Cicatricial Pemphigoid

Etiology

Autoantibodies targeted to components of the basement membrane zone have been identified as pathogenic in cicatricial pemphigoid. Patients with cicatricial pemphigoid may have antibodies detected to 180-kD bullous pemphigoid antigen (BP180), laminin 332 (previously known as epiligrin or laminin-5), beta-4-integrin, and other antigens that have not been fully described.[3][4][5]

Epidemiology

Cicatricial pemphigoid remains a rare autoimmune disorder, with precise prevalence and incidence rates yet to be fully established. Estimates from epidemiological studies vary by region. A study conducted in France reported an incidence of 1.16 cases per million individuals annually, while data from Germany indicated a slightly lower incidence of 0.87 cases per million per year.[6][7] Demographic patterns suggest a tendency toward later onset and female predominance. In a Greek study, the mean age of onset was 66 years, with a female-to-male ratio of 1.5:1.[8] A German population study reported a more pronounced gender disparity, with a female-to-male ratio reaching 7:1.[7] 

Ocular involvement appears commonly among patients with mucous membrane pemphigoid. In a retrospective review of 162 patients, 67% presented with ocular disease. Among those without ocular involvement at baseline, the risk of developing ocular mucous membrane pemphigoid was estimated at 0.014 per person-year.[9] 

Genetic predisposition may contribute to disease susceptibility. The HLA-DQB1*0301 allele has been identified as a genetic marker associated with increased risk for developing cicatricial pemphigoid.[10]

Pathophysiology

Cicatricial pemphigoid is an antibody-mediated blistering disorder. The antibodies target molecules responsible for adhesion within the basement membrane zone of the mucosa and skin. This disrupts the normal structure and function of the basement membrane, allowing the epidermis to separate from the dermis. Clinically, this manifests as blisters and erosions. Several target molecules are associated with the pathogenesis of cicatricial pemphigoid. 

Laminin 332 is a transmembrane protein that connects the alpha-6-beta-4 integrin of the hemidesmosome of the keratinocyte to the noncollagenous 1 (NC1) domain of collagen VII. Collagen VII is the attachment for the anchoring fibrils that secure the basement membrane to the dermis. Laminin 332 assists in strengthening the attachment of the epidermis to the dermis against shearing forces.

BP180, also known as collagen XVII, functions as a transmembrane collagen and serves as a structural component of the hemidesmosome in epithelial cells. Within the hemidesmosome, the dense plaque binds keratin 5 and keratin 14 inside the keratinocyte, anchoring the cytoskeleton to the basement membrane. BP180 spans the lamina lucida, with its noncollagenous N-terminal domain positioned near the cellular membrane and its collagenous C-terminal domain extending through the lamina lucida into the lamina densa.

Autoantibodies in bullous pemphigoid predominantly target the N-terminal region of BP180, whereas autoantibodies in cicatricial pemphigoid primarily target the C-terminal region. This difference in antigenic specificity likely contributes to the distinct clinical manifestations observed in each disease. In bullous pemphigoid, targeting the N-terminus results in a more superficial blistering process that rarely leads to scarring.[11][12] In contrast, the deeper disruption caused by targeting the C-terminus in cicatricial pemphigoid often results in more severe tissue damage and scarring. These pathophysiological distinctions underscore the importance of antibody profiling in differentiating between these autoimmune blistering disorders.[13]

Alpha-6-beta-4 integrin forms a critical component of the hemidesmosome, where it binds transmembrane laminin 332, which in turn anchors to collagen VII. This integrin plays a central role in maintaining epithelial adhesion and structural integrity. Research has shown that sera and IgG fractions from patients with cicatricial pemphigoid frequently target the intracellular domain of alpha-6-beta-4 integrin, suggesting a potential pathogenic role for this autoantigen in disease development.[14][15][14]

Additional evidence supports the involvement of beta-4 integrin in mucous membrane pemphigoid. A recent study revealed that sera from patients with ocular mucous membrane pemphigoid demonstrated reactivity to the beta-4 integrin subunit.[14][15] These findings underscore the significance of integrin-targeting autoantibodies in the pathogenesis of cicatricial pemphigoid, particularly in ocular variants, and may help explain the tissue-specific manifestations observed in affected individuals.

