Pemphigus (from the Greek meaning puff or blister) comprises a group of autoimmune vesiculobullous eruptions of the skin and mucous membranes that are seen primarily in middle-aged people, with both sexes being affected equally.³ Involvement of mucosae may occur as the initial manifestation in as many as 25% of cases, and it occurs at some point during the course of disease in 95% of cases.⁴ Pemphigus vulgaris and its variant, pemphigus vegetans, constitute a more acute form of the disease in which the earliest lesions appear in the oral mucosa and are then followed by a bullous eruption of the skin over the trunk and extremities within 4 to 12 months (Fig. 1). This form of pemphigus was almost uniformly fatal prior to the use of systemic corticosteroid therapy. The mortality rate was reduced to approximately 40% by the use of steroids and has been further reduced to 5% by the addition of immunosuppressive chemotherapeutic regimens for the most difficult cases. Pemphigus foliaceus and its variant, pemphigus erythematosus, follow a more chronic but benign course. Mucosal lesions are unusual in this form, which is primarily an exfoliative dermatitis.³

The characteristic histologic feature of pemphigus is acantholysis or loss of interepidermal cell bridges. This leads to bulla formation within the epidermis. The epidermis may be readily dislodged by lateral sliding finger pressure, the Nikolsky sign, a clinical feature shared with toxic epidermal necrolysis and epidermolysis bullosa.⁴

In pemphigus vulgaris, the bullae form above the basal cell layer; in the foliaceus and erythematosus forms of pemphigus, such changes occur just below the stratum corneum. Marked acanthosis, with formation of intraepidermal eosinophilic abscesses, is present in pemphigus vegetans. These changes are found in biopsy specimens of both skin and mucous membranes.⁵

Pemphigus vulgaris is by far the most common form of pemphigus, occurring predominantly in people of Jewish or Mediterranean origin, but it is reported in all races and ethnic groups, with no sex predilection.

Antibodies to intercellular components of epidermis have been demonstrated in the sera of patients with pemphigus.⁶ Tissue-fixed immunoglobulins are present in the interepidermal cell spaces, and a large percentage of these patients have circulating antibodies that react with an intercellular antigen present in many stratified squamous epithelia.⁵ These intercellular substance-reactive antibodies are typically IgG, are complement fixing, are pathogenic to tissue culture preparations of epidermal cells,⁷ and produce blistering skin lesions, identical to pemphigus vulgaris lesions, in mice injected intraperitoneally with the antibodies.⁸ The relevant antigen in the intercellular substance is a cadherin.⁹ The disease develops in the genetically susceptible individual, probably after he or she is exposed at some point in life to an environmental trigger. The disease is especially prevalent in Ashkenazi Jews, and 92% of these patients express the major histocompatibility complex class II alleles HLA-DR4, DQw8.¹⁰ It is presumed that because the disease is attributable to the presence of an antibody to an intraepidermal intercellular cement substance, the class II susceptibility gene controls the production of the antibody as a dominantly expressed immune response gene.

The intercellular cement substance against which the autoantibody is directed, pemphigus vulgaris antigen (PVA), is a novel cadherin, limited in tissue distribution to stratified squamous epithelia, with significant homology with the other known cell adhesion molecules within the cadherin family (E-cadherin, N-cadherin, P-cadherin, L-CAM, and DGI). PVA like DGI binds to plakoglobin, and with DGI forms a subfamily of cadherins; the other cadherins bind to catenions and to CAP102. DGI is the target antigen in pemphigus foliaceus and is present in all desmosome-containing tissues.⁹

Ocular complications in pemphigus are rare,⁵ but ocular manifestations of pemphigus on lids, conjunctiva, cornea, lens, and iris have been reported. Conjunctival bullae are infrequently seen in pemphigus vulgaris. More typically, a catarrhal or purulent conjunctivitis develops.³ The ocular features are similar in pemphigus foliaceus and are usually confined to the palpebral conjunctiva, with erythema, edema, and purulent discharge.^5,12 Pemphigus foliaceus may also produce entropion and trichiasis of both lids with resultant corneal damage. Lens opacities have been described in 5% of patients with a form of pemphigus foliaceus that is endemic to Brazil. Some of these patients also exhibit red, nodular iris lesions, the exact nature of which is not known.¹²

