There is no unifying pathogenic mechanism underlying the bullous diseases. Many bullous diseases (e.g., CP, pemphigus, bullous pemphigoid) are thought to have an autoimmune basis; epidermolysis bullosa, except for the acquired form, has a genetic basis.

TABLE 1. Clinical Data on Patients with Cicatricial Pemphigoid

CUTANEOUS INVOLVEMENT

Skin involvement is found less frequently than mucuos membrane involvement (see Table 1) and is reported in 9% to 24% of cases.^1–5 The skin lesions of CP may be divided into two types: (1) a recurrent, vesiculobullous, nonscarring eruption that may involve the inguinal area and extremities and occasionally becomes generalized (Fig. 1); and (2) localized, erythematous plaques with overlying vesicles and bullae that appear on the scalp and face near the affected mucous membranes and heal, leaving smooth, atrophic scars (Fig. 2).⁶

MUCOUS MEMBRANE INVOLVEMENT

Cicatricial pemphigoid may involve the following mucous membranes: conjunctiva, nose, mouth, pharynx, larynx, esophagus, anus, vagina, and urethra. In a dermatologic study, oral lesions were found in 91% and conjunctival lesions in 66% of patients with CP.⁵ In ophthalmic studies, 15% to 50% of patients showed involvement of the oral mucosa, whereas 100% had ocular involvement.^1–4

CP is associated with two types of oral lesions.⁶ The first is a desquamative gingivitis that may be patchy or diffuse, heals slowly, and may persist for years. The second type is characterized by vesicles and bullae of the oral mucosa that develop rapidly, remain intact for a few days, and then rupture. Mucous membrane erosions may heal with scarring and even strictures. Stenosis of the nasopharynx or larynx may cause obstructive sleep apnea; esophageal strictures may result in asphyxiation and death when food is swallowed.⁷

OCULAR INVOLVEMENT

Ocular CP (OCP) is a bilateral disease. The initial symptoms are similar to those of any chronic conjunctivitis and include irritation, burning, and tearing.⁸ A mucopurulent discharge suggests a complicating bacterial blepharoconjunctivitis. Breakdown of the corneal epithelium leads to foreign-body sensation, photophobia, and reduced visual acuity.

Fibrosis beneath the conjunctival epithelium is the hallmark of CP.^9,10 Symblepharons, fibrotic bands that pass between the palpebral and bulbar conjunctiva, involve the inferior fornix first and are best demonstrated early in the disease by drawing the lower eyelid down and having the patient look up (Fig. 3). CP may be associated with a dry eye. Fibrosis beneath the conjunctival epithelium may cause occlusion of the ducts of the lacrimal and accessory lacrimal glands, leading to decreased aqueous tear secretion. The reduced numbers of mucus-producing goblet cells may contribute to an unstable tear film.¹¹ Conjunctival scarring causes lagophthalmos with abnormal blinking and exposure and entropion with trichiasis and distichiasis. All these factors may cause breakdown of the ocular-surface epithelium.

Conjunctival or corneal bullae have been described¹⁰ but are rarely observed, perhaps because they rupture readily because of the blinking action of the eyelids. Breakdown of the corneal epithelium most commonly results from entropion with trichiasis; lagophthalmos with abnormal blinking and exposure; and a diminished, unstable tear film. These erosions may become complicated by secondary bacterial infiltrates and ulcers. Predisposing factors for the development of microbial keratitis include topical corticosteroids, bandage contact lenses, trichiasis, corneal surgery, lagophthalmos, and meibomianitis.¹² Corneal neovascularization may develop either as a pannus or pseudopterygium.

Smears of conjunctival scrapings from patients with CP reveal neutrophils, keratinized squamous cells, and eosinophils.¹³ In a study of the bacterial flora of patients with CP, potential pathogens—mainly mannitol-positive staphylococci—were recovered from the eyelids and conjunctiva of 81% of patients with this disease.² Glaucoma may be more prevalent in patients with CP.¹⁴

COURSE OF OCULAR DISEASE

Cicatricial pemphigoid generally runs a chronic course, characterized by progressive shrinkage of the conjunctiva. When the end stage of this disease is reached, the eye lacks tears and has obliterated conjunctival fornices, ankyloblepharon, and a keratinized ocular surface epithelium. Episodes of acute disease activity may interrupt this chronic progressive course and result in rapid shrinkage of the conjunctiva.¹⁵ Acute disease activity may be precipitated by surgical procedures, including conjunctival biopsy, lysis of symblepharon, oculoplastic procedures on the eyelids, and cataract extraction. The acute manifestations consist of localized, ulcerated conjunctival mounds (Fig. 4) or diffuse, severe conjunctival hyperemia and edema (Fig. 5). Before concluding that acute inflammatory activity is caused by the disease process, it is necessary to eliminate other confounding factors such as trichiasis, exposure, or bacterial blepharoconjunctivitis.