Histopathology

The histopathologic appearance of cicatricial pemphigoid is characterized by a subepidermal blister with a dermal lymphohistiocytic infiltrate, accompanied by variable numbers of neutrophils and eosinophils. However, this finding is nonspecific and can also be seen in other immunobullous disorders, including bullous pemphigoid, linear IgA bullous dermatosis, and epidermolysis bullosa acquisita.[13] Plasma cell infiltrate is more common in mucosal biopsies.[16] Fibrosis may be present in older lesions.[13]

History and Physical

The mouth represents the most frequently affected site in cicatricial pemphigoid and, in some cases, remains the only site involved. Any area within the oral cavity may become affected, including the buccal mucosa, gingiva, tongue, vermillion lips, and palate.[8] In some patients, the disease extends into the posterior pharynx. Clinically, oral involvement may manifest as desquamative gingivitis, blisters, erosions, or ulcers. Individuals with desquamative gingivitis often report pain or bleeding while brushing their teeth. Persistent inflammation and difficulty maintaining proper oral hygiene contribute to the development of dental caries, tooth loss, and resorption of alveolar bone.[17] Although scarring within the oral cavity occurs infrequently, some patients may develop white reticulated patches or mucosal adhesions.[17]

Ocular involvement in cicatricial pemphigoid typically follows a progressive course, with scar formation capable of leading to blindness.[18] The inflammation typically advances slowly, and patients may initially present with nonspecific symptoms, eg, ocular burning, irritation, or excessive tearing.[19][16] The disease often begins unilaterally but usually involves both eyes over time.[20] Frank blisters rarely appear in the ocular region. Early signs of scarring are commonly observed in the inferior fornices. Symblepharon, or fibrous adhesions between the lid and globe conjunctiva, may be identified by pulling down the lower eyelid and directing the patient to look upward.[20] As the disease progresses, total scarring of the conjunctival sac may occur, resulting in ankyloblepharon and an inability to close the eyelids completely.[20] Chronic conjunctival inflammation also damages the lacrimal glands and goblet cells, leading to reduced tear and mucin production.[20] Scarring of the eyelids causes entropion and trichiasis, which exacerbate corneal trauma and contribute to corneal epithelial keratinization, ultimately resulting in diminished visual acuity.[20][21]

Nasopharyngeal involvement, while less common, can present with crusted nasal lesions, epistaxis, or chronic sinusitis.[22] In some cases, mucosal adhesions form between internal structures, creating partial airway obstruction and, in rare instances, contributing to sleep apnea. Laryngeal involvement may manifest as hoarseness or a persistent sore throat.[22] When fibrosis affects the vocal cords, permanent loss of phonation can occur. In patients with advanced disease and significant airway compromise, tracheostomy has been required as a life-saving measure.[22]

Esophageal disease may lead to symptoms such as odynophagia, dysphagia, chest pain, and, in some cases, esophageal stenosis.[22] Genital and perianal involvement remains rare but can be particularly distressing. Erosions and ulcerations in the genital area produce significant discomfort, and mucosal scarring may narrow the urethra or vaginal opening, sometimes necessitating surgical correction to restore function.[23] Anal involvement most often presents with pain and muscular spasm.[23]

Cutaneous manifestations of cicatricial pemphigoid occur in 2 distinct patterns. One subtype presents as widespread, tense bullae that heal without scarring. The other form involves blisters on an erythematous base that tend to localize and result in atrophic scars, most often on the head and neck. Lesions on the scalp frequently lead to alopecia.[24] Brunsting-Perry pemphigoid, once classified as a subset of cicatricial pemphigoid, produces scarring bullous eruptions on the head and neck skin without mucosal involvement. This presentation is now recognized as a clinical phenotype of epidermolysis bullosa acquisita.

Evaluation

A biopsy of lesional skin remains essential for histopathological evaluation, offering critical insight into the diagnosis and helping to distinguish cicatricial pemphigoid from other blistering disorders. (Please refer to the Histopathology section for more information on findings.)

