The term Mapighian layer (stratum malpighi) is usually defined as both the basal and spinosum layers as a unit. The stratified squamous epithelium is maintained by cell division within the basal layer. In MMP antibodies react against antigen, binds basal cell layer of epithelium to to basement membrane resulting in separation of epithelium from underlying stroma at level of lamina Lucinda, the area betweel basal cell membrane and lamina densa.

In the stratum corneum the cells lose their nucleus and fuse to squamous sheets, which are eventually shed from the surface (desquamation). In normal skin, the rate of production equals the rate of loss, taking about two weeks for a cell to journey from the basal cell layer to the top of the granular cell layer, and an additional four weeks to cross the stratum corneum. The entire epidermis is replaced by new cell growth over a period of about 48 days.

As in other autoimmune diseases, environmental factors combined with genetic predisposition 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, as depicted in the image on the left. 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.

By direct immunofluorescence, a linear band of immunoreactants at the epidermal-dermal junction is demonstrated by using a fluorescein-tagged antibody specific for human immunoglobulin G. (IgG) 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.

Ocular manifestations of cicatricial pemphigoid include symblepharon, demonstrated in this photograph by the tethering of the lower lid to the cornea. 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.

Etiology:
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 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 al[3] 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.

History:
Patients with cicatricial pemphigoid typically present with persistent, painful erosions on the mucous membranes. The clinical manifestations are dependent on the sites involved. Although the mouth and eyes are usually the first and most common locations for pemphigoid to occur it can alsi affect the larynx, pharynx, anal and vaginal mucosa.

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. This eventually leads to a progressive subepithelial fibrosis. Early changes include keratinization of the conjunctiva and shortening of the fornices. Later, patients develop entropion with subsequent trichiasis (Condition where lashes turn inward, scratching the cornea).

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). 

With advanced disease, ankyloblepharon (a fixed globe) develops.

In a patient with more advanced ocular scarring, the eyelashes should be epilated after entropion develops to prevent scratching and scarring of the sclera.

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.

Histopathologically, blisters or bullae in subepithelial layers characterize MMP. Immunologically, perilesonal mucosa reveals one or a combination of IgG, IgM, IgA or C3 to the epithelial basement membrane. A biopsy specimen should include tissue adjacent to the blister because tissue-fixed immunoglogulins within the blister may have been destroyed by inflammatory infiltrate. When the patient has multi-membrane involvement, the biopsy specimen should be obtained from nonocular tissue adjacent to the blister. The biopsy specimen should be placed in Michel’s fixative for later processing if necessary; results for direct immunoflourescence are reliable for up to 6 months and for electron microscopy for up to 28 days. Sensivitity of detection is increased using immunos]peroxidase technique when immunoflourescence had yielded a negative result. A negative biopsy does not necessarily exclude the diagnosis, but alternative causes for progressive cicatricialization should be considered.

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 and strictures 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 Manifestations:
Early ocular lesions may manifest as conjunctivitis, progressing to keratinization of the corneal epithelium and shortening of the corneal sulcus (see first image). Progressive ocular disease leads to entropion (see first image) and progressive corneal injury secondary to trichiasis. With persistent disease activity, synchesis and symblepharon occur (see second image). Long term, ankyloblepharon (a fixed globe) may occur (see third image). 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.

Treatment:
Medical treatment of MMP involving the ocular survace should be very aggressive to prevent severe keratoconjunctival sicca and advanced cicatricializing disease leading to ankyloblepharon Because MMP is a systemic disease, topical therapy alone is insufficient. Evaluation of the clinical picture, combined with the severity of inflammation, location and rapidity of progression, should direct selection of anti-inflammatory medical treatment. Because ocular conjunctival disease is blinding, ocular disease is always considered high risk.

For patients with severe, rapidly progressive disease, the treatment should consist of prednisone (1 mg to 1.5 mg per kg body weight per day) and cyclophosphamide or azathioprine. Other promising treatments include mycophenolate combined with dapsone and steroid, intravenous immunoglobulin, and biologics such as rituximad and daclizumab. Patients usually show decreased conjunctival hyperemia within weeks of beginning therapy. Treatment is usually continued 2 to 3 years into remission.

Differential Diagnosis:

• Bullous Disease of Dialysis
• Bullous Pemphigoid
• Drug-Induced Bullous Disorders
• Epidermolysis Bullosa
• Epidermolysis Bullosa Acquisita
• Erythema Multiforme
• Linear IgA Dermatosis
• Pemphigus Vulgaris
• Pemphigus, Paraneoplastic

Lab Studies:
The histologic findings, DIF results, and IDIF results of cicatricial pemphigoid, BP, and EBA are similar; differentiation between these 3 entities depends on the clinical presentation.

Criteria for the diagnosis of cicatricial pemphigoid include an appropriate clinical presentation, histology demonstrating a subepidermal blistering process (as described below), and DIF results showing continuous deposits of any one or the combination of the following along the epithelial basement membrane zone: IgG, IgA, and/or C3. DIF study can be used to categorize the process as an autoimmune blistering disease, but it cannot be used to discriminate between cicatricial pemphigoid, BP, or EBA.

