Nonbullous pemphigoid: A systematic review

doi:10.1016/j.jaad.2017.10.035

Journal of the American Academy of Dermatology

Volume 78, Issue 5, May 2018, Pages 989-995.e2

https://doi.org/10.1016/j.jaad.2017.10.035 Get rights and content

Background

Bullous pemphigoid is an autoimmune disease that typically presents with tense bullae and severe pruritus. However, bullae can be lacking, a subtype termed nonbullous pemphigoid.

Objective

To summarize the reported characteristics of nonbullous pemphigoid.

Methods

The EMBASE and MEDLINE databases were searched using “nonbullous pemphigoid” and various synonyms. Case reports and series describing nonbullous pemphigoid were included.

Results

The search identified 133 articles. After selection, 39 articles were included, presenting 132 cases. Erythematous, urticarial plaques (52.3%) and papules/nodules (20.5%) were the most reported clinical features. The mean age at presentation was 74.9 years. Histopathology was commonly nonspecific. Linear depositions of IgG and/or C3 along the basement membrane zone were found by direct immunofluorescence microscopy in 93.2%. Indirect immunofluorescence on salt-split skin was positive in 90.2%. The mean diagnostic delay was 22.6 months. A minority of patients (9.8%) developed bullae during the reported follow-up.

Limitations

Results are mainly based on case reports and small case series.

Conclusion

Nonbullous pemphigoid is an underdiagnosed variant of pemphigoid that most often does not evolve to bullous lesions and mimics other pruritic skin diseases. Greater awareness among physicians is needed to avoid delay in diagnosis.

Section snippets

Search strategy

The literature search for this review was conducted in the EMBASE and MEDLINE databases on November 4, 2016. Various terms and synonyms for “nonbullous pemphigoid” (Supplementary Appendix; available at http://www.jaad.org) were used. There were no limitations on article type. After the selection procedure, the references of all included articles were checked for missing articles.

Selection of articles

Language was limited to Dutch, German, or English. Independent screening of the titles and abstracts was carried out

Systematic search results

A total of 39 articles presenting a total of 132 cases of nonbullous pemphigoid were identified (Supplemental Table I; available at http://www.jaad.org).10, 11, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 Fig 1 displays the selection procedure. The first case of nonbullous pemphigoid was reported in 1983 by Barker et al.²⁰ The largest case series was from Lamb et al,²¹ who described the clinical

Discussion

This systematic review summarizes the reported characteristics of nonbullous pemphigoid. The most frequently reported skin efflorescences were erythematous, urticarial plaques (52.3%). Pruritus was reported in 100% of the cases. Overall, the duration between the start of symptoms and the correct diagnosis was very long (mean 22.6 months). Only 13 patients (9.8%) developed bullae during the reported follow-up; thus only 13 cases were actually prodromal to bullous pemphigoid. However, for most of

