eMedicine Specialties > Dermatology > Bullous Diseases

Cicatricial Pemphigoid

Author: Anatoli Freiman, MD, FRCPC, DABD, Consulting Staff, Division of Dermatology, Women's College Hospital, University of Toronto
Contributor Information and Disclosures

Updated: Jan 15, 2009

Introduction

Background

Cicatricial pemphigoid (CP) refers to a group of rare chronic autoimmune blistering diseases that predominately affects the mucous membranes, including the conjunctiva, and occasionally the skin. Patients with cutaneous involvement present with tense blisters and erosions, often on the head and the neck or at sites of trauma. Scarring of the mucous membranes is common, hence the designation cicatricial, which can lead to decreased vision, blindness, and supraglottic stenosis with hoarseness or airway obstruction. The first international consensus on mucous membrane pemphigoid was published in 2002.¹

The classification of cicatricial pemphigoid patients has been difficult because some patients with other autoimmune blistering diseases, including bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA), may have mucosal involvement. Also, clinical heterogeneity exists in the clinical manifestations of this disease, with some patients presenting with ocular involvement and others with oropharyngeal involvement. The heterogeneity in clinical manifestations does not appear to be linked to the heterogeneity of the target antigens alone.

Pathophysiology

As in other autoimmune diseases, environmental factors combined with genetic susceptibility lead to development of autoantibodies. By direct immunofluorescence (DIF) study, antibodies bound in a linear band at the epidermal-dermal junction have been found in patients with cicatricial pemphigoid. By immunoelectron microscopy, these antibodies are found in the lamina lucida. In some patients, autoantibodies extend to the lamina densa. When detectable, circulating autoantibodies are present in a low titer.

Different epithelial membrane zone components have been recognized by antibodies in patients with cicatricial pemphigoid, including bullous pemphigoid antigen 1 and 2 (BPAG1 and BPAG2), laminin 5, laminin 6, type VII collagen, b4 integrin subunit, and antigens with unknown identities (a 45-kd protein, uncein, a 168-kd epithelial protein, and a 120-kd epithelial protein). While circulating autoantibodies in a given patient tend to target a single antigen, sera of patients with same clinical features may target different autoantigens.

Frequency

United States

Precise data on the incidence of cicatricial pemphigoid are not known; however, cicatricial pemphigoid is uncommon. Among white patients in the United States, cicatricial pemphigoid is associated with human leukocyte antigen DQB1*0301 (HLA-DQB1*0301).

International

Studies estimated an incidence of 1.16 cases per million population per year in France and an incidence of 0.87 cases per million population per year in Germany.

Mortality/Morbidity

Cicatricial pemphigoid is a chronic blistering disease that frequently heals with scarring. Individual blisters may itch, and subsequent erosions are often painful. Depending on the sites affected, sequelae include decreased vision or blindness, hoarseness, esophageal stenosis, or upper airway compromise. This disease is often recalcitrant to therapy.

Race

No racial predilection is known.

Sex

Most studies have demonstrated a female-to-male ratio of approximately 2:1

Age

Most patients with cicatricial pemphigoid are elderly, with a mean age of 62-66 years.

Clinical

History

• Patients with cicatricial pemphigoid typically present with persistent, painful erosions on the mucous membranes. The clinical manifestations are dependent on the sites involved.
• Patients with ocular involvement may present with pain or the sensation of grittiness in the eye and conjunctivitis. Erosions may be seen on the conjunctival surface. Early changes include keratinization of the conjunctiva and shortening of the fornices. Later, patients develop entropion with subsequent trichiasis.
  • Patients often present after ocular surgery, especially for cataracts, with severe inflammation of the eye or eyes and scar formation. With progressive scarring, patients develop symblepharon (fibrous tracts that tether bulbar and conjunctival epithelium), synechiae (adhesion of the iris to the cornea or the lens), and ankyloblepharon (a fixed globe).
  • Lacrimal gland and duct involvement leads to decreased tear and mucous production. Diminished tear formation leads to ocular dryness and further trauma.
  • The end result of ocular involvement is opacification and blindness. Some patients with ocular disease may represent a subset of patients with cicatricial pemphigoid who do not develop oropharyngeal, other mucous membrane, or cutaneous disease.
• Mouth involvement presents as recurrent, painful erosions. The gingivae are most commonly involved, followed by the palate and the buccal mucosa; however, any mucosal site in the mouth may blister. Involvement of the oropharynx may present with hoarseness or dysphagia. Progressive scarring disease may lead to esophageal stenosis requiring dilatation procedures. Supraglottic involvement may lead to airway compromise requiring tracheostomy.
• Nasal involvement may manifest as epistaxis, bleeding after blowing the nose, nasal crusting, and discomfort. Other mucosal sites, such as the perianal area or the genitalia, may be involved.
• Skin lesions develop in approximately one third of patients with cicatricial pemphigoid, manifesting as tense vesicles or bullae that may be hemorrhagic. Blisters may heal with scarring or milia. Scalp involvement may lead to alopecia. Pruritus at the sites of blisters or generalized pruritus may be present.
• Cutaneous cicatricial pemphigoid involving the head and the neck without mucosal involvement is known as the Brunsting-Perry variant of localized BP. Patients are predominately elderly and male. Patients present with a chronic, recurrent vesiculobullous eruption on the head and the neck that heals with atrophic scarring. Patients with this disorder have histologic immunofluorescent and immunoelectron microscopic features similar to other patients with cicatricial pemphigoid.