The conjunctival involvement in pemphigus may lead to symblepharon as a result of the formation and rupture of small vesicles. This does not, however, lead to progressive scarring and blindness, as is so often the case in cicatricial pemphigoid (Fig. 4).¹³

Acute pemphigus vulgaris requires high-dose systemic corticosteroid therapy (100–200 mg prednisone/day), with gradual reduction of steroid dose with cessation of new blister formation.¹⁴ Infection is the leading cause of death in patients with pemphigus vulgaris; great vigilance for and vigorous treatment of any infection is obviously indicated. Immunosuppressive chemotherapy with methotrexate (15–25 mg once a week), azathioprine (2–3 mg/kg/day), or cyclophosphamide (2–3 mg/kg/day), used for long-term control of the disease, should be started once the risk of infection has diminished, with the usual caveats vis-a-vis monitoring for and managing drug toxicity.^15,16

Cicatricial pemphigoid is probably not quite as rare as published incidence figures indicate. Bittelheim²⁶ estimated 1 in 15,000 ophthalmic patients; Hardy and Lamb²⁷ and others^28,29 estimated an incidence of 1 in 20,000 patients. Smith and colleagues³⁰ estimated 1 in 46,000. Bedell³¹ estimated 1 in 8000, and Lever and Talbott³² stated frankly that it is impossible to make an accurate estimate from available data; they guess that the incidence of CP is somewhere between 1 in 12,000 and 1 in 60,000 ophthalmic patients. But these figures estimate the incidence of relatively advanced CP. Diagnosis of this disorder in its early stages is difficult,²⁸ and most cases are not recognized as CP until they reach what we could categorize as stage III disease. There are, therefore, patients with stage I and stage II CP uncounted in the epidemiologic estimates.

Data on the average age of CP patients are also somewhat distorted by subtleties of the diagnostic signs. CP is said in many publications to be a disease of older people, with the average age given as 60)³³ or 70)²⁸ years. Although reports of CP in children may in fact represent cases of localized erythema multiforme, we certainly now recognize that CP can begin at least as early as the third decade of life.

Most reports describe a slight but clear female predilection. Thus, Klauder and Cowan³⁴ reported 8 females and 3 males, Lever³⁵ reported 3 females for every male, and Hardy and colleagues³⁶ reported 52 females and 29 males with CP; 62 of these patients had ocular involvement, but Hardy and associates³⁶ did not report the sex distribution for this subset of patients. No racial or geographic predilection is reported.³⁶

Ocular cicatricial pemphigoid (OCP) is clearly an autoimmune disease with a genetic predisposition requirement and probably a “second-hit” environmental requirement to trigger the onset of the disease. We first reported an increase in the frequency of the HLA-DR4 and HLA-DQw3 alleles in OCP patients.³⁷ Subsequently, in patient and family studies employing restriction fragment length polymorphism analysis of the DQw3 haplotypes, it was determined that the gene that provides enhanced susceptibility to OCP development is the HLA-DQw7 gene.³⁸

The second-hit environmental trigger that stimulates the genetically susceptible individual to develop OCP may be microbial (we suspect that this is so for idiopathic OCP) or may be chemical, as in the case of so-called drug-induced or pseudo-OCP, which develops in some individuals exposed to practolol³⁹ or to a limited variety of ocular medications.^40,41,42,43 We know that patients with pseudo-OCP carry the same susceptibility gene (HLA-DQw7),⁴⁴ but we further know that the autoantigens in these two forms of OCP are different. We have identified a 205-kd protein molecule in the basement membrane zone of conjunctiva and epidermis as the relevant target antigen in idiopathic OCP,⁴⁵ and we have found that sera from patients with pseudo-OCP bind to 97- and 290-kd proteins in conjunctiva and epidermis lysates, and to 45-, 150-, 290-, and 400-kd proteins in dermal lysates.⁴⁶ None of these autoantigen protein targets is absorbed from the tissue lysates by sera from patients with bullous pemphigoid, pemphigus vulgaris, or OCP, indicating that the autoantigens in OCP, pseudo-OCP, and bullous pemphigoid are distinct from each other.

