Cicatricial Pemphigoid and Erythema Multiforme

Cicatricial Pemphigoid and Erythema Multiforme BARTLY J. MONDINO, MD

Abstract: Cicatricial pemphigoid (CP) and erythema multiforme (EM) are bullous diseases that involve the skin and mucous membranes including the conjunctiva. Of all the bullous diseases, CP and EM not only involve the conjunctiva most frequently but also cause the most severe conjunctival disease. A chronic, progressive disease, CP is characterized by shrinkage of the conjunctiva, symblepharon, entropion, trichiasis, dry eye, and finally reduced vision from corneal opacification. It is primarily a disease of the elderly that affects more women than men and is characterized by blisters or bullae in a subepithelial location and immunoglobulins and complement bound to the basement membrane zone of skin and mucous membranes including the conjunctiva. Circulating antibodies to the basement membrane zone can be demonstrated occasionally. Treatment includes artificial tears, topical antibiotics, correction of entropion and trichiasis, therapeutic soft contact lenses, and systemic immunosuppressive therapy including corticosteroids. An acute, generally self-limited, inflammatory disorder of the skin and mucous membranes, EM occurs primarily in young, healthy individuals. The most frequent precipitating factors are (1) drugs and (2) infections caused by Mycoplasma pneumoniae and herpes simplex. Conjunctival involvement ranges from a mild catarrhal conjunctivitis which terminates without sequelae to membranous conjunctivitis which may heal leaving scarring, symblepharon, and even ankyloblepharon. Histopathologic findings include subepithelial bullae and perivascular mononuclear cell infiltrates. Patients with EM have circulating immune complexes and immunoreactant deposition in the blood vessel walls of the dermis. After the acute episode has subsided, they may require artificial tears, topical antibiotics, correction of entropion and trichiasis, therapeutic soft contact lenses, tarsorrhaphy, and mucous membrane grafts. Ophthalmology 1990; 97:939-952

Cicatricial pemphigoid (CP) and erythema multiforme (EM) are bullous diseases that involve the skin and mucous membranes including the conjunctiva. Of all the bullous diseases, CP and EM not only involve the conjunctiva most frequently but also cause the most severe conjunctival disease. This report reviews the clinical, his-

Originally received: September 29, 1989. Revision accepted: February 23, 1990. From the Jules Stein Eye Institute and Department of Ophthalmology, UCLA School of MediCine, Los Angeles. Presented at the American Academy of Ophthalmology Meeting Annual Meeting, New Orleans, Oct/Nov 1989. Supported in part by NEI grant EY04607 and the Wasserman Fund. Reprint requests to Bartly J. Mondino, MD, Jules Stein Eye Institute, UCLA School of Medicine, 800 Westwood Plaza, Los Angeles, CA 90024.

topathologic, and immunopathologic features of these diseases and their treatment.

CICATRICIAL PEMPHIGOID The striking feature of CP is recurrent blisters or bullae of the skin and mucous membranes with a tendency for scar formation.l Ocular involvement is characterized by progressive shrinkage of the conjunctiva, symblepharon, entropion with trichiasis, dry eye, and finally reduced vision from corneal opacification. 2 The disease has no geographic or racial predilection. In one ophthalmic study of 130 patients, the average age at onset was 64 years (range, 20-87 years).3 In my experience with 108 patients, the mean age at initial examination was 70 years (range, 43-88 years) (Table 1). Although CP is primarily a disease of the elderly, it may begin in the third decade. 3 The dis939

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Table 1. Clinical Data on Patients with Cicatricial Pemphigoid No. of patients Mean age (yrs) Range Ratio of female to male patients No. of patients with skin lesions (%) No. of patients with lesions of oral mucosa (%)

108

70

43-88 1.8/1

17 (16) 45 (42)

Fig 3. Symblepharon formation is demonstrated by drawing lower lid down and having patient look up.

Fig 1. Intact and ruptured blisters of forearm in patient with cicatricial pemphigoid.

becoming 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). 5

MUCOUS MEMBRANE INVOLVEMENT

Fig 2. Localized, erythematous plaque with intact and ruptured blisters on it in patient with cicatricial pemphigoid.

ease affects more women than men, with ratios varying from 1.6: 1 to 1.8: 1. 2.3

CUTANEOUS INVOLVEMENT Skin involvement is less frequent than mucous membrane involvement and is reported in 9 to 24% of cases. 2-4 In my experience, 16% of patients have skin lesions (Table 1). The skin lesions may be divided into two types: (1) a recurrent, vesiculobullous, nonscarring eruption that may involve the inguinal area and extremities, occasionally 940

The mucous membranes that may be involved include the 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.4 In ophthalmic studies, 15 to 50% of patients showed involvement of the oral mucosa, with 100% ocular involvement. 2 •3 In my experience, 42% of patients have lesions of the oral mucosa (Table 1). It is associated with two types of oral lesions: desquamative gingivitis and a vesiculobullous eruption. 5 The gingivitis may be patchy or diffuse, heals slowly, and may persist for years. Vesicles and bullae of the oral mucosa 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 and require surgical repair. 6 Esophageal strictures may result in asphyxiation and death when food is swallowed. 6

OCULAR INVOLVEMENT Cicatricial pemphigoid is a bilateral disease. The initial symptoms are similar to those of any nonspecific chronic conjunctivitis and include irritation, burning, and tearing. 7 A mucopurulent discharge may be found if a bacterial blepharoconjunctivitis develops. Breakdown of the corneal epithelium leads to foreign body sensation, photophobia, and finally reduced vision. Fibrosis beneath the conjunctival epithelium is the essential, destructive process in CP. 8 ,9 Symblepharons are fibrotic bands that pass between the palpebral and bulbar conjunctiva. They involve the inferior fornix first and are

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best demonstrated early in the disease by. drawing the lower eyelid down and having the patient look up (Fig 3). The disease may be associated with 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. Reduced numbers of mucus-producing goblet cells lO may contribute to an unstable tear film. Conjunctival scarring causes lagophthalmos with abnormal blinking and exposure and entropion with trichiasis and distichiasis. All these factors may result in breakdown of the ocular surface epithelium. Conjunctival or corneal bullae have been described 9 but are rarely observed, perhaps because they rupture readily due to the blinking action of the eyelids. Breakdown of the corneal epithelium usually 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. Over an II-year period, 17 (10%) of 178 patients with ocular CP had 18 episodes of microbial keratitis. II Predisposing factors included topical corticosteroids, bandage contact lenses, trichiasis, corneal surgery, lagophthalmos, and meibomianitis. Corneal neovascularization may develop either as a pannus or pseudopterygium. Smears of conjunctival scrapings from patients with CP show neutrophils, keratinized squamous cells, and eosinophils. 12 In a study of the bacterial flora of patients with CP, potential pathogens were recovered from the eyelids and/or conjunctiva of 81 % of patients with this disease? Mannitol-positive staphylococci were the potential pathogens that were most prevalent in both patients and controls in the study. Glaucoma may be more prevalent in patients with CPo In a retrospective review of 111 patients with CP, 29 (26%) had glaucoma.13 The patients with CP and glaucoma were more likely to have continued high-grade conjunctival inflammation after treatment than those with CP alone.