When evaluating a patient with CP, the extent of conjunctival shrinkage that has taken place should⁵ be determined. The most useful positions for examination and photography include upward gaze with the lower eyelid retracted and downward gaze with the upper eyelid retracted. The staging system of Mondino and Brown¹⁶ is based on the percentage of conjunctival shrinkage (Fig. 6).² The staging system of Tauber and coworkers¹⁷ describes conjunctival destruction, as follows:

  Stage I—chronic conjunctivitis and subepithelial fibrosis
  Stage II—early fornix foreshortening
  Stage III—symblephara
  Stage IV—ankyloblepharon and a frozen globe.

A patient with CP is more likely to have a dry eye, corneal vessels, trichiasis, and positive cultures of the lids and conjunctiva for potential pathogens as the disease advances in stage (Table 2).¹

TABLE 2. Correlation of Clinical Data With Stage in Patients With Cicatricial Pemphigoid

In addition to staging the extent of conjunctival shrinkage that has taken place, it is important to assess the degree of conjunctival inflammatory activity. Stage and inflammatory activity are important parameters to assess but are not necessarily correlated. For example, an eye at stage IV may show no conjunctival inflammatory activity, whereas an eye at stage II may show severe conjunctival inflammatory activity.

Disease progression should be determined by clinical examination and comparison with previous photographs of the external eye.^8,16 Progression is defined as increased conjunctival shrinkage—which may involve loss of fornix—new symblepharon formation, or enlargement of an existing symblepharon.

One study suggested that CP may be asymmetric in severity (i.e., both eyes may not be at the same stage) and progression (i.e., both eyes may not necessarily progress or fail to progress).¹⁶ Although most eyes progressed, the untreated disease had a variable course because there were eyes in all stages that did not progress. Progression was more likely to occur over a given period in the later stages (i.e., an eye at stage III was more likely to progress than an eye at stage I; see Table 2).

DRUG-INDUCED OCULAR CICATRICIAL PEMPHIGOID

Topical drugs associated with conjunctival scarring include idoxuridine,¹⁸ echothiophate iodide,¹⁹ pilocarpine,²⁰ demecarium,²⁰ epinephrine,²¹ and timolol.²² A study of drug-induced conjunctival shrinkage concluded that the spectrum of disease ranges from a self-limited toxic form to a progressive, immunologic form indistinguishable from CP.²³ Patients in four studies did not have extraocular involvement of mucous membranes or skin.^18–20,23 Patients with drug-induced conjunctival shrinkage may show immunoglobulins bound to conjunctival basement membrane.^18,19,24 In a histopathologic study of drug-induced CP affecting the conjunctiva, light and electron microscopy of the conjunctiva revealed findings identical to those previously reported for idiopathic CP.²²

There are five possible explanations offered for the relation between drugs and conjunctival scarring:

1. The drug may cause conjunctival scarring that mimics CP but is not CP because the scarring is not progressive.
   
2. The taking of a drug and the development of CP may be coincidental.
   
3. The drug may promote or accelerate the development of CP that may have developed later anyway.
   
4. The drug may be a cause of CP.
   
5. CP may cause scarring that obstructs collecting vessels of the outflow pathway and results in glaucoma requiring drug therapy.
   

A practical approach to the problem of drug-induced conjunctival scarring is to discontinue the topical agents, if this can be done, and follow the patient for progressive conjunctival shrinkage.²⁵ If the drugs are absolutely essential to control glaucoma, they should be continued. If progressive conjunctival shrinkage occurs, the patient probably has CP and immunosuppressant therapy may be warranted. The determination of whether these drugs simply cause scarring that mimics CP or whether they cause or promote CP in a particular patient can be made only by long-term follow-up after drug discontinuation for the development of chronic, progressive conjunctival shrinkage or the development of extraocular lesions.