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Citation Excerpt :
Non-bullous pemphigoid has a variable clinical spectrum, characterized by erythematous patches, plaques or nodules, eczematous lesions, or rarely, erythroderma. Multiple studies have found urticarial lesions to be the most common manifestation of non-bullous pemphigoid [8,107,108]. Pruritus is a common feature of most forms of non-bullous pemphigoid [109].
Autoimmune bullous dermatoses are characterized by the presence of tissue-bound and often circulating pathogenic autoantibodies targeting structural components of the skin and/or mucous membranes. The diagnostic workup for this heterogeneous group of disorders consists of a multi-step process, of which the light microscopic examination is a crucial component. This review is organized following a classification scheme that is based on two main histopathologic features, namely level of intraepithelial split and composition of the inflammatory infiltrate. Overall, we aim to place emphasis on the histopathologic clues that can assist pathologists in differential diagnosis and review the updates in the literature.
Annular urticarial lesions
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Severe pruritus is associated with bullae; however, the disease usually begins with a pruritic nonbullous phase which can last for months. In this prebullous period, the disease can appear with erythematous annular, round, or arcuate shaped urticarial or excoriated eczematous plaques which may delay the diagnosis.6,69 In acute infantile hemorrhagic edema, the skin lesions initially appear on the face, ears, and extremities, as erythematous macules or urticarial plaques with symmetric distribution, and progress within 24 to 48 hours to purpuric annular, circumscribed, or targetoid lesions.
Annular urticarial configurations are often associated with acute and chronic urticaria. Such lesions may be short-lived, migratory, transient, pruritic, and resolving with no residual evidence, making the diagnosis of urticaria an obvious one. Annular urticarial lesions can be the presenting signs of various cutaneous and systemic diseases. The differentiation of urticarial lesions may be made by considering the duration of an individual lesion longer than 24 hours, with burning and pain sensation in the lesions or lack of pruritus; skin marks such as postinflammatory pigmentation or purpura after resolution of the lesions; associated scaling or vehiculation in the lesions; systemic symptoms such as arthralgia, fever or fatigue; and several abnormal laboratory findings. The main differential diagnoses of annular urticarial lesions include urticarial vasculitis, autoinflammatory syndromes, hypersensitivity reactions, and connective tissue diseases.
Bullous Diseases of the Skin and Mucous Membranes
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Autoimmune bullous diseases (AIBDs) comprise about a dozen clinically and immunopathologically heterogeneous disorders. They can be divided into three groups: pemphigus diseases, pemphigoid diseases, and dermatitis herpetiformis. The common denominators of AIBDs are the occurrence of blisters and erosions on the skin and/or surface-close mucous membranes, with accompanying characteristic patterns of deposition of IgG, IgA, and/or complement C3 in these tissues. While in pemphigus and pemphigoid diseases autoantibodies target structural proteins of the epidermal/epithelial desmosomes and the dermal–epidermal junction, respectively, autoantibodies in dermatitis herpetiformis are directed against transglutaminase 2 and 3. Within the last decade, considerable progress has been made in both the diagnosis and the understanding of the pathophysiology of AIBDs. In pemphigus, cellular events of the keratinocytes themselves are sufficient for intraepidermal/-epithelial splitting after the binding of autoantibodies. In pemphigoid diseases, Fc receptor-mediated mechanisms such as local complement activation and the subsequent influx of inflammatory cells induce subepidermal splitting due to the release of reactive oxygen species and specific proteases. C5a, IL-17A, and LTB4 have recently been described as key mediators in this process. In pemphigoid diseases, treatment typically relies on the long-term use of corticosteroids in combination with immunomodulants or immunosuppressants; the anti-CD20 antibody rituximab induces complete remission in 80% to 90% of pemphigus patients.
Pathogenesis-based treatments in bullous pemphigoid
2022, Translational Autoimmunity: Autoimmune Diseases in Different Organs
Pemphigoid is one of the most common autoimmune bullous diseases in the elderly, characterized by subepidermal blisters due to autoantibodies against the adhesion proteins of hemidesmosomes (BP180/collagen type XVII and BP230/dystonin-e). It usually affects patients over 70 years of age, causing tense mucocutaneous blisters. The disease generally shows a chronic and recurrent often recalcitrant course, usually requiring long-term corticosteroid use, alone or in combination with systemic immunosuppressants (called steroid-sparing agents). At present, there is no curative treatment, and current alternatives may trigger adverse events, thus increasing mortality rates; therefore, it is necessary to develop pathogenesis-based therapies with fewer side effects. The treatment of choice for bullous pemphigoid mainly depends on disease activity. Class I topical corticosteroids, including clobetasol propionate, are often used in mild-to-moderate disease, whereas in cases of extensive or refractory disease, the selected therapy usually includes systemic steroids alone or in combination with other immunosuppressants, providing a steroid-sparing effect. New treatments such as rituximab, intravenous immunoglobulin, and omalizumab are promising options; however, their use is limited due to the high cost. In this review, we will address the status of bullous pemphigoid therapy and the most used treatments in dermatological practice.
Immunoglobulin M pemphigoid
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Pemphigoid diseases are a heterogeneous group of autoimmune blistering disorders characterized by predominant deposition of immunoglobulin G or immunoglobulin A autoantibodies against structural proteins of the dermoepidermal junction (DEJ). Sole linear immunoglobulin M (IgM) deposits at the DEJ in pemphigoid diseases have been observed; however, IgM-specific target antigens have not been identified.
Characterization of patients with IgM pemphigoid.
Skin biopsy specimens and sera from IgM-positive patients were assessed using histopathology, direct and indirect immunofluorescence microscopy, enzyme-linked immunosorbent assays, immunoblotting, cryosection assay, complement fixation test, and internalization assays.
Tissue-bound linear IgM deposits along the DEJ and circulating IgM autoantibodies against type XVII collagen (Col17) were detected. These circulating IgM autoantibodies showed no complement activating or blister inducing capacity, but the ability of Col17 internalization ex vivo.
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: Funding sources: None.