Fig 4. Localized, ulcerated conjunctival mound indicated by arrow and slit beam.

Fig 5. Same patient as in Figure 4 shows fluorescein staining of ulcerated, conjunctival mound.

COURSE OF OCULAR DISEASE

A chronic disease, CP is generally characterized by progressive conjunctival shrinkage. The end stage of this disease is characterized by absent tears, obliterated conjunctival fornices, ankyloblepharon, and a keratinized ocular surface epithelium. Episodes of acute disease may interrupt the chronic progressive course and result in rapid shrinkage of the conjunctiva. 14 Acute disease may be precipitated by surgical procedures including conjunctival biopsy, lysis of symblepharon, oculoplastic procedures on the eyelids, and cataract extraction. The acute manifestations consist oflocalized, ulcerated conjunctival mounds (Figs 4, 5) or diffuse, severe conjunctival hyperemia and edema (Fig 6). Before concluding that acute inflammatory activity is caused by the disease process itself, 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 should be determined. The most useful positions for examination and

Fig 6. Diffuse conjunctival hyperemia and edema as an acute manifestation of ocular cicatricial pemphigoid.

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Fig 7. Stage I of ocular cicatricial pemphigoid shows 25% or less shrinkage of the conjunctival fornices.

Fig 8. Stage 2 of ocular cicatricial pemphigoid shows 25 to 50% conjunctival shrinkage.

Fig 9. Stage 3 of ocular cicatricial pemphigoid shows conjunctival shrinkage of approximately 75%. Inferior fornix is nearly obliterated, whereas a shallow superior fornix is still present.

photography include upward gaze with the lower eyelid retracted and downward gaze with the upper eyelid retracted. The following staging system of Mondino and 942

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Fig 10. Stage 4 or endstage of ocular cicatricial pemphigoid shows obliteration of conjunctival fornices.

Brown2.15 is based on the percentage of conjunctival shrinkage: stage 0, no conjunctival shrinkage; stage 1,25% or less shrinkage of the conjunctival fornices (Fig 7); stage 2, 25 to 50% conjunctival shrinkage (Fig 8); stage 3, conjunctival shrinkage of approximately 75% (Fig 9); stage 4, end stage (Fig 10). The staging system of Foster3 also is based on conjunctival scarring: stage 1, chronic conjunctivitis with subepithelial fibrosis; stage 2, inferior fornix foreshortening; stage 3, appearance of symblepharon; stage 4, end stage. In addition to staging, the extent of conjunctival shrinkage that has taken place, it is important to assess the degree of conjunctival inflammatory activity that is present. Foste~ grades conjunctival inflammatory activity from 0 to 4+. Both stage and inflammatory activity are important parameters to assess but are not necessarily correlated. For example, an eye at stage 4 may have 0 conjunctival inflammation, but an eye at stage 2 may have 4+ conjunctival inflammation. Using the staging system of Mondino and Brown,2.15 I found that a patient with CP is more likely to have a dry eye, corneal vessels, trichiasis, and positive cultures of the lids and/or conjunctiva for potential pathogens with advancing stage (Table 2). Disease progression should be determined by clinical examination and comparison with previous photographs of the external eye. 7 •15 Progression is defined as increased conjunctival shrinkage which may involve loss of the fornix or new symblepharon formation. A previous study suggested that CP may be asymmetric in severity (both eyes may not be at the same stage) and progression (both eyes do not necessarily progress or fail to progress).15 Although most eyes progressed, the untreated disease had a variable course because there were eyes in all stages that did not necessarily progress. In a prospective study of disease progression, I followed 35 patients for an average of24 months. These patients were not being treated with topical corticosteroids or systemic immunosuppressive agents. Progression occurred in 40% of eyes in stage 1,62% of eyes in stage 2, and 73% of eyes in stage 3 (Table 3). These findings indicated that the

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Table 2. Correlation of Clinical Data with Stage in 81 Patients with Cicatricial Pemphigoid

Stage*

No. of Eyes

No. of Eyes with Dry Eye (%)t

1 2 3 4

65 62 28 7

19/65 (29) 20/62 (32) 17/28 (61) 7/7 (100)

Total

162

63 (39)

No. of Eyes with Corneal Vessels (%) 20/65 49/62 28/28 7/7

No. of Positive Cultures of Lid and/or Conjunctiva for Pathogens (%)+

No. of Eyes with Trichiasis (%)

(31) (79) (100) (100)

38/65 52/62 24/28 7/7

104 (64)

(58) (84) (86) (100)

22/54 (41) 26/55 (47) 17/25 (67) 5/5 (100)

121 (75)

70/139 (50)

* See Course of Ocular Disease section for description of stages. t Less than 5 mm of wetting on Schirmer filter strips after 5 minutes without topical anesthesia. + Mannitol-positive or coagulase-positive Staphylococcus was the most prevalent potential pathogen recovered.

