eMedicine Specialties > Dermatology > Bullous Diseases

Cicatricial Pemphigoid

Anatoli Freiman, MD, FRCPC, DABD, Consulting Staff, Division of Dermatology, Women's College Hospital, University of Toronto

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.

Differential Diagnoses

Other Problems to Be Considered

Desquamative gingivitis

Workup

Laboratory 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.

Treatment

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 al⁴ 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.

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.

Activity

Patients are encouraged to lead as normal a life as possible; however, cutaneous and mucosal blisters may be induced by trauma. Contact lenses, dental plates, or bridges may precipitate or exacerbate mucosal disease. Patients may benefit by minimizing activities, such as contact sports, that traumatize the skin and precipitate blistering. Nontraumatic exercises, such as swimming or aquatic exercises, may be beneficial.

Medication

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 pemphigoid¹ reports expert panel opinion on the management of the disease.

Anti-inflammatory agents

These agents decrease the inflammatory response.

Triamcinolone (Kenalog, Kenalog in Orabase)

Agent for mild disease or used as an adjuvant in patients receiving concurrent systemic therapy. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.

Dosing

Adult

Apply topically to gingiva and oral blisters tid

Pediatric

Apply as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; fungal, viral, and bacterial skin infections; not indicated in extensive mucosal involvement

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use in decreased skin circulation; prolonged use, applying over large areas, and using potent steroids and occlusive dressings may result in systemic absorption; systemic absorption may cause Cushing syndrome, reversible HPA-axis suppression, hyperglycemia, and glycosuria

Dapsone (Avlosulfon)

DOC for ocular cicatricial pemphigoid and often beneficial in patients with oral mucosal disease. Bactericidal and bacteriostatic against mycobacteria. Mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.

Dosing

Adult

50 mg PO qd initial; increase to 100 mg/d as tolerated

Pediatric

>1 month: 1 mg/kg/d PO; not to exceed 100 mg

Interactions

May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during second and third months of therapy); probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both drugs; because of increased renal clearance, levels may significantly decrease when administered concurrently with rifampin; concomitant administration of zidovudine may increase risk of hematologic toxicity; amprenavir and saquinavir may inhibit cytochrome P4503A (CYP3A), the hepatic isoenzyme group with major activity related to dapsone metabolism, thereby leading to increased dapsone serum concentrations and potential toxicity

Contraindications

Documented hypersensitivity; known G-6-PD deficiency (assay for G-6-PD activity prior to initiation of therapy)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Associated with a variety of systemic toxicities, including agranulocytosis, anemia, methemoglobinemia, hepatitis, and neuropathy; patients may experience headache and/or GI distress on initiation of therapy; perform weekly blood counts (first mo), then monthly WBC counts (6 mo), then semiannual WBC counts; discontinue if a significant reduction in platelets, leukocytes, or hematopoiesis occurs; caution in methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light; pancreatitis may occur; various forms of renal complications including acute renal failure, acute tubular necrosis, and oliguria have occurred with dapsone use

Prednisone (Deltasone, Orasone, Sterapred)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

20-40 mg/kg/d PO qam or in divided doses initially; if no response, dose is typically increased by 50% q3-5d

Pediatric

1-2 mg/kg PO qd or divided bid/qid; taper over 2 wk as symptoms resolve

Interactions

Coadministration with estrogens may decrease clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; coadministration with ritonavir may significantly increase serum concentrations of prednisone; concomitant therapy with montelukast may result in severe peripheral edema; clarithromycin may increase risk of psychotic symptoms
Postmarketing surveillance reports indicate that risk of tendon rupture may be increased in patients receiving concomitant fluoroquinolones and corticosteroids, especially elderly patients; administration of asparaginase concurrently with or before prednisone therapy may result in increased toxicity

Contraindications

Documented hypersensitivity; viral, fungal, tubercular skin, or connective tissue infections; peptic ulcer disease; hepatic dysfunction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May unmask hypertension or diabetes or exacerbate peptic ulcer disease and tuberculosis; long-term sequelae associated with long-term steroid use include osteoporosis, cataracts, and pituitary-hypothalamic axis suppression; with high doses, patients may develop a steroid psychosis and are at increased risk of infections, particularly when oral steroids are used in conjunction with other immunosuppressants; frequently monitor patient's blood sugar level, blood pressure, and weight; monitor for Cushing syndrome