Physical

• Early ocular lesions may manifest as conjunctivitis, progressing to keratinization of the corneal epithelium and shortening of the corneal sulcus. Progressive ocular disease leads to entropion and progressive corneal injury secondary to trichiasis. With persistent disease activity, synchesis and symblepharon occur. Long term, ankyloblepharon (a fixed globe) may occur. Patients with pure ocular involvement may constitute a distinct subset of patients with cicatricial pemphigoid. These patients are distinct from patients with classic BP because they have a lower frequency of immunoglobulin G (IgG) and C3 as depicted by DIF, and they are usually negative for circulating autoantibodies as depicted by indirect immunofluorescence (IDIF). These patients do not have detectable reactivity to BP antigens.
• Nasal involvement can be detected as erosions and crusting in the nasal vestibule, best seen by nasal speculum examination.
• Oral erosions often begin on the gingiva, particularly near the teeth. Erosions can also be seen on the palate, the buccal mucosa, the lips, the posterior part of the pharynx, the tongue, and the floor of the mouth. Intact blisters are rarely seen, but they may appear flaccid or tense.
• On the genitalia, painful erosions involving the clitoris, the labia, the glans, or the shaft of the penis may be seen. Perianal involvement manifests as perianal blisters and erosions.
• On the skin, tense blisters or erosions may be seen on either normal-appearing skin or erythematous plaques. Common sites include the scalp, the head, the neck, the distal extremities, or the trunk. In patients with active disease, erosions may be persistent and difficult to heal. Scarring and milia frequently develop in this condition and are helpful in clinically differentiating cicatricial pemphigoid from BP and linear immunoglobulin A (IgA) bullous dermatosis, both of which do not tend to scar.
• Localized cicatricial pemphigoid on the head and the neck is known as Brunsting-Perry cicatricial pemphigoid. This disease heals with scarring and milia.

Causes

• Cicatricial pemphigoid is an autoimmune blistering disease associated with autoantibodies directed against basement membrane zone target antigens. Autoantibodies of the IgG subclass, particularly IgG4, are associated with cicatricial pemphigoid; however, IgA antibodies have also been detected. The 2 major antigens associated with cicatricial pemphigoid are BPAG2 and epiligrin (laminin-5). Patients with clinical features of cicatricial pemphigoid may have antibodies directed against BPAG1 or the EBA antigen (type VII collagen). No clinical difference between patients with anti-BPAG2 and antiepiligrin reactivity is present.
• BPAG2 is also known as collagen XVII. It is a 180-kd hemidesmosomal protein with multiple extracellular collagenous domains.² BPAG2 is also a major target antigen for patients with BP and linear IgA bullous dermatosis. Patients with cicatricial pemphigoid react with epitopes on BPAG2 distinct from those associated with BP and linear IgA bullous dermatosis. Recent studies suggest that BPAG2 is cleaved to form a 120-kd fragment that contains the cicatricial pemphigoid epitope. Circulating autoantibodies in patients with autoantibodies specific for BPAG2 bind to the epidermal side of salt-split skin as depicted by IDIF study.
• A subset of patients with cicatricial pemphigoid reacts with laminin-5. These patients have circulating autoantibodies that bind to the dermal side of salt-split skin as depicted by IDIF study. By immunoelectron microscopy, these autoantibodies deposit at the lower lamina lucida, extending to the lamina densa. Laminin-5 contains disulfide-linked alpha, beta, and gamma chains, of which the alpha subunit is the major site of cicatricial pemphigoid reactivity. Laminin-5 plays a major role in the adhesion of human keratinocytes to the dermis by binding alpha-6-beta-4 integrin. Because defects in laminin-5 are associated with junctional epidermolysis bullous, one group has suggested calling cicatricial pemphigoid associated with antiepiligrin autoantibodies acquired junctional EB; however, most clinicians refer to this disease as antiepiligrin cicatricial pemphigoid.
• Autoantibodies specific for epiligrin and BPAG2 are believed to be important in blister formation. Lazarova et al³ have developed an animal model of antilaminin-5 cicatricial pemphigoid in which passive transfer of rabbit antilaminin-5 into neonatal mice leads to a subepidermal blistering disease with features consistent with cicatricial pemphigoid. Passive transfer of antilaminin-5 antibodies to mast cell and complement deficient neonatal mice can also induce blistering, suggesting a direct effect of the circulating autoantibodies in inducing dermal-epidermal cleavage.
• The incidence of the HLA haplotype HLA-DQB1*0301 is increased in patients with ocular cicatricial pemphigoid. This HLA haplotype may be important in the presentation of specific epitopes on target antigens in the generation of an autoimmune response; however, the precise events relevant in the initiation of autoantibody production in patients with this disease are unknown.

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