Table 3. Number of Eyes Showing Progression of Conjunctival Shrinkage* in Control and Treatment Groups Using Staging System of Mondino and Brown 2.15

Group

No. of Patients

No. of Eyes

Azathioprine Cyclophosphamide Prednisone Cyclophosphamide and prednisone Treatment groups combined Control

10 13 11 17+ 51+ 35+

20 26 22 33 101 69

Stagest

1/3 (33%) 1/4 (25%) 0/9 (0%) 1/6 (17%) 3/22 (14%) 13/32 (40%)

2

3

5/9 (56%) 1/10 (10%) 1/7 (14%) 4/19 (21%) 11/45 (24%) 16/26 (62%)

4/8 (50%) 9/12 (75%) 3/6 (50%) 2/8 (25%) 18/34 (53%) 8/11 (73%)

* Progression defined as any increase in conjunctival shrinkage including loss of fornix or new symblepharon formation. t See Course of Ocular Disease section for description of stages. + One eye from one patient excluded from analyses because it was already at stage 4 or endstage.

percentage of eyes that progressed increased from stage 1 to 3, suggesting that progression was more likely to occur over a given period of time in the later stages. DRUG-INDUCED OCULAR CICATRICIAL PEMPHIGOID

A relationship between drug use and conjunctival scarring has been shown by scarring that developed unilaterally in the eye treated with topical idoxuridine (3 cases),16 echothiophate iodide (2 cases),17 pilocarpine (1 case),t8 and demecarium (1 case).tS In another report, 14 of 29 eyes with CP had been treated with topical epinephrine. 19 A study of five cases of drug-induced conjunctival shrinkage concluded that there is a spectrum of disease ranging from a self-limited toxic form to a progressive, immunologic form indistinguishable from CP.2° The patients in four of these studies did not have extraocular involvement of the mucous membranes or skin. 16- 18 ,20 Patients with drug-induced conjunctival shrinkage may have immunoglobulins bound to conjunctival basement membrane. 16,17,21 In a histopathologic study of drug-induced CP affecting the conjunctiva, ten patients had conjunctival shrinkage in association with topical pilocarpine, timolol, epinephrine, phospholine iodide, and dipivefrin. 22 Light

and electron microscopy of the conjunctiva found results identical to those previously reported for idiopathic CP, There are several possible explanations for the relationship between drugs and the induction of conjunctival scarring or actual CP: (1) drug use and the development of CP may be independent events and occur coincidentally; (2) the drug may cause conjunctival scarring which mimics but is not really CP because the scarring is not progressive; (3) the drug may promote or accelerate the development of CP to which the patient may be predisposed; (4) the drug may be a cause ofCP; or (5) preexisting but undiagnosed CP causes scarring which may obstruct collecting vessels of the outflow pathway and result in glaucoma that requires drug therapy. A practical approach to the problem of drug-induced conjunctival scarring involves discontinuing the topical agents if this can be done and following the patient for progressive conjunctival shrinkage. 23 If the latter develops, then the patient probably has CP and will require immunosuppressive therapy, If the drugs are essential to control glaucoma, then they should be continued. Ifprogressive conjunctival shrinkage occurs, then immunosuppressive therapy may be warranted. The determination of whether these drugs simply cause scarring that mimics CP or whether they promote or cause CP in a particular 943

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patient. can ~e m~de only by long-term follow-up after drug discontmuatIOn for the development of chronic progressive conjunctival shrinkage, the most characteristi~ feature of CP, or the development of extraocular lesions. HISTOPATHOLOGIC FINDINGS

Cicatricial pemphigoid is characterized by blisters or bullae in a subepithelial location. Results of 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 electrondense lamina densa. 4 The conjunctival epithelium shows squamous metaplasia with parakeratosis and keratinization. 24 Mucusproducing goblet cells are scarce or absent. 10.25 The mitotic rate in cells of patients with CP was higher than that in normals, suggesting that this disease is associated with hyperproliferation of the conjunctival epithelium and failure of conjunctival differentiation because of reduced goblet cells. 26 . In t~e early stages of conjunctival disease, granulation tIssue IS found beneath the conjunctival epithelium with an infiltration predominantly of lymphocytes, plasma cells, occasional eosinophils, and relatively few neutrophils. 12 ,24 Later, pronounced fibrosis occurs in the conjun.ctival stroma and is responsible for the conjunctival shnnkage that characterizes this disease. 8.9 One report described perivascular inflammatory cell infiltration in 20% ~f .spe~imens. 3 It also showed substantial mast cell partICIpatIOn and degranulation. In addition to the chronic inflammatory cells typical of this disease, conjunctival biopsy specimens from patients with acute manifestations of CP show numerous neutrophils within and beneath the conjunctival epithelium. 14 Results of electron microscopic studies of conjunctival epithelium from patients with CP showed increased desmosomes and prominent tonofilaments and tonofibrils throughout the epithelial cytoplasm. 27 ,28 There were areas of discontinuity, duplication, and focal thickening in the basal lamina. Collagen fibrils were disorganized, and the vascular space was reduced. In specimens of conjunctiva from patients treated with immunosuppressive agents there was a relative absence of desmosomes between th~ epithelial cells and less prominent tonofibrils within epithelial cells. 28 Results of a scanning electron microscopic study of conjunctival surfaces in patients with CP showed a homogeneous granular sheet of amorphous mucin-like material covering extensive areas of the conjunctiva. 29 This material was absent from normal conjunctival specimens, The patie!lts with CP had ocular surface mucus that appeared thIcker and more continuous than normal ocular mucus; this agreed with the clinical observation of thick mucus strands in the inferior fornix of these patients. IMMUNOPATHOLOGY

This disease is characterized by the binding of immunoglobulins (most commonly IgG) and components of 944

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both the classic and alternative complement pathways to the basement membrane zone of skin and oral mu3031 C'IrcuIatmg ' antI' b ' to the basement memcosa,' odies bra!le zone can be demonstrated occasionally.30,31 The antIgens of CP and bullous pemphigoid are distinct but have a common localization within the lamina lucida of the ~e~al-epidermal junction. 32 The bullous pemphigoid antIgen IS present on the blister roof in close association with basal cells while the CP antigen is present on the blister floor. The percentage of conjunctival biopsy specimens from patients with CP that show immunoglobulins bound to the basement membrane varies from 20 to 84%.2 1,33-37 Complement also may be bound to the conjunctival basement membrane. Foster3 believes that ifimmunofluorescence is negative for basement-membrane-bound immunoreactants then the more sensitive avidin-biotincomplex immunoperoxidase technique should be used, With both these techniques, basement-membrane-bound immunoreactants were demonstrated in nearly all of his cases . . The deposition of immunoglobulins on the conjunctIval basement membrane is not absolutely diagnostic of CPo In one study, immunoreactant deposition at the basement membrane zone of the conjunctiva was found in patients with Mooren's ulcer and staphylococcal keratitis.34 A more linear deposition of immunoglobulins was found in CP and a more granular deposition in the other conditions. However, a CP case has been reported with granular IgA and C3 complement deposition along the basement membrane zone, suggesting that immunecomplex deposition may provide an alternative pathogenetic mechanism to basement-membrane-zone auto. 38 Another study also suggested that a~tI'b O.d y fiormatIOn. d~rect l1l~munofluorescence is useful, but not absolutely diagnostIc for CP, because linear deposition of immunoglobulins was found along the conjunctival basement membrane of two of seven patients with cicatrizing conjunctivitis associated with other diseases. 21 Additionally, both bullous pemphigoid39 and linear IgA disease40 can cause conjunctival shrinkage associated with linear immunoreactant deposition at the conjunctival basement membrane zone. The percentage of patients with circulating antibodies to conjunctival basement membrane varies from 0 to 50%.3,33-35,41 The ability to detect these antibodies in one study correlated with the degree of clinical activity.41 I~ CP, autoimmune phenomena may be directed agamst the conjunctival epithelium as well as its basement membrane. Some patients have immunoglobulins bound to .the co?jun~tival ep~thelium.34,35,39 Iq addition, circulatmg antIbodIes that bmd to the conjunctival and corneal epithelium can be found. 34,35 In the conjunctiva of CP patients there are increased numbers of T-Iymphocytes within the epithelium and substantia propria. 42 More helper than suppressor T-cells were found. Macrophages were the next most common cells in the substantia propria followed by B-cells and plasma cells.

