Pemphigus

The diagnosis of pemphigus is based on four criteria:[1]Joly P, Horvath B, Patsatsi Α, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1900-13. https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 http://www.ncbi.nlm.nih.gov/pubmed/32830877?tool=bestpractice.com [26]Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: recommendations of an international panel of experts. J Am Acad Dermatol. 2020 Mar;82(3):575-85.e1. http://www.ncbi.nlm.nih.gov/pubmed/29438767?tool=bestpractice.com

• Clinical findings

• Histopathology

• Direct immunofluorescence (DIF) examination of a perilesional skin or mucosal biopsy

• Serologic detection of autoantibodies against epithelial cell surface by indirect immunofluorescence (IIF) and/or enzyme-linked immunosorbent assay (ELISA Dsg1 and Dsg3).

Pemphigus vulgaris (PV) typically involves the oral mucosa and skin. It can also involve the mucosa of the nasopharynx, conjunctiva, and esophagus. Rarely, PV is confined only to the skin or oral mucosa.

Pemphigus foliaceus (PF) is limited to the skin, but may progress to involve the mouth.

The classic lesion of PV and PF is an erosion or superficial blister. Often these blisters are not inflamed, but in more chronic cases, secondary bacterial or yeast infection is common and makes the prototypical noninflammatory erosion or bulla less apparent.

Paraneoplastic pemphigus (PNP) is characterized by an aggressive mucosal involvement, but can also involve the skin and lungs.

Delays in diagnosis of pemphigus are not uncommon. In people with PV and PF, up to 25% have positive desmoglein-1 or desmoglein-3 titers prior to symptoms.[27]Raneses E, McGinley Simpson M, Rosenberg A, et al. A retrospective review of autoimmune bullous disease antibody positivity before clinical symptoms. J Am Acad Dermatol. 2021 Feb 4;S0190-9622(21)00315-7. http://www.ncbi.nlm.nih.gov/pubmed/33549648?tool=bestpractice.com Misdiagnoses initially include conditions such as pityriasis rosea and aphthous stomatitis. 

At initial diagnosis important points to consider include:[1]Joly P, Horvath B, Patsatsi Α, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1900-13. https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 http://www.ncbi.nlm.nih.gov/pubmed/32830877?tool=bestpractice.com [26]Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: recommendations of an international panel of experts. J Am Acad Dermatol. 2020 Mar;82(3):575-85.e1. http://www.ncbi.nlm.nih.gov/pubmed/29438767?tool=bestpractice.com [28]Harman KE, Brown D, Exton LS, et al. British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol. 2017 Nov;177(5):1170-1201. https://onlinelibrary.wiley.com/doi/10.1111/bjd.15930 http://www.ncbi.nlm.nih.gov/pubmed/29192996?tool=bestpractice.com

• Identifying risk factors and comorbidities

• Specifying the type of initial involvement (skin, mucosa), and its extent

• Assessing prognosis based on age and general condition

• Recording disease severity according to one of the two validated scoring systems: the Pemphigus Disease Area Index (PDAI) or the Autoimmune Bullous Skin Intensity and Severity Score (ABSIS)

• Measuring the impact of disease on quality of life using dermatology-specific score (DLQI).

History and examination

Salient points to cover or address in the history and exam include:[1]Joly P, Horvath B, Patsatsi Α, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1900-13. https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 http://www.ncbi.nlm.nih.gov/pubmed/32830877?tool=bestpractice.com [26]Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: recommendations of an international panel of experts. J Am Acad Dermatol. 2020 Mar;82(3):575-85.e1. http://www.ncbi.nlm.nih.gov/pubmed/29438767?tool=bestpractice.com [28]Harman KE, Brown D, Exton LS, et al. British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol. 2017 Nov;177(5):1170-1201. https://onlinelibrary.wiley.com/doi/10.1111/bjd.15930 http://www.ncbi.nlm.nih.gov/pubmed/29192996?tool=bestpractice.com

• Time from onset of first symptoms

• Functional symptoms (pain, pruritus, intensity of dysphagia, ocular and ENT symptoms, dysuria, anogenital problems, and weight loss)

• Hematologic, oncologic, endocrine, cardiovascular and infectious medical history to identify risk factors for oral corticosteroid treatment and evolving complications of immunosuppressive therapy

• Discussing possible future pregnancy (especially if immunosuppressive treatment is being considered) with female patients

• Performing a drug history to identify drugs that may potentially induce pemphigus

• Evaluation of the impact on quality of life using validated questionnaires, e.g., DLQI

• Checking for updated vaccination; inquire about a possible future travel which may impact immunosuppression.