Immunosuppressants

These agents inhibit immune reactions resulting from diverse stimuli.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Dosing

Adult

1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d
Alternatively, may dose on RBC thiopurine methyltransferase activity level checked prior to initiating treatment

Pediatric

Administer as in adults

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine; coadministration with mycophenolate may increase toxicity; alfalfa, black Cohosh, and echinacea may reduce immunosuppressive drug effectiveness

Contraindications

Documented hypersensitivity; deficiency of thiopurine methyltransferase (can result in severe myelosuppression and leukopenia); history of treatment with alkylating agents

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; hepatotoxicity and pancreatitis reported

Cyclosporine (Sandimmune, Neoral)

Demonstrated to be helpful in a variety of skin disorders. Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight.

Dosing

Adult

3-9 mg/kg/d PO

Pediatric

Administer as in adults

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UV-B radiation in patients with psoriasis because it may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzyme levels and blood pressure; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO; adverse effects include nephrotoxicity, hypertension, hepatotoxicity, gingival enlargement, hyperkalemia, hypomagnesemia, pancreatitis, and paresthesia; factors that may increase risk for neurotoxicity from cyclosporine include hypomagnesemia, hypocholesterolemia, fever, infection, hypertension, intravenous administration, and rapidly increasing cyclosporine blood levels; caution with medications metabolized by cytochrome P450 3A4

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Dosing

Adult

1-5 mg/kg/d IV; alternatively 2.5-3 mg/kg/d PO divided qid

Pediatric

Administer as in adults

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; concurrent use of NSAIDs has resulted in increases in cyclosporine levels, nephrotoxicity, and increased plasma creatinine concentrations
Concomitant use of ACE inhibitors may decrease renal function; coadministration with nevirapine and St. John's wort may reduce immunosuppressive drug effectiveness
Increased risk of infection by live vaccine; coadministration with trastuzumab may increase cardiac toxicity; coadministration with tamoxifen may increase risk of thromboembolism

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; adverse effects include oligospermia or azoospermia, cardiomyopathy, infectious disease, interstitial pneumonia, increase risk of malignancy, possibility of increased toxicity in adrenalectomized patients

Mycophenolate (CellCept)

Inhibits purine synthesis and proliferation of human lymphocytes.

Dosing

Adult

1-1.5 g PO bid

Pediatric

<3 months: Not established
>3 months : 600 mg/m²/dose susp PO bid; not to exceed 2 g/d PO
Alternatively, administer according to BSA
>3 months or 1.25-1.5 m²: 750 mg PO cap bid
>3 months or >1.5 m²: 1000 mg PO cap or tab bid

Interactions

May elevate levels of acyclovir and ganciclovir; antacids and cholestyramine decreases absorption, reducing levels (do not administer together); probenecid may increase levels; salicylates may increase toxicity; concomitant use with azathioprine not recommended; use cautiously in elderly patient and with drugs that affect enterohepatic recirculation; live attenuated vaccines should not be used during treatment and other vaccines may be less effective

Contraindications

Documented hypersensitivity; hypersensitivity to polysorbate 80 (IV formulation)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk for infection; increases toxicity in patients with renal impairment; caution in active peptic ulcer disease; other adverse reactions include diarrhea, vomiting, and leukopenia
Increases risk for infection; increases toxicity in patients with renal impairment; caution in active peptic ulcer disease
Bone marrow suppression may occur, including severe neutropenia; due to increased risk of skin cancer, limit exposure to sunlight and UV light; increased risk for developing lymphomas or other malignancies; concomitant use with azathioprine is not recommended; oral susp contains aspartame so should be used with caution in patients with phenylketonuria; use cautiously in elderly patient and with drugs that affect enterohepatic recirculation; live attenuated vaccines should not be used during treatment and other vaccines may be less effective; avoid in patients with hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase
Avoid in pregnant women unless benefit clearly outweighs risk; negative pregnancy test should be obtained in women of childbearing potential; contraception should be used during treatment and for 6 wk after stopping treatment
Serious adverse effects may include confusion, GI hemorrhage, hypertension, increased frequency of cough, infectious disease, myelosuppression, peripheral edema, sepsis, and tremor

Follow-up

Complications

• Complications of cicatricial pemphigoid include visual loss or blindness, airway stenosis, esophageal stricture, or cutaneous blistering with scarring and milia formation.
• Keratinization of the cornea, foreshortening of the fornices, trichiasis, synechia, symblepharon, ankyloblepharon, diminished tear formation, and blindness are consequences of cicatricial pemphigoid.