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Approximately one half of patients with CP have elevated serum IgA levels. 34,35 Patients with CP have reduced numbers of circulating T-Iymphocytes as determined by E-rosette formation. 43 In one study, an association ofCP with HLA-BI2 was shown, suggesting that there is an immunogenetic susceptibility to the development of this disease. 44 In another study, CP was associated with HLADR4, -DRS, -DQw3, -A2, -B8, -B35, and _B49. 45

conjunctival shrinkage is rare but has been reported. 51 Erythema multiforme major may cause conjunctival shrinkage as a result of the acute episode, but the shrinkage is not chronically progressive as it is with CPo Conjunctival scarring has been reported with linear IgA disease. 4o However, this disease is more likely to involve the skin which has pruritic, urticarial lesions that heal without scarring.

DIFFERENTIAL DIAGNOSIS

TREATMENT

The clinical diagnosis of CP depends on the documentation of progressive conjunctival shrinkage. The presence of skin and extraocular mucosal lesions and the demonstration of immunoglobulins and complement bound to the basement membrane zone of the conjunctiva support the diagnosis. Other causes of conjunctival shrinkage and symblepharon must be excluded. Conjunctival scarring may result from radiation and severe chemical burns, especially alkali. Symblepharons have also been reported with Sjogren's syndrome,46 atopic keratoconjunctivitis, and sarcoidosis,47 but not to the extent and not with the relentless progression of CPo Conjunctival scarring may develop in association with scleral buckles and conjunctival carcinoma, but these conditions are usually unilateral unlike CPo Progressive systemic sclerosis (scleroderma) may be associated with a dry eye and progressive conjunctival shrinkage. 48 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, diphtheria, and beta-hemolytic streptococci. 37 ,49 The acute, self-limited nature of these infections contrasts with the chronic, progressive conjunctival shrinkage found in CPo Conjunctival shrinkage may be associated with systemic practolol50 and topical epinephrine, echothiophate iodide, idoxuridine, pilocarpine, timolol, and dipivefrin. 16- 2o,22 Whether this drug-induced conjunctival shrinkage is selflimited or actual CP has been discussed, Other bullous diseases usually do not cause much diagnostic confusion with CPo Bullous pemphigoid primarily involves the skin and has large, tense, tough, subepidermal bullae. I Oral mucosal lesions are found occasionally but are less frequent and severe than those of CP or pemphigus. Immunofluorescent studies show immunoglobulins (mainly IgG) and complement bound to the basement membrane zone as well as circulating antibodies to it. Bullous pemphigoid may involve the conjunctiva and cause shrinkage, but this is rare. 39 Pemphigus vulgaris is characterized by small, flaccid, easily broken blisters of the skin in an intraepidermal location. I Like CP, pemphigus may be associated with severe oral lesions. Immunofluorescent studies show immunoglobulins and complement bound to the intercellular space of the epidermis and circulating antibodies to this location. Although pemphigus may be associated with conjunctivitis,

When the patient with CP develops a dry eye from aqueous tear deficiency, artificial tears should be used. Those without preservatives may be necessary if the preservatives in commercial tear preparations irritate the eyes or allergies develop. Punctal occlusion can be done if the puncta have not already been occluded by scarring. There may be secondary bacterial blepharoconjunctivitis. Potential pathogens have been recovered from the eyelids or conjunctiva of 81 % of patients with this disease. 2 Cultures of the eyelids and conjunctiva should be done initially and periodically. Topical antibiotics should be administered on the basis of 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 meibomianitis. In the presence of fornices that are sufficiently deep, therapeutic soft contact lenses may be used to protect the cornea from trichiasis and drying. Some patients with CP have 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 the patients comfortable. Artificial tears may have to be used frequently to prevent the lens from drying out. Because patients who have dry eyes and wear contact lenses are at increased risk of infection, they must be followed at regular intervals. Cryotherapy or electrocautery using a Hyfrecator (Birtcher, Los Angeles, CA) may be used 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 ofoculoplastic procedures including mucous membrane grafts may be nullified by the disease itself. In fact, surgery on the conjunctiva may entail a risk of activating acute inflammation that may lead to rapid and alarming shrinkage of the conjunctiva. 14 If patients with CP have 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 immunosuppressive therapy including corticosteroids. Once disease activity is controlled, mucous membrane grafts could be used to reconstruct or expand the fornices. Favorable results were reported for patients receiving systemic immunosuppression at the time of cat945