HISTOPATHOLOGIC FINDINGS

Cicatricial pemphigoid is characterized by subepithelial blisters or bullae. Electron-microscopic studies show that the separation at the margin of a blister is located within the lamina lucida between the plasma membrane of the basal cells and the electron-dense lamina densa.⁵

The conjunctival epithelium in CP shows squamous metaplasia, with parakeratosis and keratinization (Fig. 7).²⁶ Mucus-producing goblet cells are scarce or lacking.^11,27 Because the mitotic rate of conjunctival epithelium is higher in patients with CP, it has been suggested that CP is associated with hyperproliferation of the conjunctival epithelium, with a failure of conjunctival differentiation because of reduced goblet cells.²⁸

In the early stages of conjunctival disease, granulation tissue is found beneath the conjunctival epithelium, with an infiltration predominantly of lymphocytes and plasma cells, with occasional eosinophils and relatively few neutrophils.^13,26 Later, pronounced fibrosis takes place in the conjunctival stroma and is responsible for the conjunctival shrinkage that characterizes the disease.^9,10 Hyperproliferation of conjunctival fibroblasts from patients with CP has been demonstrated in tissue culture.²⁹ One study described perivascular inflammatory cell infiltration in 20% of specimens and substantial mast cell participation and degranulation.⁴ In addition to the chronic inflammatory cells typical of CP, conjunctival biopsy specimens from patients with acute manifestations of CP show numerous neutrophils within and beneath the conjunctival epithelium (Fig. 8).¹⁵

An electron-microscopic study of conjunctival epithelium from patients with CP showed increased desmosomes and prominent tonofilaments and tonofibrils throughout the epithelial cytoplasm. The basal lamina showed areas of discontinuity, duplication, and focal thickening. Collagen fibrils were highly disorganized, and the vascular space was reduced.³⁰ A scanning electron-microscopic study of conjunctival surfaces demonstrated a homogeneous granular sheet of amorphous, mucin-like material covering extensive areas of the conjunctiva in patients with CP that was absent from normal subjects.³¹

IMMUNOPATHOLOGY

CP is characterized by the binding of immunoglobulins (most commonly IgG) and components of both the classic and alternative complement pathways to the basement membrane zone of skin and oral mucosa.^32,33 Circulating antibodies to the basement membrane zone can be demonstrated occasionally, and decreased serum levels of interleukin-6 and increased serum levels of tumor necrosis factor-alpha may be present.^33,34 OCP and bullous pemphigoid antigens are distinct but have a common localization within the lamina lucida of the dermal-epidermal junction.³⁵ Patients with systemic features of CP may also have antigens in the lamina densa.³⁶ The bullous pemphigoid antigen is present on the blister roof in close association with basal cells; CP antigen is present on the blister floor.

Conjunctival biopsies taken from patients with CP demonstrate immunoglobulins and complement bound to the basement membrane (Fig. 9) ^24,37–43 One targeted basement membrane component may be laminin.⁴⁴ The destruction of laminin, which normally binds basal epithelium to its basement membrane, leads to blister formation.⁴⁵ An animal model of subepithelial blistering diseases has been developed using antilaminin antibodies in neonatal mice.⁴⁶ Further damage causes fragmentation of the basement membrane and subsequent repair with aberrant forms of basement membrane collagen.⁴⁷ Immunoglobulin deposition on the conjunctival basement membrane also may be found in other diseases.^24,38,43,48

The percentage of patients who demonstrate circulating antibodies to conjunctival basement membrane varies from 0% to 50%.^4,37–39,49 In one study, the detection of these antibodies correlated with the degree of clinical activity.⁴⁹

In CP, antibodies may be directed against specific T-cell antigens expressed in the conjunctival epithelium and its basement membrane (Fig. 10).^38,39,43,50 In addition, circulating antibodies that bind to the conjunctival and corneal epithelium have been demonstrated.^38,39 Studies showing the presence of transforming growth factor-beta 1 and 3, IL-2, and b-fibroblast growth factor suggest that these cytokines play a role in fibrosis.^51,52

The conjunctiva of patients with CP showed increased numbers of T lymphocytes within the epithelium and substantia propria.⁵³ More helper than suppressor T cells were found. Macrophages were the next most common cells found in the substantia propria, followed by B cells and plasma cells.⁵² About half of patients with CP have elevated serum IgA levels.^38,39 Patients with CP have reduced numbers of circulating T lymphocytes, as determined by E rosette formation.⁵⁴ The presence of costimulatory molecules may upregulate T-cell activity.⁵⁵ In one study, CP was associated with HLA-B12, suggesting an immunogenetic susceptibility to the development of this disease.⁵⁶ Other studies have shown CP to be associated with HLA-DP, HLA-DR4, HLA-DR5, HLA-DQw3, HLA-A2, HLA-B8, HLA-B35, and HLA-B49,^57,58 or HLA-DQB1.^59,60

DIFFERENTIAL DIAGNOSIS

The clinical diagnosis of CP depends on the documentation of progressive conjunctival shrinkage. The presence of skin and extraocular mucosal lesions suggests the diagnosis. The finding of immunoglobulins and complement bound to the conjunctival basement membrane also support CP as the cause of cicatrization. Immunofluorescence studies on cultured skin keratinocytes may become a corroborative test for circulating antibodies associated with CP.⁶¹ Other causes of conjunctival shrinkage and symblepharon must be excluded.