Prognosis

• 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.

Patient Education

• Be certain that patients understand the chronic nature of this disorder.
• Help patients in identifying factors that precipitate disease activity, and instruct them to avoid conditions that exacerbate the condition.
• Discuss the medications, including the dose, the adverse effects, and the symptoms of toxicity, with the patient.
• Teach patients appropriate wound care.

Miscellaneous

Medicolegal Pitfalls

• Failure to accurately diagnose the condition before embarking on therapy is a pitfall. Cicatricial pemphigoid shares some common features with other autoimmune blistering diseases making the diagnosis more difficult. Criteria for diagnosis include a compatible clinical picture, a subepidermal blistering disease as demonstrated by the histopathologic findings, and a linear band of immunoglobulin and complement components at the epidermal-dermal junction as demonstrated by DIF study.
• Failure to assess the risks and the benefits of each medication for each patient before a therapeutic regimen is chosen is a pitfall.
• Failure to educate patients on the risks, adverse effects, contraindications, and drug interactions of medications is a pitfall.
• The Medscape Medical Malpractice and Legal Issues Resource Center may be of interest.

Multimedia

Media file 1: Ocular manifestations of cicatricial pemphigoid include symblepharon, demonstrated in this photograph by the tethering of the lower lid to the cornea.

Media file 2: In a patient with more advanced ocular scarring, note the thickening of the lid margins, shortening of the conjunctival sulcus, and scarring. The eyelashes have been epilated after entropion developed.

Media file 3: 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.

Media file 4: With advanced disease, ankyloblepharon (a fixed globe) develops.

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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6. Domloge-Hultsch N, Anhalt GJ, Gammon WR, Lazarova Z, Briggaman R, Welch M, et al. Antiepiligrin cicatricial pemphigoid. A subepithelial bullous disorder. Arch Dermatol. Dec 1994;130(12):1521-9. [Medline].

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. Rashid KA, Gürcan HM, Ahmed AR. Antigen specificity in subsets of mucous membrane pemphigoid. J Invest Dermatol. Dec 2006;126(12):2631-6. [Medline].

12. Sacher C, Hunzelmann N. Cicatricial pemphigoid (mucous membrane pemphigoid): current and emerging therapeutic approaches. Am J Clin Dermatol. 2005;6(2):93-103. [Medline].

13. Saw VP, Dart JK. Ocular mucous membrane pemphigoid: diagnosis and management strategies. Ocul Surf. Jul 2008;6(3):128-42. [Medline].

14. Shimizu H, Masunaga T, Ishiko A, Matsumura K, Hashimoto T, Nishikawa T, et al. Autoantibodies from patients with cicatricial pemphigoid target different sites in epidermal basement membrane. J Invest Dermatol. Mar 1995;104(3):370-3. [Medline].

Keywords

CP, benign mucous membrane pemphigoid, Brunsting-Perry disease, autoimmune blistering disease, bullous pemphigoid, BP, epidermolysis bullosa acquisita, BPAG1, bullous pemphigoid antigen 1, BPAG2, bullous pemphigoid antigen 2, mucous membrane pemphigoid

Contributor Information and Disclosures

Author

Anatoli Freiman, MD, FRCPC, DABD, Consulting Staff, Division of Dermatology, Women's College Hospital, University of Toronto
Anatoli Freiman, MD, FRCPC, DABD is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, Canadian Dermatology Association, Canadian Medical Association, Ontario Medical Association, Royal College of Physicians and Surgeons of Canada, and Women's Dermatologic Society
Disclosure: Nothing to disclose.

Medical Editor

Russell Hall, MD, Chief, Professor, Department of Internal Medicine, Division of Dermatology, Duke University
Russell Hall, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Federation for Medical Research, American Society for Clinical Investigation, and Society for Investigative Dermatology
Disclosure: Genetech Grant/research funds Principle Investigator; Centecor  Grant/research funds Principle Investigator

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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