IDIF study of patients' sera depicts circulating antibasement membrane zone specific for IgG in 20% of patients, and, when present, it usually has a low titer (1:10-1:20).

Imaging Studies:
For evaluation of the upper airway or the esophagus, CT scans, barium swallows, or other imaging studies may be helpful. In patients with antiepiligrin cicatricial pemphigoid, imaging may be required as part of malignancy search.

Other Tests: 
DIF study should be performed on noninvolved perilesional skin or mucous membrane. Patients with cicatricial pemphigoid typically demonstrate linear deposits of complement and IgG at the dermal-epidermal junction. The most commonly assayed complement component is C3; however, C4, properdin, and other complement components have been described. Linear deposits of IgG are detectable in 25% of patients. Linear deposits of IgA, in addition to IgG, have been reported in 20% of patients in one series. This pattern of DIF is also seen in patients with BP and EBA, and DIF assay cannot be used to differentiate among these disorders. Conjunctival specimens have been reported to be less sensitive than biopsy specimens of oral mucosa on DIF results.

IDIF assay detects the presence of circulating antibodies directed against normal epithelial basement membrane in the sera of patients who are affected. In patients with cicatricial pemphigoid, IDIF assay reveals circulating IgG in 20% of patients, typically a low titer. When healthy human skin preincubated in 1 mol/L sodium chloride (salt-split skin) is used as a substrate, autoantibodies in patients with cicatricial pemphigoid associated with reactivity to BPAG2 bind to the epidermal roof. IDIF results demonstrate a similar localization in patients with BP. Patients with autoantibodies associated with epiligrin have circulating autoantibodies that bind to the blister floor, similar to that in patients with EBA. One laboratory has reported an increased sensitivity by IDIF study by concentrating serum samples prior to assay.

Immunoblot (Western blot), immunoprecipitation, and immunoelectron microscopy are investigational tools used to better define target antigens. By immunoblot (Western blot) and immunoprecipitation, patients with cicatricial pemphigoid can have autoantibodies directed against BPAG2 (180 kd), BPAG1 (230 kd), and epiligrin (a chain of laminin-5). Enzyme-linked immunoassays using recombinant target antigens may ultimately be available to characterize autoantibody reactivity.

Routine laboratory studies are not helpful in establishing the diagnosis of cicatricial pemphigoid. Most hematologic studies are within the reference range. Laboratory values that may be elevated include immunoglobulins, erythrocyte sedimentation rate, and acute phase reactants.

Histologic Findings:
Biopsy of the edge of an early blister typically reveals a noninflammatory, subepidermal blister. When present, the inflammatory infiltrate localizes to the dermal-epidermal junction and the perivascular areas. This histologic feature can also be seen in other autoimmune subepidermal blistering diseases, including cell-poor BP, EBA, and linear IgA bullous dermatosis. The histologic features of porphyria cutanea tarda and variegate porphyria may also resemble cicatricial pemphigoid.

Medical Care:
The goal of treatment is to suppress extensive blister formation, to promote healing, and to prevent scarring. The lowest dose of medication to suppress disease activity and to minimize the risk for the patient should be used. This disorder is extremely difficult to treat. Even with optimum control, blisters may continue to develop in some patients. The risks and the benefits of therapy must always be evaluated for each patient.

Wound care of erosions includes daily gentle cleaning or compresses, topical agents to promote wound healing, and biologic dressings. The goals of wound care are to minimize trauma to the surrounding skin, to promote healing, and to diminish scarring.

Increased risk of malignancies has been documented in patients with antiepiligrin cicatricial pemphigoid, especially in the first year of disease; hence, appropriate screening is warranted.

Surgical Care:
Surgical intervention may be required to improve functioning or to prevent further morbidity. Such intervention is directed at the sequelae of chronic blistering.

Patients with cicatricial pemphigoid and ocular involvement require ongoing ophthalmologic care. Surgical intervention to ablate ingrown eyelashes prevents further ocular damage. Procedures to release entropion have been successful. Tsubota et al[4] recently reported the long-term outcome in patients with cicatricial ocular disorders treated with limbal allografts. The transfer of epithelial stem cells restored useful vision in these patients, including several patients with ocular cicatricial pemphigoid. Care should be taken to control the inflammatory component of the disease before and immediately after surgery because patients with cicatricial pemphigoid frequently experience flare-ups after surgery.

Patients with upper airway disease may develop respiratory compromise requiring tracheostomy. Patients with esophageal obstruction may require dilatation procedures.

Consultations:
The management of cicatricial pemphigoid requires a coordinated team approach. Specific consultations are dictated by the phenotype of the disease and the target organ or organs that are involved.

The patient management team typically includes a dermatologist with expertise in this area; an internist to assist with monitoring therapy, adverse effects of medications, and the patient's overall health; an ophthalmologist for ocular disease; an otolaryngologist for upper airway evaluation and management; and a dentist for oral disease.

Additional specialists, such as a gynecologist (vulvar disease), a gastroenterologist (esophageal involvement), and an endocrinologist (prophylaxis of osteoporosis in patients receiving chronic systemic corticosteroids), may be indicated.