Conjunctival scarring may result from irradiation and severe chemical burns, especially alkali. Symblepharons have also been reported with Sjögrens syndrome,⁶² atopic keratoconjunctivitis, and sarcoidosis⁶³ but not to the extent and not with the relentless progression of CP. Conjunctival scarring may develop in association with scleral buckles and conjunctival carcinoma but these conditions are usually unilateral, unlike CP. Progressive systemic sclerosis (scleroderma) may be associated with a dry eye and progressive conjunctival shrinkage.⁶⁴ Trachoma causes conjunctival scarring but this usually begins and predominates in the superior fornix and the upper palpebral conjunctiva.

A membranous conjunctivitis that results in conjunctival scarring may be caused by adenovirus types 8 and 19, a primary infection of herpes simplex virus, diphtheria, or β-hemolytic streptococcus.^41,65 The acute self-limited nature of these infections contrasts with the chronic, progressive conjunctival shrinkage found with CP.

Conjunctival shrinkage may be associated with systemic practolol⁶⁶ or penicillamine⁶⁷ and topical epinephrine, echothiophate iodide, idoxuridine, pilocarpine, timolol, and dipivefrin.^18–23 Whether drug-induced conjunctival shrinkage is self-limited or is actually CP is discussed in the section on “Drug-Induced Ocular Cicatricial Pemphigoid.”

Other bullous diseases usually do not cause much diagnostic confusion with CP (Table 3). Bullous pemphigoid and pemphigus do not usually cause conjunctival scarring.^43,68 An acute episode of EM major may cause conjunctival shrinkage but the shrinkage is not chronically progressive, as it is with CP.

TABLE 3. Differential Diagnosis of Bullous Diseases

TREATMENT

Artificial tears should be used to treat the dry eye associated with CP. Artificial tears without preservatives may be necessary if the preservatives in commercial tear preparations irritate the eyes or if allergies develop to them. Punctal occlusion can be performed if the puncta have not already been occluded by scarring. CP may be complicated by secondary bacterial blepharoconjunctivitis. As mentioned, potential pathogens—especially mannitolpositive staphylococci—were recovered from the eyelids or conjunctiva of 81% of patients with CP.² Cultures of the eyelids and conjunctiva should be performed at initial examination and at regular intervals. Topical antibiotics should be administered, based on specific antibiotic-sensitivity testing. The staphylococcal blepharitis that frequently accompanies this condition may be treated with eyelid scrubs followed by an antibiotic ointment such as erythromycin or bacitracin. Oral tetracycline or doxycycline may be useful in the treatment of meibomian dysfunction.

In the presence of sufficiently deep fornices, therapeutic soft contact lenses may be used in selected patients to protect the corneal epithelium from trichiasis and drying. Some patients with CP develop large, recurrent corneal epithelial defects that are painful and require almost continuous use of a pressure patch or tarsorrhaphy. In these cases, therapeutic soft contact lenses may keep the corneal epithelium intact and enhance patient comfort. Artificial tears may have to be used frequently to prevent the lens from drying out. Patients who have dry eyes and wear contact lenses are at increased risk of infection and must be followed-up at regular intervals.

Cryotherapy or electrocautery using a hyfrecator may be performed to eliminate trichiasis. Entropion with trichiasis may be corrected early in the disease by oculoplastic surgical techniques. In the advanced stages of the disease, the benefits of oculoplastic procedures, including mucous membrane grafts, may be nullified by the disease. Surgery on the conjunctiva may entail a risk of triggering acute inflammatory activity that may lead to rapid and alarming shrinkage of the conjunctiva.¹⁵ Use of intraoperative mitomycin C may prevent this complication.⁶⁹

If patients with CP show conjunctival inflammation or evidence of progressive conjunctival shrinkage, cataract surgery or oculoplastic surgery on the lids and conjunctiva should not be attempted until the disease is controlled by systemic immunosuppressant therapy, including corticosteroids. Once disease activity is controlled, mucous membrane grafts may be used to reconstruct or expand the fornices. Favorable results were reported for patients on systemic immunosuppression during cataract surgery.⁷⁰ Conversely, CP patients who are stable and do not show conjunctival inflammation may not require systemic immunosuppression before surgery but may require postoperative systemic corticosteroids if acute inflammatory activity develops. Systemic corticosteroids are useful in the treatment of the acute manifestations of CP (Figs. 11 and 12).¹⁵