: Conflicts of interest: Prof dr Jonkman received a grant from Castle Creek Pharma; received honoraria from and was a consultant for Roche and Genentech; and has shares in Philae Pharmaceuticals. Other authors have no conflicts of interest.

: Reprints not available from the authors.

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ReviewNonbullous pemphigoid: A systematic review

Background

Objective

Methods

Results

Limitations

Conclusion

Section snippets

Search strategy

Selection of articles

Systematic search results

Discussion

Lancet

J Invest Dermatol

Autoimmun Rev

J Am Acad Dermatol

Clin Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Invest Dermatol

Clin Exp Dermatol

J Am Acad Dermatol

Autoimmun Rev

J Am Acad Dermatol

J Am Acad Dermatol

J Invest Dermatol

Quality of life, depression, anxiety and loneliness in patients with bullous pemphigoid. A case control study

An Bras Dermatol

Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort

Br J Dermatol

Incidence of bullous pemphigoid and pemphigus in switzerland: a 2-year prospective study

Br J Dermatol

Bullous pemphigoid and pemphigus vulgaris–incidence and mortality in the UK: population based cohort study

BMJ

Clinical variations in bullous pemphigoid with respect to early symptoms

Acta Derm Venereol

Bullous pemphigoid: a review of its diagnosis, associations and treatment

Am J Clin Dermatol

Bullous pemphigoid as pruritus in the elderly a common presentation

JAMA Dermatol

Clinical classification of itch: a position paper of the international forum for the study of itch

Acta Derm Venereol

‘Bullous’ pemphigoid: what are you? Urgent need of definitions and diagnostic criteria

Dermatology

Toward a practical renaming of bullous pemphigoid and all its variants: cutaneous pemphigoid

JAMA Dermatol

Toward a practical renaming of bullous pemphigoid and all its variants-reply

JAMA Dermatol

Management of bullous pemphigoid: the european dermatology forum consensus in collaboration with the European Academy of Dermatology and Venereology

Br J Dermatol

Non-bullous lesions as the first manifestation of bullous pemphigoid: a retrospective analysis of 181 cases

J Dermatol

Underrecognition of the heterogeneous clinical spectrum of bullous pemphigoid

JAMA Dermatol

Generalized pruritus as the presenting feature of bullous pemphigoid

Br J Dermatol

Prodromal bullous pemphigoid

Int J Dermatol

Pemphigoid nodularis

Arch Dermatol

Granuloma annulare-like presentation of bullous pemphigoid

J Am Acad Dermatol

The prodrome of bullous pemphigoid

Int J Dermatol

Erythema multiforme-like bullous pemphigoid drug eruption

Ann Allergy Asthma Immunol

Erythematous variety of bullous pemphigoid: case report and literature review

Acta Derm Venereol

Two cases of annular erythema without bullous lesions by autoimmune blistering diseases

Mod Rheumatol

An eczema-like, pruritic, nonbullous form of bullous pemphigoid

J Dermatol Case Rep

Review
Nonbullous pemphigoid: A systematic review