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aract surgery.52 On the other hand, CP patients who are stable and do not have conjunctival inflammation may not require systemic immunosuppression before surgery but may require postoperative systemic corticosteroids if acute inflammation occurs. Systemic corticosteroids are useful in the treatment of the acute manifestations ofCP.14 Long-term immunosuppressive therapy may be useful in suppressing conjunctival inflammatory activity and preventing progressive conjunctival shrinkage in CPo Foster et ae 3 reported that immunosuppressive therapy altered progression of disease in 14 of 15 patients, but the disease progressed in all eight control patients. Mondino and Brown l5 also found that systemic immunosuppressive agents, including corticosteroids, suppressed conjunctival inflammation and inhibited progression of conjunctival shrinkage. In Table 3, I compare the results of progression in patients treated with various immunosuppressive agents with those in a control group with a mean follow-up of approximately 2 years for all groups. The protocols used in the treatment and follow-up of these patients have been described previously.15 An eye at stage 1 or 2 was less likely to progress and more likely to respond to immunosuppressive therapy than one at stage 3. However, not all patients responded to immunosuppressive therapy, and some developed complications that required tapering or even discontinuation. Therefore, elderly patients with limited life spans should not be subjected to the risk of immunosuppressive therapy unless their eyes have ongoing progression of conjunctival shrinkage. Additionally, patients taking immunosuppressive agents should be followed not only by the ophthalmologist but also by an internist, oncologist, or rheumatologist who is familiar with the toxicity and side effects of these potent drugs. Dapsone is useful in the treatment of CP.53 It should not be used in patients who have a history of sulfa allergy or who are glucose-6-phosphate dehydrogenase deficient. Tauber et al (unpublished data; presented at the 1988 American Academy of Ophthalmology Annual Meeting) believe that dapsone may be the best initial therapy for patients with CP with mild to modest inflammatory activity that is not rapidly progressive, although cyclophosphamide may be the best initial choice for highly active cases. In the final stages ofCP when the conjunctival fornices are obliterated and the ocular surface epithelium is keratinized, a keratoprosthesis may be inserted to restore some sight to these unfortunate patients. 54

ERYTHEMA MULTIFORME Erythema multiforme is an acute, generally self-limited, inflammatory disorder of the skin and mucous membranes. For practical purposes, EM may be divided into minor or major forms. The minor form primarily involves the skin with mucosal involvement either limited to one surface or absent altogether. On the other hand, EM major, also known as Stevens-Johnson syndrome, is characterized by mucosal and cutaneous lesions, toxemia with

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fever and prostration, and ocular involvement. Although ocular involvement is frequent, it is not an absolute prerequisite for the diagnosis. Suggested diagnostic criteria for EM major include: (1) skin lesions; (2) erosive involvement of two or more mucous membranes; and (3) systemic toxicity, usually including malaise, fever, headache, and prostration. 55 Toxic epidermal necrolysis, which is characterized by massive denudation of the epidermis, may be a severe variant of EM major. 56- 58 Although EM minor may last 1 to 4 weeks, EM major may last up to 6 weeks. It has no racial or geographic predilection and may be found in patients of almost any age, but it occurs primarily in young, healthy individuals in the first three decades oflife (rarely in infancy or old age).57,59 Males are affected more often than females. 57 ,59 PRECIPITATING FACTORS

Although EM may be associated with various precipitating factors, the most frequent and important associations are drugs and infections. 57 ,60 The microbial agents that have been 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.59 Herpes simplex is more likely to be associated with EM minor, and drugs and M. pneumoniae are more likely to be associated with EM major. 57 Epidemics of EM have been described in association with respiratory tract infections caused by M. pneumoniae. 57 Patients with mycoplasma-associated EM show rising titers of antibodies to this agent. Moreover, M. pneumoniae has been isolated from the blister fluid of patients with EM. The disease may be associated with preceding episodes of Herpes simplex type 1 and 2 infections. 57 The percentage of cases of EM that are associated with recurrent Herpes simplex ranges from 15 to 63%.57 A patient with a 7-year history of recurrent episodes of EM preceded by herpes simplex infections developed bullae that were clinically and histologically interpreted as EM after intradermal skin tests with a formaldehyde-inactivated Herpes simplex preparation. 60 This patient developed not only a local reaction after this skin test but also a widespread vesiculobullous eruption 48 hours later. In another study, 10 of 54 patients with EM had a long-standing history of either herpes febrilis or genitalis, which were temporally related to the onset of EM in several cases. 55 Herpes simplex virus has been isolated from lesions of EM.61 A history of recurrent bacterial infections was found in 20% of cases of EM major. 55 In one patient, the intradermal injection of various heat-killed gram-negative bacteria and endotoxin produced classic target lesions that were grossly and microscopically indistinguishable from those associated with EM.62 This suggested that endotoxin might be an important precipitating factor in some cases of EM associated with gram-negative bacterial infections. Drugs are probably the most frequent and important precipitating factors in the development of EM. 55 ,57,59,60

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Drugs often associated with its development include sulfonamides, penicillin, barbiturates, salicylates, mercurials, arsenicals, phenylbutazone, and phenytoin sodium. Of all these drugs, sulfonamides have the best-documented association with EM. Recurrences of EM may develop on rechallenge with sulfonamides or other suspected drugs. It may be difficult to determine in some cases whether a drug is responsible for the development of EM because the prodromal symptoms of EM closely mimic upper respiratory infections that are commonly treated with antibiotics or other drugs. Therefore, it may be difficult to determine whether the drug itself caused EM or if the prodromal symptoms would have developed into the fullblown syndrome even if the drugs were not administered. In a study of 54 cases of EM, 55 drugs were not associated with this syndrome in 31 % of patients. In 20% of patients, it was difficult to determine if drugs caused EM or if 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. Topical ophthalmic scopolamine,63 tropicamide,63 sulfonamides,64 and proparacaine65 have also been associated with EM. It has also been related to neoplasms, radiation therapy, collagen vascular diseases, and vaccinations. 57,60

Fig 11. Target lesions of the palms in patient with erythema multiforme.

CLINICAL MANIFESTATIONS

The prodromal symptoms include malaise, fever, symptoms of upper respiratory tract infection, prostration, and headache. 57 These symptoms are more prominent in EM major than in EM minor. The cutaneous lesions are found most frequently on the extremities with a predilection for the dorsal aspect of the hands and feet and the extensor surfaces of the extremities. 57 ,66 The lesions spare the trunk except for the more severe cases. Accordingly, EM major is more likely to be generalized with involvement of the trunk. Crops of skin lesions may develop every 2 weeks for approximately 6 weeks. These lesions are distributed symmetrically. The usual primary lesion 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 11). If extensive necrosis and denudation of the epidermis result, then the condition may be labeled toxic epidermal necrolysis. 58 The skin lesions may be associated with burning or itching and resolve leaving residual hyperpigmentation. The major form of EM may involve any mucous membrane. However, the mouth and eyes are affected most frequently and severely. In one study of predominant clinical features of EM major over a lO-year period, lOO% of patients had stomatitis, 63% had conjunctivitis, and 61 % had balanitis, vaginitis, or urethritis. 55 The lips are swollen and crusted (Fig 12); the gingivae are usually spared. Oral lesions which occur in crops begin as small,

Fig 12. Swollen, crusted lips in patient with erythema multiforme.

erythematous macules that rapidly develop into clear or hemorrhagic bullae. 59 Rupture of the bullae leaves an inflamed, painful hemorrhagic base with a white pseudomembrane. Mucosal erosions may be associated with pain. Over the course of 1 week, epithelialization occurs. The process may involve the external nares, pharynx, larynx, trachea, bronchi, and esophagus. Except for the conjunctiva mucosal and cutaneous lesions usually disappear without scarring. However, esophagitis with stricture formation has been reported. 67 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. 68 Approximately 20% of cases of EM recur.68 Recurrences are more common with the minor than major form of EM. OCULAR INVOLVEMENT

The acute phase of ocular disease lasts 2 to 3 weeks. 69 The eyelids are swollen, ulcerated, and crusted. Conjunc-

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Fig 13. Subepithelial scarring of upper tarsal plate is present after resolution of an acute attack of erythema multiforme.