Foster and associates³⁷ and Mondino and Brown¹⁶ found that long-term systemic immunosuppressant therapy suppressed conjunctival inflammatory activity and inhibited progression of conjunctival shrinkage. In another report, the results of progression in patients treated with various systemic immunosuppressant agents were compared with those in a control group, with a mean follow-up of about 2 years for all groups (Table 4).¹ An eye at stage I or II was less likely to progress and more likely to respond to immunosuppressant therapy than an eye at stage III. Not all patients responded to immunosuppressant therapy, however, and some developed complications that required tapering or even discontinuation. Therefore, older patients should not be subjected to the risk of immunosuppressant therapy unless their eyes demonstrate ongoing progression of conjunctival shrinkage. In addition to being followed-up by an ophthalmologist, patients taking immunosuppressant agents should be monitored by an internist, oncologist, or rheumatologist who is familiar with the toxicity and side-effects of these potent drugs. If immunosuppressant therapy is discontinued, the patient should be monitored for recurrence.⁷¹

TABLE 4. Number of Eyes Showing Progression of Conjunctival Shrinkage* in Control and Treatment Groups (Mean Follow-up, 2 Years)

Dapsone has been used to treat CP.⁷² It should be avoided in patients who have a history of sulfa allergy or who are glucose-6-phosphate dehydrogenase-deficient. Tauber and associates⁷³ believe that dapsone may be the best initial therapy for patients with CP that shows mild to modest inflammatory activity and is not rapidly progressive, whereas cyclophosphamide may be the best initial choice for highly active cases. Cyclophosphamide may also be combined with systemic prednisone in difficult cases.⁷⁴ Sulphapyride may also be useful for treating CP.⁷⁵

In the final stages of CP, when the conjunctival fornices are obliterated and the ocular surface epithelium is keratinized, a keratoprosthesis may be inserted to restore some sight to these patients.⁷⁶

PRECIPITATING FACTORS

The most frequent and important precipitating factors are drugs and infections.^79,83–85 The microbial agents associated with EM include viruses, bacteria, fungi, and Mycoplasma pneumoniae. Of these infectious agents, herpes simplex and M. pneumoniae have the strongest association with EM.⁸² Herpes simplex is more likely to be associated with EM minor; drugs and M. pneumoniae are more likely to be associated with EM major.⁷⁹

Drugs are probably the most frequent and important precipitating factor in the development of EM.^77,79,82,83 Drugs often associated with its development include sulfonamides, penicillin, barbiturates, salicylates, mercurials, arsenic, phenylbutazone, and phenytoin sodium. Of these drugs, sulfonamides have the best-documented association with EM. Recurrences of EM may develop on rechallenge with sulfonamides or other suspected drugs. In a study of 54 cases of EM, drugs were not associated with the development of this syndrome in 31% of patients.⁷⁷ In 20% of patients, it was difficult to determine whether drugs caused EM or whether they were administered after the prodromal symptoms of EM had already begun. Drugs were strongly implicated as the cause of EM in 48% of patients because they were administered for symptoms unrelated to the prodromata of EM.

Herpes simplex is frequently associated with recurrent episodes of EM minor.⁸⁶ Although a direct causal relation has not been proved, two studies have demonstrated viral particles within bullae.^87,88 Other viral diseases associated with EM are hepatitis C, varicella,⁸⁹ Epstein-Barr,⁹⁰ and parvovirus 19.⁹¹

EM has been reported after the use of topical ophthalmic scopolamine, tropicamide,⁹² sulfonamides,⁹³ proparacaine,⁹⁴ timolol maleate, and chloramphenicol.⁹⁵

EM has also been related to neoplasms, irradiation therapy, collagen vascular diseases, vaccinations, and administration of digestive enzymes.^79,83,96

CLINICAL MANIFESTATIONS

The prodromal symptoms include malaise, fever, symptoms of upper respiratory tract infection, prostration, and headache.⁷⁹ These symptoms are more prominent in the major form of EM.

The cutaneous lesions are distributed symmetrically. They are found most frequently on the extremities^79,97 and spare the trunk, except for the more severe cases. Crops of skin lesions may develop every 2 weeks for about 6 weeks. Usually, the primary lesion of EM is a round erythematous macule that rapidly develops into a papule. Vesicles, bullae, and epidermal necrosis may develop. The characteristic target lesion consists of a red center surrounded by a pale zone, with another red ring peripheral to the pale zone (Fig. 13). If extensive necrosis and denudation of the epidermis result, the condition may be labeled TEN.⁸⁰ The skin lesions may be associated with burning or itching and resolve leaving residual hyperpigmentation.