The autoantibodies that develop in patients with OCP²² can be detected in all OCP patients when the disease is active, and the autoantibodies are probably pathogenic, just as the autoantibodies in patients with pemphigus are.^7,8 The binding of the autoantibody to the autoantigen at the epithelial basement membrane then sets in motion a complex drama in which an impressive cast of characters participates.²⁰ CD4 (helper) T lymphocytes far outnumber CD8 (suppressor) T cells in the inflammatory cell population that develops in the substantia propria of the conjunctiva; plasma cells, histiocytes, and mast cells are present in very large numbers, and a panoply of cytokines is elaborated from these cells, the effects of which are only now being dissected by molecular biologic techniques in our laboratory. However, the result of this complex drama is corneal epithelial damage from inflammatory cytokines and from the xerosis, meibomian gland dysfunction, and trichitic trauma developing as a consequence of cytokine-induced conjunctival fibroblast proliferation and activation, with resultant subepithelial fibrosis.

Clinically, the ocular disease in cicatricial pemphigoid (OCP) may present unilaterally in the form of a chronic, recurrent catarrhal conjunctivitis, but it eventually becomes bilateral. Subepithelial fibrosis is characteristic of stage 1 of OCP (Fig. 7). Stage 2 shows fornix foreshortening (Fig. 8), and symblepharon formation is the hallmark of stage 3 (Fig. 9). Stage 4, end-stage disease, is characterized by ankyloblepharon and surface keratinization (Fig. 10). Obstruction of the lacrimal ductules and meibomian gland ducts eventually produces an unstable tear film and progressive sicca syndrome, but it is to be emphasized that OCP is not a dry-eye syndrome until late in the disease course.²⁰ Trichiasis and entropion occur because of the subepithelial fibrosis, with eventual keratopathy, corneal neovascularization, and corneal ulceration and scarring.²⁰

In a series reported from the Mayo Clinic, 21 of 81 patients with cicatricial pemphigoid were blind at the time of the report; 17 of these patients were blind in both eyes. Sixty-two of the 81 patients had ocular involvement; approximately 88% of the 62 patients had the ocular disease bilaterally.¹⁸

Medical treatment of the ocular complications of cicatricial pemphigoid was once difficult, protracted, and not very effective. Herron reported on the management of a case with ocular, skin, and mucosal involvement of the pharynx and larynx. Oral triamcinolone was used, along with injections of the drug into the areas of symblepharon. The skin and mucosal lesions responded in 10 weeks, but the ocular disease did not.⁴⁷

BP typically occurs in individuals of either sex between the ages of 50 and 80, without racial or geographic predilection. Its true prevalence and incidence are unknown.

A genetic predisposition to this disease, HLA-DQw7 accompanied by some (as yet unknown) environmental trigger, results in IgG autoantibodies that recognize and attach to 180-kd and 230- to 240-kd proteins associated with the hemidesmosomes and the lamina lucida of the epidermal basement membrane zone.^52,53 The 230-kd autoantigen, or BPAG1, is a glycoprotein encoded on chromosome 6p,⁵² whereas the 180-kd autoantigen, or BPAG2, is a novel collagen encoded by a gene on the long arm of chromosome 10, at locus 10q24.3.⁵³ These proteins or autoantigens are distinct from those recognized by the autoantibodies of cicatricial pemphigoid, pemphigus vulgaris, dermatitis herpetiformis, and epidermolysis bullosa.

The BP autoantibodies are complement fixing, and they are pathogenic. Fixation of the autoantibodies to the BP antigens, followed by complement fixation, results in complement split-product-mediated attraction of neutrophils and eosinophils, with release of their cytokines and production of tissue damage and blister formation.⁵⁴ Mast cells also play a role in lesion development,⁵⁵ and itch is a common symptom during acute phases of the disease. The disease is chronic, remitting, and recurrent when untreated, lasting from months to years, with little or no tendency for the healing skin lesions to scar. Death, however, may occur as a result of sepsis.