In addition to the lesional biopsy, sampling of perilesional skin for direct immunofluorescence (DIF) is recommended. DIF typically reveals a linear band of IgG and C3 at the basement membrane zone, which serves as a hallmark of the disease.[25] Occasionally, linear deposition of IgA may also appear along the basement membrane zone.[26] To enhance diagnostic sensitivity, multiple and repeated biopsies from different perilesional sites may be warranted.[27]

Although indirect immunofluorescence (IIF) is also recommended, positive results occur in only a small subset of patients, with antibody titers generally remaining low.[25] IIF performed on salt-split skin may reveal either an epidermal or dermal staining pattern, reflecting the targeted antigen. Detection of circulating IgG or IgA autoantibodies through IIF can assist in diagnosis, particularly when a concentrated assay is employed alongside the salt-split technique.[13] This approach improves diagnostic utility by allowing simultaneous evaluation for both IgG and IgA reactivity.

Enzyme-linked immunosorbent assay (ELISA) testing may further aid in diagnosis, particularly when used to identify autoantibodies directed against the C-terminal domain of BP180 or laminin 332. Although highly informative, these ELISA tests may not be accessible in all clinical laboratories due to resource limitations or availability constraints.[28][29]

Treatment / Management

Topical Therapies

For the mild disease of the oral mucosa and skin, topical therapies can be effective. Moderate to high-potency topical steroids, in gel or ointment form, can be used initially 2 to 3 times daily. The frequency of topical steroid application can be gradually tapered based on the patient's response. To improve the effectiveness of topical therapies, blotting the area with a disposable tissue to remove moisture before applying the medication may be helpful. Patients may apply the medication with a finger or a cotton swab and gently rub it into the affected areas for 30 seconds. Patients should be advised to abstain from eating or drinking for 30 minutes after application to increase absorption.[30] 

Customized prosthetic devices, eg, dental trays, can occlude the topical steroid over the affected sites in the mouth.[31] Calcineurin inhibitors (eg, tacrolimus) have also been reported as a topical therapeutic option.[32] If topical therapies are not effective for mild to moderate disease, dapsone may be an effective alternative.[33] Typical dose ranges from 50 to 200 mg daily. Systemic corticosteroids can be used in addition to the dapsone.(B3)

Complications of long-term use of topical steroids are uncommon. A cutaneous application may lead to hypopigmentation and atrophy. Although these adverse effects are not commonly seen in the mucous membranes, the risk for oral candidiasis and herpes simplex reactivation is a concern.[30] In addition to topical therapies, the importance of oral care should be emphasized as a critical part in the treatment of mucous membrane pemphigoid. This consists of brushing teeth with a soft-bristle toothbrush twice daily, flossing daily, and visiting the dentist every 3 to 6 months.[30] 

Systemic Therapies

If topical therapies are not effective for mild to moderate disease, dapsone may be an effective alternative.[33] Typical dose ranges from 50 to 200 mg daily. Systemic corticosteroids can be used in addition to the dapsone. For mild to moderate ocular involvement, systemic corticosteroids (prednisone 1 to 2 mg/kg/day) alone or in combination with dapsone can be considered. Proper ocular care is important. Since dry eyes are common with ocular pemphigoid, frequent use of lubricants is recommended in the form of artificial tear drops or petrolatum-based ointments. Cleansing away excess exudates from the eyes helps to prevent secondary bacterial infections.[30](B3)

Immunosuppressive Therapy

For severe or rapidly progressive disease involving the ocular, nasopharyngeal, or anogenital mucosa, a combination of systemic corticosteroids (prednisone 1 to 2 mg/kg/day) plus an additional immunosuppressive agent has been recommended. Immunosuppressive agents that have shown efficacy include azathioprine 1 to 2 mg/kg/day, mycophenolate mofetil 2 to 2.5 g/day, or cyclophosphamide 1 to 2 mg/kg/day.[30][34][35][36][37] (B2)

The goal of adjuvant immunosuppressive therapy is to allow the taper of prednisone over 6 to 12 months. Intravenous immunoglobulin has been successfully used to treat cicatricial pemphigoid.[38][39] Tumor necrosis factor-alpha inhibitors have been used in the treatment of cicatricial pemphigoid.[40][41] Rituximab has been used alone or as adjuvant therapy for the treatment of mucous membrane pemphigoid.[42][43] (B2)

Differential Diagnosis

Cicatricial pemphigoid has clinical features that closely resemble and must subsequently be differentiated from the following dermatoses:

• Bullous pemphigoid: Bullous pemphigoid is a common autoimmune subepidermal blistering disorder. The age of onset is typically between 65 and 75 years. This typically affects the skin and presents as tense bullae on a normal or urticarial background. This is less commonly affected by the oral mucosa. Lesions do not cause scarring.[13] The disease is typically steroid-responsive.