The mouth and eyes are affected most frequently and severely. In one study of predominant clinical features of EM major over a 10-year period, 100% of patients showed stomatitis, 63% showed conjunctivitis, and 61% showed balanitis, vaginitis, or urethritis.⁷⁴ The lips are swollen and crusted (Fig. 14). Oral lesions, which occur in crops, begin as small erythematous macules that rapidly develop into clear or hemorrhagic bullae.⁷⁹

Rupture of the bullae leaves an inflamed, painful hemorrhagic base with a white pseudomembrane. Over the course of 1 week, epithelialization occurs. The process may involve the external hares, pharynx, larynx, trachea, bronchi, and esophagus. Except for the conjunctiva, mucosal and cutaneous lesions usually disappear without scarring. Esophagitis with stricture formation has been reported, however.⁹⁸

Complications of EM major include pneumonitis, septicemia, myocarditis, myositis, and glomerulonephritis. The reported mortality is less than 1% for EM minor and 2% to 25% for EM major.⁹⁹ About 20% of EM patients develop recurrences.⁹⁹ Recurrences are more common with the minor form of EM.

OCULAR INVOLVEMENT

The acute phase of ocular disease lasts 2 to 3 weeks.¹⁰⁰ The eyelids are swollen, ulcerated, and crusted. Conjunctival vesicles have been reported^101,102 but are rarely noted. Conjunctival involvement ranges from a mild catarrhal conjunctivitis, which terminates without sequela, to pseudomembranous or membranous conjunctivitis, which may involve both the palpebral and bulbar conjunctiva.¹⁰³ Purulent conjunctivitis may develop secondary to bacterial infections.^100–102

The severity of late ophthalmic complications depends more on the severity of systemic disease and conjunctival involvement than on the local treatment.¹⁰⁴ In other words, patients with pseudomembranous or membranous conjunctivitis tend to develop late ophthalmic complications. The conjunctival surfaces of patients with membranous or pseudomembranous conjunctivitis may heal, leaving scarring, symblepharon, and even ankyloblepharon (Figs. 15 and 16). Late complications of conjunctival scarring include entropion with trichiasis and lagophthalmos with exposure.

Obliteration of the lacrimal puncta and canaliculi by fibrosis may cause epiphora in some patients. Destruction of conjunctival goblet cells and fibrotic obstruction of the ducts of the lacrimal and accessory lacrimal glands may result in a dry eye condition similar to CP. In severe cases, keratinization of the conjunctival and corneal epithelium may be found. The dry eye condition, entropion with trichiasis, and lagophthalmos with exposure may result in corneal complications that include punctate erosions, pannus, ulcers, opacification, and even perforation (Fig. 17).^100–102

Recurrences of EM major rarely involve the conjunctiva.¹⁰³ Thus, EM leaves conjunctival shrinkage and symblepharon in its wake but progressive scarring does not usually occur once the acute stage has subsided, unlike the chronic progressive course of CP. Further destruction of the eye usually depends on complications resulting from the acute event, such as entropion with trichiasis, lagophthalmos with exposure, and the dry eye condition with its propensity for secondary bacterial infections. All these complications may result in a chronically hyperemic eye with a tendency for breakdown of the corneal epithelium that may eventuate in corneal ulcers and even perforations.

Foster and associates¹⁰⁵ reported a small subset of SJS patients with recurrent episodes of conjunctival inflammation. This inflammation was not associated with external factors such as lid margin keratinization, dry eye, trichiasis, or entropion. The histopathologic, ultrastructural, and immunopathologic characteristics of conjunctival biopsies from these patients suggested an underlying vasculitis or perivasculitis. Recurrent inflammation has been described in the skin and oral mucosa.⁷⁹

Microbial keratitis in patients with SJS is most commonly caused by gram-positive cocci and is associated with the use of bandage contact lenses and topical corticosteroids.¹²

HISTOPATHOLOGY

A consistent finding in the skin lesions of EM is a mononuclear cell infiltrate in the dermis, predominantly around the upper dermal blood vessels.¹⁰⁶ The perivascular infiltrate contains mainly lymphocytes and histiocytes.⁸² This perivascular infiltrate may be the only finding in the macules and papules of EM. A necrotizing vasculitis is not found.⁷⁹ Damage to the overlying epidermis is a characteristic finding. The bullae of EM are subepithelial, with adjacent lymphocytes, histiocytes, and a few neutrophils or eosinophils.¹⁰⁷

Histopathologic findings in mucosal lesions are similar to those in skin lesions.¹⁰⁸ Unlike the skin, blisters are transient and rupture rapidly, leaving erosions. Neutrophils are found at an earlier stage and are more prominent in mucosal than cutaneous lesions.