Ocular manifestations of BP are not as impressive (Fig. 12) as those of cicatricial pemphigoid affecting the conjunctiva; therefore, they may go undetected. A study of 36 patients with BP in England disclosed that some had fine striae of tarsal subepithelial fibrosis, and one had frank symblepharon formation.⁵⁶ Seventy-three percent of those who had conjunctival biopsy performed showed immunoreactant deposition at the BMZ.⁵⁷

The treatment of BP is essentially the same as that for pemphigus vulgaris, with systemic prednisone (50–100 mg/day) acutely and immunosuppressants, such as azathioprine, combined with alternate-day prednisone for long-term care.⁵⁸ Sulfones may also be of some value in selected patients.⁵⁹

DH affects both sexes of any age, with peak incidence at ages 10 to 40 years. It is unclear how common this disease is.

Just as in cases of systemic lupus erythematosus, myasthenia gravis, celiac disease, and juvenile onset diabetes mellitus, dermatitis herpetiformis is associated with the HLA-B8, HLA-DR3, DQw2 phenotype. Such genetically predisposed individuals tend to make IgA autoantibodies directed against proteins in the dermal papillary tips, specifically in anchoring fibrils below the basal lamina.⁶¹ They may be provoked to make such antibodies through gastrointestinal contact with gluten, a protein in rye, barley, oats, and wheat.⁶² IgA and/or IgA-containing immune complexes deposit in the apices of the dermal papillae and activate complement via the alternative pathway, thereby attracting neutrophils, with resultant microabscess formation and the clinical appearance of the papulovesicular rash characteristic of DH.⁶³

Ocular manifestations of dermatitis herpetiformis are rare. Keratoconjunctivitis sicca, iritis, choroiditis, and papillitis have occurred in individual patients, but the causal relationship between dermatitis herpetiformis and the ocular problem is debatable.

SJS, although it has no racial or geographic predilection, occurs in young males more commonly than in other groups of individuals, with winter and spring seasonal peaks.⁶⁷ The disease is relatively common, accounting for up to 1% of dermatologic outpatient visits.^68,69

Histologically, the skin lesions exhibit diffuse inflammatory infiltration and edema of the dermis. When bullae are present, they are subepidermal in location and without acantholysis.⁶⁶

The exact pathogenetic mechanism of this disease is unknown; autoimmune, infective, and allergic factors have all been considered possible causes. Most evidence now favors a hypersensitivity to microbes and drugs.⁷⁰ Erythema multiforme has been associated with various bacterial (especially Mycoplasma pneumoniae), viral (especially herpes simplex virus), mycotic, and protozoan infections, with drugs and vaccines, with allergic contactants, with collagen disorders, and with internal malignancies. Some of the incriminated precipitating drugs include sulfonamides, tetracyclines, penicillin, bromides, iodides, salicylates, phenytoin sodium, barbiturates, phenylbutazone and other nonsteroidal antiinflammatory drugs, cortisone, and vaccines against polio, smallpox, influenza, diphtheria, and tetanus. The development of or exacerbation of Stevens-Johnson syndrome has been reported after ophthalmic application of proparacaine,⁷¹ sulfonamide,⁷² tropicamide,⁷³ and scopolamine.⁷³

Herpes simplex virus (HSV) is a vastly underappreciated cause of EM,⁷⁴ with 15% to 63% of cases associated with this virus.^75,76 Recurrent EM is especially associated with recurrent HSV infection,⁷⁷ and herpes simplex virus has been isolated from the skin lesions of erythema multiforme.⁷⁸

The results of our research,⁷⁹ as well as that of others,^{80,81,82,83,84,85,86,87} suggest that episodic showers of circulating immune complexes may result in immune complex deposition in previously damaged, predisposed vessels, with resultant immune complex vasculitis/perivasculitis with lymphocyte and neutrophil participation in the vessel damage. Leakage of plasma and cells may progress to subepidermal blister formation and to necrosis of the epidermis over the blister.⁶⁶