The key component in the history of PV or PF is a chronic erosive, blistering dermatitis of the skin, mucosa, or both with pruritus and pain. In PV, the oral mucosa is frequently involved. The skin is commonly involved. The nasal mucosa and conjunctiva can also be involved. Nasal lesions may lead to nosebleeds.

In PF, lesions are confined to the skin and often accentuated on the scalp, face, and upper trunk. On examination, the presence of a Nikolsky sign (i.e., superficial desquamation with lateral pressure on the skin) indicates PV and PF. Guidelines state that the majority of experts no longer recommend performing the Nikolsky sign, noting that there are other tools to measure disease activity.[1]Joly P, Horvath B, Patsatsi Α, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1900-13. https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 http://www.ncbi.nlm.nih.gov/pubmed/32830877?tool=bestpractice.com

Paraneoplastic pemphigus is characterized by an aggressive mucositis, particularly of the lips and tongue. Conjunctival involvement can lead to a scarring conjunctivitis suggestive of mucous membrane pemphigoid (i.e., a cicatricial conjunctivitis). Involvement of the lung epithelium is prominent, and respiratory failure is the leading cause of death in these patients.[29]Nousari HC, Deterding R, Wojtczack H, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med. 1999 May 6;340(18):1406-10. http://www.ncbi.nlm.nih.gov/pubmed/10228191?tool=bestpractice.com Patients may also have lesions suggestive of erythema multiforme, lichen planus, or graft-versus-host disease.

Skin biopsy, hematoxylin and eosin stain

The first diagnostic test for pemphigus is a biopsy of the skin, mucosa, or both. The skin biopsy should include the epidermis and dermis. Routine staining with hematoxylin and eosin on fixed tissue and direct immunofluorescence staining on frozen tissue are needed. This skin biopsy should be from involved skin adjacent to an active blister. A biopsy of an active blister can make the diagnosis of pemphigus difficult as the epidermis is missing.

Skin biopsy, immunofluorescence

Immunofluorescence staining is a more specific diagnostic test than hematoxylin and eosin staining and should be performed as part of the initial investigation.

The direct immunofluorescence (DIF) test involves demonstrating the presence of IgA, IgG, IgM, C3, and fibrin in the epidermis. The presence of IgG, C3, or both between epithelial keratinocytes is diagnostic for PV and PF.

Staining of the epithelial surface of keratinocytes (as seen in PV and PF) and along the dermal-epidermal junction strongly supports the diagnosis of PNP.

Indirect immunofluorescence (IIF) staining involves applying the patient's serum to a substrate (i.e., normal human skin, monkey esophagus, guinea pig esophagus, or rodent bladder). The presence of autoantibodies that characteristically stain the substrate strongly supports the diagnosis of pemphigus.

The DIF test is more sensitive than IIF staining in diagnosing pemphigus; however, IIF staining adds further specificity during the diagnostic workup.

As with routine hematoxylin and eosin staining, the skin biopsy should be from involved skin adjacent to any blister.

Extent of disease

Pemphigus guidelines recommend recording:[1]Joly P, Horvath B, Patsatsi Α, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1900-13. https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 http://www.ncbi.nlm.nih.gov/pubmed/32830877?tool=bestpractice.com [26]Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: recommendations of an international panel of experts. J Am Acad Dermatol. 2020 Mar;82(3):575-85.e1. http://www.ncbi.nlm.nih.gov/pubmed/29438767?tool=bestpractice.com

• Extent of skin and mucous membrane lesions, the degree of mucosal damage and functional impairment (dysphagia, dysphonia, weight loss, impairment of vision, dyspareunia)

• The severity of skin and mucosal lesion using one of the two validated scoring systems (PDAI or ABSIS)

• Bodyweight

• Arterial blood pressure

• General condition, comorbidities (neoplastic, cardiovascular, musculoskeletal, diabetes, etc).

Affected body systems should be further investigated after initial biopsies. For example, upper gastrointestinal endoscopy is indicated to define the extent of mucosal involvement in a patient with dysphagia.

Pulmonary investigations, including chest x-ray, chest computed tomography, and pulmonary function tests, should be carried out in patients with dyspnea or those with PNP.

Specialized immunologic tests

Indirect serum tests such as ELISA and serum immunoprecipitation can be used to detect specific autoantibodies, particularly antibodies to desmoglein 1 and 3.

Immunoblotting (Western blot) can demonstrate autoantibodies to either the desmosome or hemidesmosome of keratinocytes.