Fig 14. Symblepharon of nasal aspect of right inferior fornix (indicated by arrow) after resolution of acute attack of erythema multiforrne.

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domembranous or membranous conjunctivitis which may involve both the palpebral and bulbar conjunctiva.72 Purulent conjunctivitis may develop secondary to bacterial infections. Anterior uveitis has been reported. 69- 71 The severity oflate ophthalmic complications depends more on the severity of systemic disease and conjunctival involvement than local treatment. 73 In other words, patients with pseudomembranous or membranous conjunctivitis may have late ophthalmic complications. The conjunctival surfaces of patients with membranous or pseudomembranous conjunctivitis may heal leaving scarring, symblepharon, and even ankyloblepharon (Figs 13, 14). 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. However, 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 ocular CPo In severe cases, keratinization of the conjunctival and corneal epithelium may be found. The dry eye, entropion with trichiasis, and lagophthalmos with exposure may result in corneal complications (Fig 15) that include punctate erosions, pannus, ulcers, opacification, and even perforation. 69 - 71 Recurrences of EM major may but do not commonly involve the conjunctiva.72 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 ocular CPo Further destruction of the eye usually depends on complications resulting from the acute event, such as entropion with trichiasis, lagophthalmos with exposure, and dry eye 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 lead to corneal ulcers and perforations. Foster et ar 4 reported a small subset of Stevens-Johnson syndrome 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 biopsy specimens from these patients suggested an underlying vasculitis or perivasculitis. Recurrent inflammation has been described in the skin and oral mucosa. 57 A study of microbial keratitis in patients with StevensJohnson syndrome showed that most corneal ulcers were caused by gram-positive cocci. I I The use of bandage contact lenses and topical corticosteroids was prevalent in these patients.

Fig 15. Dry eye after resolution of acute attack of erythema multiforrne. Notice mucus in inferior fornix and vascularization of inferior cornea.

HISTOPATHOLOGY

tival vesicles have been reported70,71 but are rarely noted. Conjunctival involvement ranges from a mild catarrhal conjunctivitis which terminates without sequelae to pseu-

A consistent EM skin finding is a mononuclear cell infiltrate in the dermis, predominantly around the upper dermal blood vessels. 75 The perivascular infiltrate contains mainly lymphocytes and histiocytes59 and may be the only

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finding in the macules and papules of EM. The presence of large numbers of neutrophils as early inflammatory cells and a necrotizing vasculitis with neutrophil invasion of blood vessel walls and endothelial destruction are not found in EM.57 Damage to the overlying epidermis is a characteristic finding in EM. The bullae of EM are subepithelial with adjacent lymphocytes, histiocytes, and a few neutrophils or eosinophils. 76 The blister fluid contains polymorphic cellular elements. The epidermis may show intercellular edema, hydropic degeneration of basal cells, and necrosis. Histopathologic findings in mucosal lesions are similar to skin lesions. 77 Important findings include the perivascular mononuclear cell infiltrate and degenerative changes in the overlying epithelium. 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. 7o Pseudomembranes may form from the fibrinous exudate, inflammatory cells which are predominantly neutrophils, and necrotic epithelial cells. In some cases with severe necrotizing reactions, true membranes result. After the acute episode, the conjunctival epithelium from patients with Stevens-Johnson syndrome may show squamous metaplasia with surface keratinization. Conjunctival goblet cell densities are reduced in StevensJohnson syndrome. 78 ,79 However, Stevens-Johnson syndrome may not represent a mucin-deficient condition because substantial amounts of ocular mucous glycoproteins were present in the eyes of these patients. so However, the mucus from these patients was more viscous than normal suggesting that qualitative differences exist. Conjunctival biopsy specimens from Stevens-Johnson syndrome patients with recurrent conjunctival inflammatory episodes showed vascular involvement. 74 In some cases, a classic vasculitis was found with inflammatory cell infiltration into the vessel wall and fibrinoid necrosis of the wall. Other cases showed prominent perivasculitis with lymphocytes, macrophages, and plasma cells surrounding the vessels. Substantial numbers of degranulating mast cells were noted. On the other hand, conjunctival biopsies from patients with the chronic consequences of a single, nonrecurrent episode showed a diffuse, mild mononuclear cell infiltrate in the subepithelial stroma but no vasculitis, perivasculitis, or mast cell degranulation. IMMUNOPATHOLOGY

Circulating immune complexes have been found in the sera of patients with EM. 75 ,77,sl-s3 Additionally, direct immunofluorescent studies of involved skin showed deposition ofC3, IgM, fibrin, and occasionally IgG in the blood vessel walls of the dermis. 75 ,77,sl-s3 The normal unaffected skin from patients with EM does not have immunoglobulin and complement deposition in blood vessel walls. However, injections of histamine can cause them to deposit there, suggesting that the immune complexes of EM

circulate rather than form locally in the tissue. 75 Patients with EM may have immunoglobulin and complement deposition at the dermal-epidermaljunction. s1 ,s2 Results of 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/suppressor cells than helper/inducer cells in the epidermis but the reverse in the dermis. s4 Foster et aC4 reported a vasculitis or perivasculitis with immunoglobulin and complement deposition in vessel walls of conjunctiVal biopsy specimens from a small subset of patients with Stevens-Johnson syndrome and recurrent conjunctival inflammation. Each of their patients had one or more immunoreactants in the vessel wall including IgG, IgA, IgD, IgM, C3, and C4. To date, immunoreactants have not been demonstrated in conjunctival blood vessels from patients with a primary, acute attack of Stevens-Johnson syndrome. This undoubtedly reflects the difficulty and reluctance of ophthalmologists to obtain such specimens. We S5 reported that Stevens-Johnson syndrome with ocular involvement was associated with HLA-Bw44 (the dominant subgroup ofHLA-B12). These results suggested that there was an immunogenetic susceptibility to the development of Stevens-Johnson syndrome with ocular manifestations. This association with HLA-B12 was supported in two other studies of patients with Stevens-J ohnson syndrome and toxic epidermal necrolysis (a severe variant of EM).56,s6 These results suggest that there may be an immunogenetic susceptibility not only to the development of Stevens-Johnson syndrome with ocular involvement but also to all the severe variants of EM. TREATMENT