A chronic, nonspecific inflammatory reaction of the conjunctiva is found with a perivascular infiltration of lymphocytes.¹⁰¹ Pseudomembranes may form from the fibrinous exudate made up of inflammatory cells that are predominantly neutrophils and necrotic epithelial cells. In some patients with severe necrotizing reactions, true membranes result. After the acute episode, the conjunctival epithelium from patients with SJS may show squamous metaplasia with surface keratinization. Conjunctival goblet cell densities are reduced in SJS.^109,110 SJS may not represent a mucin-deficient condition because substantial amounts of ocular mucus glycoproteins are present in the eyes of these patients.¹¹¹ The mucus from these patients was more viscous than normal, however, suggesting that qualitative differences may exist.

Conjunctival biopsies from SJS patients with recurrent conjunctival inflammatory episodes showed vascular involvement.¹⁰⁵ In some patients, a classic vasculitis was found with inflammatory cell infiltration into the vessel wall and fibrinoid necrosis of the wall. Others showed prominent perivasculitis with lymphocytes, macrophages, and plasma cells surrounding the vessels. Substantial numbers of degranulating mast cells were noted.

IMMUNOPATHOLOGY

Circulating immune complexes have been demonstrated in the sera of patients with EM.^{106,108,112–114} Additionally, direct immunofluorescent studies of involved skin show deposition of C3, IgM, fibrin, and occasionally IgG in the blood vessel walls of the dermis.^{106,108,112–114} The normal unaffected skin from patients with EM does not have immunoglobulin and complement deposition in blood vessel walls. Injections of histamine can cause them to deposit there, however, suggesting that the immune complexes of EM circulate rather than form locally in the tissue.¹⁰⁶ Immunoglobulin and complement may deposit at the dermal-epidermal junction, and may be directed against desmosomes.^{112,113,115,116} A study of the cellular infiltrate of skin lesions from patients with EM showed that T lymphocytes were the major infiltrating cells, with more cytotoxic or suppressor cells than helper or inducer cells in the epidermis but the reverse in the dermis.¹¹⁷

Foster and colleagues¹⁰⁵ demonstrated a vasculitis or perivasculitis with immunoglobulin and complement deposition in vessel walls of conjunctival biopsies from a small subset of patients with SJS and recurrent conjunctival inflammation. SJS with ocular involvement has been associated with HLA-Bw44 (the dominant sub-group of B 12) and HLA-DQB1.^118,119 These results suggested an immunogenetic susceptibility to the development of SJS with ocular manifestations. This association with HLA-B12 was supported in two other studies of patients with SJS and TEN (a severe variant of EM).^78,120 Malo and associates¹²¹ found an association between herpes simplex virus-induced SJS and HLA-DQB1. These results suggest that there may be an immunogenetic susceptibility not only to the development of SJS with ocular involvement but to all the severe variants of EM.

TREATMENT

There is no specific treatment for EM. Eliminating any suspected etiologic factors and treating related infection are important.¹²² In patients taking multiple medications, patch testing has been used to identify the causative agent.¹²³ Nonessential drugs should be discontinued.

Wet dressings may be used to debride crusted skin lesions, and baths may minimize discomfort.⁸² Hydration may be necessary to maintain fluid balance in patients with severe and extensive cutaneous and mucosal involvement. Analgesics may be needed to relieve pain. Treatment of oral lesions includes saline mouthwashes, topical anesthetics, and topical corticosteroids.⁸²

Systemic corticosteroids have been recommended for the general manifestations of EM.^82,124 An initial dose of 60 to 80 mg of prednisone daily has been recommended until improvement is noted, after which the prednisone is gradually tapered over 3 to 4 weeks. The value of systemic corticosteroids has not been established by a well-controlled, prospective, randomized clinical trial. Indeed, several studies have questioned and challenged the efficacy of systemic prednisone in EM.^125–128 Retrospective reviews of hospitalized patients with EM suggest that patients treated with systemic corticosteroids had more complications and a prolonged recovery with a longer average length of hospital stay, compared with patients receiving only supportive care. Local treatment appears to have little influence on the severity of ophthalmic complications, which are related to the severity of systemic disease and conjunctival involvement.¹⁰⁴ Early lysis of symblepharons should be attempted but may not be effective. Conjunctival cultures should be obtained and appropriate topical antibiotics should be administered for suspected bacterial infections.