Medication Summary:
Patients with mild localized disease may benefit from topical steroids (eg, triamcinolone [Kenalog in Orabase]) in gel-based topical agents for oral disease or in ointment-based topical steroids for cutaneous disease. Intralesional steroids can be administered as triamcinolone acetonide (Kenalog susp) 10 mg/mL injected weekly or biweekly for oral and cutaneous lesions. Patients with more extensive disease and progressive scarring require systemic therapy with prednisone and/or steroid-sparing agents, such as cyclophosphamide, azathioprine, cyclosporin, mycophenolate mofetil. Evidence from 2 small randomized controlled trials indicates that ocular cicatricial pemphigoid responds best to cyclophosphamide, while mild-to-moderate disease seems effectively suppressed by treatment with dapsone.

High-dose intravenous immune globulin has been used successfully in the treatment of cicatricial pemphigoid in patients who were refractory to other therapies. Immunosuppressive agents should be prescribed and monitored by physicians familiar with these medications. The 2002 consensus statement on cicatricial pemphigoid[1] reports expert panel opinion on the management of the disease.

Complications:
Complications of cicatricial(scarring)pemphigoid include:

• visual loss or blindness
• airway stenosis (constriction or narrowing of an opening or passage way)
• esophageal stricture, or cutaneous blistering with scarring and milia (keratin-filled cyst) formation. Keritan is a fibrous protein which provide structural strength to hair, nails, and skin when used by the body appropriately
• Keratinization of the cornea
• foreshortening of the fornices (loose folds of the eye)
• trichiasis (inversion of the eyelashes so they rub against the cornea, causing a continual irritation)
• synechia (adhesion [sticking] of the iris to the cornea)
• symblepharon (adhesion between the conjunctivae of the lid and the eyeball, which constricts free movement of the eye)
• ankyloblepharon (adhesion of the edges of the upper eyelid to the lower one)
• diminished tear formation, and
• blindness are consequences of cicatricial pemphigoid.

Severe keratoconjunctivitis sicca and advanced ocular cicatricial desease and especially active inflammation have a poor prognosis.

Diet:
Although no dietary restrictions are necessary, patients with oral disease may benefit from avoiding foods high in acid, such as tomatoes and orange juice, and foods with hard surfaces that may mechanically traumatize the oral epithelium, such as chips, nuts, raw vegetables, and uncut fruit.

Patients on oral prednisone should maintain adequate calcium and vitamin D intake through diet and supplements. The daily calcium requirement in patients with no history of kidney stones is 1.5 g/d, and the daily minimum dose of vitamin D is 800 IU/d.

Prognosis:
Early diagnosis and aggressive local and systemic therapy are critical to long-term visual outcome in cases with ocular involvement. Extensive studies on the long-term outcome of patients with cicatricial pemphigoid have not been performed. In general, cicatricial pemphigoid is a chronic, progressive disorder that responds poorly to therapy. Some patients may experience long-term remissions. The disease is characterized by intermittent exacerbations and waning of disease activity.

A recent cohort study of 35 patients with antiepiligrin cicatricial pemphigoid indicated an increased risk of malignancy that approximates that for adults with dermatomyositis. The risk is particularly high in the first year of disease.

References:

1. Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. Mar 2002;138(3):370-9. [Medline].
2. Bernard P, Prost C, Durepaire N, Basset-Seguin N, Didierjean L, Saurat JH. The major cicatricial pemphigoid antigen is a 180-kD protein that shows immunologic cross-reactivities with the bullous pemphigoid antigen. J Invest Dermatol. Aug 1992;99(2):174-9. [Medline].
3. Lazarova Z, Yancey K. Cicatricial pemphigoid: immunopathogenesis and treatment. Derm Ther. 2002;15:382-88.
4. Tsubota K, Satake Y, Kaido M, Shinozaki N, Shimmura S, Bissen-Miyajima H, et al. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med. Jun 3 1999;340(22):1697-703. [Medline].
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7. Egan CA, Lazarova Z, Darling TN, Yee C, Yancey KB. Anti-epiligrin cicatricial pemphigoid: clinical findings, immunopathogenesis, and significant associations. Medicine (Baltimore). May 2003;82(3):177-86. [Medline].
8. Fleming TE, Korman NJ. Cicatricial pemphigoid. J Am Acad Dermatol. Oct 2000;43(4):571-91; quiz 591-4. [Medline].
9. Foster CS, Sainz De La Maza M. Ocular cicatricial pemphigoid review. Curr Opin Allergy Clin Immunol. Oct 2004;4(5):435-9. [Medline].
10. Kirtschig G, Murrell D, Wojnarowska F, Khumalo N. Interventions for mucous membrane pemphigoid/cicatricial pemphigoid and epidermolysis bullosa acquisita: a systematic literature review. Arch Dermatol. Mar 2002;138(3):380-4. [Medline].
11. Freiman, Anatoli, MD, FRCPC, DABD; Cicatricial Pemphigoid Workup, Editor: Dirk M Elston, MD; Website: http://emedicine.medscape.com/article/1062534-workup
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