There is no specific treatment for EM. Obviously, eliminating any suspected etiologic factors is important. Nonessential drugs should be discontinued. Wet dressings may be used to debride crusted skin lesions, and baths may minimize discomfort. 59 Hydration may be necessary to maintain fluid balance in cases 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. 59 If an underlying infection is present, it should be treated with systemic administration of antibiotics. Systemic corticosteroids have been recommended for the general manifestations of EM. 59 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. In fact, several studies have questioned and challenged the efficacy of systemic prednisone in EM. S7-S9 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

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only supportive care. Some patients with Stevens-Johnson syndrome or toxic epidermal necrolysis have been managed in burn centers because of extensive loss of the epidermis and mucosal ulcerations. Patients managed in a burn center without systemic corticosteroids showed an improvement in survival compared with those who received high doses of corticosteroids in the same setting. 58 This report concluded that systemic corticosteroids were contraindicated in burn-center management of toxic epidermal necrolysis and Stevens-Johnson syndrome. 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. 73 Early lysis of symblepharon should be attempted but may not be effective. Conjunctival cultures should be obtained, and appropriate topical antibiotics should be administered for suspected bacterial infections. After the acute inflammation has subsided, patients with Stevens-Johnson syndrome may require artificial tears for dry eye, destruction of aberrant lashes by electrocautery using a Hyfrecator or cryotherapy, soft contact lenses to protect the cornea from drying and trichiasis, and lid scrubs followed by antibiotic ointment for chronic blepharitis. 72 The lacrimal puncta are generally scarred and closed by the disease. If not, they should be closed if the patient has a dry eye. 90 Topical retinoids such as tretinoin (all-trans retinoic acid, a vitamin A analogue) may reverse conjunctival keratinization. 91 ,92 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 fullthickness buccal mucous membrane. 93 In cases with severe symblepharon or ankyloblepharon and keratinization of the ocular surface epithelium, a keratoprosthesis may be attempted. 94

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10. Ralph RA. Conjunctival goblet cell density in normal subjects and in dry eye syndromes. Invest Ophthalmol1975; 14:299-302. 11. Ormerod LD, Fong LP, Foster CS. Comeal infection in mucosal scarring disorders and Sjogren's syndrome. Am J Ophthalmol 1988; 105: 512-8. 12. Nom MS, Kristensen EB. Benign mucous membrane pemphigoid. II. Cytology. Acta Ophthalmol (Copen h) 1974; 52:282-90. 13. Tauber J, Melamed S, Foster CS. Glaucoma in patients with ocular cicatricial pemphigoid. Ophthalmology 1989; 96:33-7. 14. Mondino BJ, Brown SI, Lempert S, Jenkins MS. The acute manifestations of ocular cicatricial pemphigoid: diagnosis and treatment. Ophthalmology 1979; 86:543-55. 15. Mondino BJ, Brown SI. Immunosuppressive therapy in ocular cicatricial pemphigoid. Am J Ophthalmol 1983; 96:453-9. 16. Lass JH, Thoft RA, Dohlman CH. Idoxuridine-induced conjunctival cicatrization. Arch Ophthalmol1983; 101:747-50. 17. Patten JT, Cavanagh HD, Allansmith MR. Induced ocular pseudopemphigoid. Am J Ophthalmol1976; 82:272-6. 18. Hirst LW, Werblin T, Novak M, et al. Drug-induced cicatrizing conjunctivitis simulating ocular pemphigoid. Comea 1982; 1: 121-8. 19. Kristensen EB, Nom MS. Benign mucous membrane pemphigoid. I. Secretion of mucus and tears. Acta Ophthalmol (Copenh) 1974; 52: 266-81. 20. Fiore PM, Jacobs IH, Goldberg DB. Drug-induced pemphigoid: a spectrum of diseases. Arch Ophthalmol1987; 105:1660-3. 21. Leonard IN, Hobday CM, Haffenden GP, et al. Immunofluorescent studies in ocular cicatricial pemphigoid. Br J Dermatol 1988; 118: 209-17. 22. Pouliquen Y, Patey A, Foster CS, et al. Drug-induced cicatricial pemphigoid affecting the conjunctiva. Ophthalmology 1986; 93:775-83. 23. Mondino BJ. Discussion, 782-3, of: Pouliquen Y, Patey A, Foster CS, et al. Drug-induced cicatricial pemphigoid affecting the conjunctiva. Ophthalmology 1986; 93:775-83. 24. Andersen SR, Jensen OA, Kristensen EB, Nom MS. Benign mucous membrane pemphigoid. III. Biopsy. Acta Ophthalmol (Copenh) 1974; 52:455-63. 25. Kinoshita S, Kiorpes TC, Friend J, Thoft RA. Goblet cell density in ocular surface disease: a better indicator than tear mucin. Arch Ophthalmol1983; 101:1284-7. 26. Thoft RA, Friend J, Kinoshita S, et al. Ocular cicatricial pemphigoid associated with hyperproliferation of the conjunctival epithelium. Am J Ophthalmol 1984; 98:37-42. 27. Carroll JM, Kuwabara T. Ocular pemphigus: an electron microscopic study of the conjunctival and comeal epithelium. Arch Ophthalmol 1968; 80:683-95. 28. Galbavy EJ, Foster CS. Ultrastructural characteristics of conjunctiva in cicatricial pemphigoid. Comea 1985; 4:127-36. 29. Foster CS, Shaw CD, Wells PA. Scanning electron microscopy of conjunctival surfaces in patients with ocular cicatricial pemphigoid. Am J Ophthalmol 1986; 102:584-91. 30. Griffith MR, Fukuyama K, Tuffanelli 0, Silverman S Jr. Immunofluorescent studies in mucous membrane pemphigoid. Arch Dermatol1974; 109:195-9. 31. Rogers RS III, Perry HO, Bean SF, Jordan RE. Immunopathology of cicatricial pemphigoid: studies of complement deposition. J Invest DermatoI1977; 68:39-43. 32. Fine J-D. Epidermolysis bullosa: variability of expression of cicatricial pemphigoid, bullous pemphigoid, and epidermolysis bullosa acquisita antigens in Clinically uninvolved skin. J Invest Dermatol 1985; 85: 47-9. 33. Foster CS, Wilson LA, Ekins MB. Immunosuppressive therapy for progressive ocular cicatricial pemphigoid. Ophthalmology 1982; 89:34053.

