussion. This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed.

Conclusions: This first international consensus conference established generally agreed–upon clinical and laboratory criteria defining the clinical classification of and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting.

Introduction

The International Bullous Diseases Group (IBDG) was formed in 2005 following a research meeting at the National Institutes of Health for experts in blistering diseases to work towards a consensus for the development and validation of definitions and outcome measures in autoimmune bullous diseases (AIBDs).^[1] The IBDG focused its efforts initially on pemphigus, with consensus definitions, development and validation of the Pemphigus Disease Area Index and the Autoimmune Bullous Skin Intensity Score.^[1,2] Subsequently, the IBDG published consensus definitions for bullous pemphigoid (BP) and proposed the BP Disease Area Index severity tool,^[3] and then consensus definitions for mucous membrane (MM) pemphigoid (MMP) and the MMP Disease Area Index.^[4] The current project relates to international consensus definitions on diagnostic criteria for epidermolysis bullosa acquisita (EBA).

Two cases of an adult–onset, acquired blistering disease that was reminiscent of patients with hereditary dystrophic epidermolysis bullosa (EB) were reported in 1895 by Elliott.^[5] A landmark paper on the subject was published in 1971 by Roenigk et al., who described three new cases of EBA, reviewed the world literature and proposed the first diagnostic criteria for EBA.^[6] These criteria were soon modified by the advent of immunofluorescence (IF) and the finding that all patients with EBA had IgG and sometimes C3 deposits in their dermoepidermal junction (DEJ) and that by immunoelectron microscopy (IEM), these DEJ immune deposits were clearly in a different location than immune deposits observed in BP.^[7–10] The IgG autoantibodies (autoAbs) accounting for these DEJ immune deposits were found to be autoAbs directed against a 290–kDa protein called type VII collagen (Col7), the major component of anchoring fibrils (AFs) in the DEJ.^[11,12] Since these initial observations, the diagnostic testing for EBA has undergone significant refinement.^[13–15]

Authors and Disclosures

Table 1. Definitions of clinical forms of epidermolysis bullosa acquisita (EBA)
Classical/mechanobullous
One subtype only, characterized by:⁶ trauma–induced lesions (skin fragility)^a bullous/vesicular lesions or erosions encompassed by noninflamed or scarred skin scarring^a and milia formation^a preferably located in trauma–prone sites and the extensor skin surface (dorsal hands,^a elbows,^a knees,^a Achilles tendon, feet^a) possible nail dystrophy^a possible scarring alopecia
Nonclassical/nonmechanobullous
BP–like EBA, defined as an eruption:^{18, 20–24} with features characteristic of BP (pruritus, tense bullae on erythematous or urticarial skin, involvement of trunk and folds) usually mixed with atypical lesions for a BP (skin fragility, bullae on normal skin, milia, involvement of face or extensor area of the limbs)
MM–EBA, defined as a disease that predominantly affects MM lined by squamous epithelium, i.e. MM of:^20–27 mouth pharynx oesophagus epiglottis conjunctiva genitalia anus respiratory tract (in malpighian metaplasia)
Brunsting–Perry–type EBA, defined as a chronic recurrent blistering dermatosis confined to the head and neck^28–32
IgA–EBA, defined as a disease that presents with linear IgA deposits in the BMZ that can be observed by direct IF:^{20, 33, 34} it may resemble LABD it may be more aggressive with mucosal scarring

C. Prost-Squarcioni^1,2,3, F. Caux¹, E. Schmidt⁴, M.F. Jonkman⁵, S. Vassileva⁶, S.C. Kim⁷, P. Iranzo⁸, M. Daneshpazhooh⁹, J. Terra⁵, J. Bauer¹⁰, J. Fairley¹¹, R. Hall¹², M. Hertl¹³, J.S. Lehman¹⁴, B. Marinovic¹⁵, A. Patsatsi¹⁶, D. Zillikens⁴, the International Bullous Diseases Group, V. Werth¹⁷, D.T. Woodley¹⁸ and D.F. Murrell¹⁹

¹Department of Dermatology and Referral Center for Autoimmune Bullous Diseases; and ³Department of Pathology, APHP, Avicenne Hospital, Bobigny, France
²Department of Histology, UFR Léonard de Vinci, University Paris 13, Bobigny, France
⁴Department of Dermatology, University of Lübeck, Lübeck, Germany
⁵Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
⁶Department of Dermatology, Medical University of Sofia, Sofia, Bulgaria
⁷Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
⁸Department of Dermatology, Hospital Clinic de Barcelona, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
⁹Autoimmune Bullous Diseases Research Center, Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
¹⁰Division of Molecular Dermatology, Department of Dermatology, Paracelsus Medical University Salzburg, Salzburg, Austria
¹¹Department of Dermatology, University of Iowa and Department of Veterans Affairs Medical Center, Iowa City, IA, U.S.A.
¹²Department of Dermatology, Duke Medical Center, Durham, NC, U.S.A.
¹³Department of Dermatology, University Hospital, Marburg, Germany
¹⁴Department of Dermatology, Mayo Clinic, Rochester, MN, U.S.A.
¹⁵Department of Dermatology and Venereology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
¹⁶Second University Dermatology Department, Aristotle University School of Medicine, Papageorgiou General Hospital, Thessaloniki, Greece
¹⁷Department of Dermatology, University of Pennsylvania and Philadelphia Department of Veterans Affairs Medical Center, Philadelphia, PA, U.S.A.
¹⁸Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, U.S.A.
¹⁹Department of Dermatology at St George Hospital, University of New South Wales, Sydney, Australia

Correspondence
Catherine Prost-Squarcioni. E-mail: catherine.prost@aphp.fr

Conflicts of interest
E.S. and D.Z. have received honoraria for lectures from Roche and Fresenius Medical Care, and funding for research and development projects from Euroimmun (E.S., D.Z.), Fresenius Medical Care (D.Z.), Biotest (D.Z.) and Novartis (E.S.). M.H. has received honoraria for participation on advisory boards from Roche, Janssen, Biogen and Novartis, and grants from Biotest, Fresenius and Topas. D.T.W. holds patents with the University of Southern California Stevens Institute on various forms of human recombinant type VII collagen, has received grants for epidermolysis bullosa acquisita and type VII collagen research from the National Institutes of Health, Lotus Tissue Repair and Shire Pharmaceuticals, and has been a consultant for Biofusion, Lotus Tissue Repair and Shire Pharmaceuticals. R.J.F. (co-author) receives fees for consulting from Roche. S.Y. (co-author) received Principal Investigator fees from Roche.