• Epidermolysis bullosa acquisita (EBA): This condition represents a rare autoimmune subepidermal blistering disorder. The most common clinical manifestation involves the formation of noninflammatory, tense bullae, typically appearing on extensor surfaces following friction or trauma. Frequently affected areas include the hands, elbows, knees, and buttocks. These blisters often heal with residual scarring and the formation of milia. Oral involvement may also occur in affected individuals.[13] EBA can present in association with underlying systemic diseases, suggesting an immune-mediated pathogenesis linked to broader autoimmune dysregulation. Management of EBA remains particularly challenging, as the condition tends to be recalcitrant to standard therapies.[44]

• Linear IgA bullous dermatosis: This is a rare subepidermal bullous dermatosis. Its clinical presentation varies and can mimic bullous pemphigoid, dermatitis herpetiformis, and cicatricial pemphigoid. Linear IgA bullous dermatosis may have oral and, less likely, ocular involvement.[45][46]

• Bullous systemic lupus erythematosus: Bullous systemic lupus erythematosus is an autoimmune subepidermal blistering disorder that develops in patients with systemic lupus. The eruption consists of erythematous macules, plaques, and bullae that typically occur in sun-exposed areas and do not usually result in scarring. Oral lesions can occur.

• Paraneoplastic pemphigus: This condition is a rare autoimmune disease associated with malignancy, most commonly non-Hodgkin lymphoma and chronic lymphocytic leukemia. This condition is characterized by painful and erosive stomatitis, as well as polymorphous cutaneous lesions that may resemble those of bullous pemphigoid, lichen planus, or erythema multiforme. Indirect immunofluorescence on rodent bladder can detect serum autoantibodies directed against plakin proteins. This is rapidly progressive and often results in death.[13]

• Pseudo-ocular cicatricial pemphigoid: This condition closely mimics the clinical presentation of true cicatricial pemphigoid but arises from a distinct etiology and is a complication associated with the prolonged use of medicated eye drops, which are commonly prescribed for the management of glaucoma. Unlike cicatricial pemphigoid, which typically involves both eyes, pseudo-ocular forms generally affect only 1 eye. Disease progression usually halts once the offending eye drops are discontinued.[47]

Prognosis

Cicatricial pemphigoid represents a chronic and progressive autoimmune disease characterized by scarring of the affected tissues. Long-term follow-up remains essential for monitoring complications related to fibrosis and the potential for relapse. The risk of serious sequelae, including blindness and airway obstruction, underscores the importance of initiating treatment early and with sufficient intensity to control disease activity.

Management often requires an interprofessional approach, involving dermatologists, ophthalmologists, otolaryngologists, dentists, and other specialists to address the multisite involvement and prevent functional impairment. While some individuals respond well to immunosuppressive therapy and achieve durable remission, others experience refractory disease that fails to respond or relapses shortly after initial control. These cases demand close monitoring and tailored therapeutic strategies to optimize outcomes.[13]

Complications

Complications associated with cicatricial pemphigoid vary depending on the mucosal surfaces involved. Oral mucosal involvement often leads to painful scarring lesions and the formation of adhesions, which may restrict oral movement. Gingival disease can lead to dental caries, loss of gingival tissue, destruction of alveolar bone, and ultimately, tooth loss.

Ocular complications may include persistent irritation, reduced tear and mucin production, secondary infections, and the development of symblepharons and ankyloblepharons. These changes can lead to corneal irritation, neovascularization, ulceration, and, in advanced cases, blindness. Nasal involvement frequently causes discharge, epistaxis, crusting, chronic sinusitis, scarring, and impaired nasal airflow. Pharyngeal disease may present with hoarseness, progressive loss of voice, supraglottic stenosis, and potentially life-threatening airway compromise.

Involvement of the esophagus may lead to symptoms, eg, dysphagia, odynophagia, aspiration, and stricture formation. Anogenital complications typically include painful ulcerations and the development of stenoses and strictures, which can significantly affect function and quality of life.