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60. Shelley WB. Herpes simplex virus as a cause of erythema multiforme. JAMA 1967; 201:153-6. 61. Major PP, Morisset R, Kurstak C, Kurstak E. Isolation of herpes simplex virus type 1 from lesions of eryfhema multiforme. Can Med Assoc J 1978; 118:821-2. 62 . Shelley WB. Bacterial endotoxin (lipopolysaccharide) as a cause of erythema multiforme. JAMA 1980; 243:58-60. 63. Guill MA, Goette OK, Knight CG , et al. Eryfhema multiforme and urticaria: eruptions induced by chemically related ophthalmic anticholinergic agents. Arch Dermatol1979; 115:742-3. 64. Genvert GI, Cohen EJ, Donnenfeld ED, et al. Erythema multiforme after use of topical sulfacetamide. Am J Ophthalmol 1985; 99: 465-8. 65. Ward B, McCulley JP, Segal RJ . Dermatologic reaction in StevensJohnson syndrome after ophthalmic anesthesia with proparacaine hydrochloride. Am J Ophthalmol 1978; 86:133-5. 66. Huff JC. Erythema multiforme. Dermatol Clinics 1985; 3:141-52. 67. B0e J, Dalgaard JB, Scott D. Mucocutaneous-ocular syndrome with intestinal involvement: a clinical and pathological study of four fatal cases. Am J Med 1958; 25:857-67. 68. Chanda JJ. Erythema multiforme. Perspect Ophthalmol 1979; 3: 183-8 69. Dohlman CH, Doughman OJ. The Stevens-Johnson syndrome. In: Symposium on the Cornea. Transactions of the New Orleans Academy of Ophthalmology. St. Louis: CV Mosby, 1972; 236-52. 70. Howard GM. The Stevens-Johnson syndrome: ocular prognosis and treatment. Am J Ophthalmol 1963; 55:893-900. 71. Patz A. Ocular involvement in erythema multiforme. Arch Ophthalmol 1950; 43:244-56. 72. Mondino BJ. Cicatricial pemphigoid and erythema multiforme. Int Ophthalmol Clin 1983; 23:63-79. 73. Arstikaitis MJ. Ocular aftermath of Stevens-Johnson syndrome. Arch Ophthalmol1973; 90:376-9. 74. Foster CS, Fong LP, Azar 0 , Kenyon KR. Episodic conjunctival inflammation after Stevens-Johnson syndrome. Ophthalmology 1988; 95:453-62. 75. Wuepper KD, Watson PA, Kazmierowski JA. Immune complexes in erythema multiforme and the Stevens-Johnson syndrome. J Invest Dermatol1980; 74:368-71. 76. Korting GW, Denk R. Differential Diagnosis in Dermatology. Philadelphia: WB Saunders, 1976; 421-2. 77. Buchner A, Lozada F, Silverman S Jr. Histopathologic spectrum of oral erythema multiforme. Oral Surg Oral Med Oral Pathol 1980; 49: 221-8. 78. Nelson JD, Wright JC. Conjunctival goblet cell densities in ocular surface disease. Arch Ophthalmol1984; 102:1049-51 . 79. Ohji M, Ohmi G, Kiritoshi A, Kinoshita S. Goblet cell density in thermal and chemical injuries. Arch Ophthalmol1987; 105:1686-8. 80. Wells PA, Ashur ML, Foster CS. SDS-gradient polyacrylamide gel electrophoresis of individual ocular mucus samples from patients with normal and diseased conjunctiva. Curr Eye Res 1986; 5:823-31. 81. Bushkell LL, Mackel SE, Jordon RE. Erythema multiforme: direct immunofluorescence studies and detection of circulating immune complexes. J Invest Dermatol 1980; 74:372-4. 82. Huff JC, Weston WL, Carr RI. Mixed cryoglobulinemia, 1251C1 q binding and skin immunofluorescence in erythema multiforme. J Invest Dermato11980; 74:375-8. 83. Imamura S, Yanase K, Taniguchi S, et al. Erythema multiforme: demonstration of immune complexes in the sera and skin lesions. Br J Dermatol 1980; 102:161-6. 84. Margolis RJ , Tonnesen MG, Harrist TJ, et al. Lymphocyte subsets and Langerhans celis/indeterminate cells in erythema multiforme. J Invest Dermatol 1983; 81 :403-6. 85. Mondino BJ, Brown SI, Biglan AW. HLA antigens in Stevens-Johnson

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syndrome with ocular involvement. Arch Ophthalmol 1982; 100: 1453-4. Roujeau J-C, Bracq C, Huyn NT, et al. HLA phenotypes and bullous cutaneous reactions to drugs. Tissue Antigens 1986; 28:251-4. Rasmussen JE. Erythema multiforme in children: response to treatment with systemic corticosteroids. Br J Dermatol1976; 95:181-6. Ginsburg CM. Stevens-Johnson syndrome in children. Pediatr Infect Dis 1982; 1:155-8. Nethercott JR, Choi BCK. Erythema multiforme (Stevens-Johnson syndrome)-chart review of 123 hospitalized patients. Dermatologica 1985; 171:383-96. Tuberville AW, Frederick WR, Wood TO. Punctal occlusion in tear deficiency syndromes. Ophthalmology 1982; 89: 1170-2.

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91. Wright P. Topical retinoic acid therapy for disorders of the outer eye. Trans Ophthalmol Soc UK 1985; 104:869-74. 92. Soong HK, Martin NF, Wagoner MD, et al. Topical retinoid therapy for squamous metaplasia of various ocular surface disorders: a mUlticenter, placebo-controlled double-masked study. Ophthalmology 1988; 95:1442-6. 93. McCord CD, Chen WP. Tarsal polishing and mucous membrane grafting for cicatricial entropion, trichiasis and epidermalization. Ophthalmic Surg 1983; 14:1021-5. -_94. Kozarsky AM, Knight SH, Waring GO III. Clinical results with a ceramic keratoprosthesis placed through the eyelid. Ophthalmology 1987; 94: 904-11.