In recurrent herpes simplex associated with EM, oral acyclovir may suppress recurrence of both viral disease and its accompanying EM rash.¹²⁹

After the acute inflammation has subsided, patients with SJS may require artificial tears for the dry eye condition, destruction of aberrant lashes by electrocautery using a Hyfrecator or by cryotherapy, soft contact lenses to protect the cornea from drying and trichiasis, and lid scrubs followed by antibiotic ointment for chronic blepharitis.¹⁰³ The lacrimal puncta are generally scarred and closed by the disease process. If not, they should be closed if the patient has a dry eye.¹³⁰ Topical retinoids such as tretinoin (all-transretinoic acid, a vitamin A analog) may reverse conjunctival keratinization.^131,132 Chronic corneal ulceration may require tarsorrhaphy. Mucous membrane grafts may be used to reconstruct the fornices. Patients with localized conjunctival epidermalization may be treated by tarsal polishing followed by grafting with full-thickness buccal mucous membrane.¹³³ In patients with severe symblepharon or ankyloblepharon and keratinization of the ocular surface epithelium, a keratoprosthesis may be attempted.¹³⁴

BULLOUS PEMPHIGOID

Bullous pemphigoid is a relatively benign disease that occurs predominantly in patients older than 60 years of age and primarily involves the skin, which develops large, tense, tough, subepidermal bullae.⁶ Oral mucosal lesions are occasionally found but are less frequent and severe than those in CP or pemphigus. Antibodies are directed against protein components of hemidesmosome, which are crucial to the integrity of the dermal-epidermal junction.¹³⁵ Circulating antibody levels do not correlate consistently to disease severity.¹³⁶ Bullous pemphigoid may involve the conjunctiva and cause shrinkage⁴³ but this is not common.

PEMPHIGUS VULGARIS

Pemphigus vulgaris (Fig. 18) occurs primarily in middle-aged people and is characterized by small, flaccid, easily broken blisters of the skin in an intraepidermal location.⁶ Like CP, pemphigus may be associated with severe oral lesions. The cutaneous and mucosal lesions show little tendency to heal spontaneously but heal without scarring. Immunofluorescent studies show immunoglobulins and complement bound to the intercellular space of the epidermis, in addition to circulating antibodies to this location. Severity of disease correlates with circulating antibody levels.⁶⁸ Immunity is directed against the desmosome portion of intercellular junctional complexes.¹³⁷ Although pemphigus may be associated with conjunctivitis,⁹ conjunctival shrinkage is rare, although it has been reported.⁶⁸

EPIDERMOLYSIS BULLOSA

Epidermolysis bullosa refers to a group of skin diseases characterized by a tendency to form blisters after minor trauma¹³⁸ and can be divided into hereditary and acquired forms.¹³⁹ The hereditary forms of epidermolysis bullosa may be divided into three types. The simple form (autosomal dominant) is associated with blister formation in the basal cell layer of the epidermis, and mutations have been found in keratins localized to basal keratinocytes. The junctional form of epidermolysis bullosa (autosomal recessive) is thought to be caused by a defect in production of basement membrane laminins or integrins, causing a separation within the dermal-epidermal basement membrane at the lamina lucida. In the dystrophic form (autosomal dominant or recessive), separation occurs beneath the basement membrane in the papillary dermis, and mutations have been identified in the collagen VII gene.¹⁴⁰

Ocular problems have been described in all types of epidermolysis bullosa but are most common in dystrophic epidermolysis bullosa.¹⁴¹ Patients with the more common dystrophic form have fewer corneal problems but more frequent and marked conjunctival scarring, including symblepharon formation. Patients with junctional epidermolysis bullosa, one of the rarest types, have more corneal problems (e.g., recurrent corneal erosions) but relatively little conjunctival involvement.¹⁴¹ In the acquired autoimmune form, the immune response is believed to be directed against the basement membrane proteins uncein and collagen VII.¹⁴² It may be associated with small subepithelial vesicles in the cornea, symblepharon, and scarring of the lacrimal puncta.¹⁴³

DERMATITIS HERPETIFORMIS

Dermatitis herpetiformis is a rare, chronic, recurrent eruption characterized by successive crops of papules, vesicles, and blisters on an erythematous base and in a symmetric distribution.⁶ Men are affected more frequently than women, and the disease usually occurs between the second and fifth decades. The eruption is responsible for intense pruritus and burning. Superficial scars rarely develop. Mucous membrane lesions are rare and heal rapidly. Direct immunofluorescence of skin shows deposits of IgA and complement at the basement membrane zone of the epidermis. Circulating antibodies to the basement membrane zone of the skin are not found in the sera. Microabscesses of neutrophils and eosinophils form at the tips of dermal papillae and result in subepidermal vesicles and occasionally bullae.

Ocular changes are not common but cases have been reported with conjunctival involvement.⁹ Conjunctival vesicles, erosions, pseudomembranes, symblepharon, shrinkage, and keratinization have been described, resulting in a clinical picture that resembles CP. The conjunctival scarring found in dermatitis herpetiformis is not as extensive as that found in CP, however.

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