Ocular involvement is common in Stevens-Johnson syndrome, occurring in more than half of patients with this disease.⁷⁰ The acute ocular manifestations vary from mild mucopurulent conjunctivitis to severe, pseudomembranous conjunctivitis leading to symblepharon, lid scarring, keratoconjunctivitis sicca, corneal ulceration, corneal scarring, and neovascularization. The chronic consequences of SJS depend on the degree of subepithelial fibrosis and tarsal conjunctival keratinization that occurs as a result of the acute exanthem. The former (fibrosis) results in variable degrees of meibomian duct and lacrimal ductule obstruction (with resultant deficient or unstable tear film problems), trichiasis, distichiasis (with resultant chronic abrasive trauma to the cornea), and cicatricial entropion; tarsal conjunctival keratinization results in a chronic sandpapering trauma effect on the cornea with each blink. The combined effects of these external aggravants produce chronic keratopathy, with eventual corneal scarring, neovascularization, or ulceration (Fig. 15).

One other chronic, rare ocular manifestation of SJS may develop: recurrent, immunologically mediated conjunctivitis. Just as such recurrent episodes may occur in skin⁸⁷ and in oral mucosa,⁸⁸ so too may they occur in conjunctiva.⁷⁹ The diagnosis of this phenomenon is not easy and depends on eradication of all external aggravants, eliminating these as confounding variables, and then demonstration, by immunohistochemical techniques employed on a biopsy specimen from the inflamed conjunctiva, of a lymphocytic microangiopathy with IgA deposition in the vessels. Herpes simplex virus is one inciting agent for recurrent SJS, and this possibility should be carefully investigated.

Therapy of the acute phase of the ocular disease includes use of topical steroids as well as topical antibiotics applied frequently to combat superinfection, especially that from Staphylococcus aureus and (if the patient is hospitalized in a burn unit) Pseudomonas species. Lubricants should be generously employed, especially if lid involvement has resulted in even mild lagophthalmos. If anterior uveitis is present, mydriatic therapy is appropriate. Howard has pointed out that the pseudomembranes should not be stripped, because doing so leads to bleeding and increased scarring.⁸⁹ Lid-globe adhesions should be lysed twice daily to maintain the fornices. I use my scleral depressor for this purpose after cleaning it with 70% isopropyl alcohol, having found no advantage to use of a glass rod. In an effort to prevent corneal scarring, Arstikaitis has advocated early tarsorrhaphy before deep stromal vessels invade the cornea.⁹⁰ This is appropriate in instances of lagophthalmos and persistence of corneal epithelial defects.

The chronic phase of ocular involvement in Stevens-Johnson syndrome necessitates caring for the consequences of the acute exanthem: punctal occlusion for sicca syndrome, electro- or cryoepilation for trichiasis, soft or scleral contact lens therapy for chronic keratopathy arising from residual trichiasis and from tarsal conjunctival keratinization, mucous membrane grafting, and corneal surgery for preservation of globe integrity and, in rare instances, for attempted visual rehabilitation.⁹¹

Recurrent SJS may respond to chronic systemic acyclovir therapy if herpes simplex virus is the agent provoking the attacks. Some cases of recurrent SJS not associated with herpes have responded to long-term systemic immunosuppressive chemotherapy.⁷⁹

TEN has no ethnic or geographic predilections, and it can affect patients of any age. The adult type of disease is more commonly associated with drug ingestion and affects all ages, although females are affected one and a half times more frequently than males.

The disease may affect all age groups, but when seen in infants and children under 10 years of age, it is usually associated with staphylococcal infection and is called Ritter’s disease (see Fig. 16). The most commonly involved organisms are phage group 2 staphylococci.⁹² The drugs often associated with this disease are penicillin, phenytoin, sulfonamides, phenolphthalein, and phenylbutazone. A case has been described in a patient on allopurinol therapy.⁹⁵ The mortality rate in this group may be as high as 40%.⁹³

Ocular involvement in TEN is limited to the conjunctiva; it is usually less severe than is the ocular involvement in Stevens-Johnson syndrome. A mucopurulent conjunctivitis is the most common early manifestation, and, unlike the involvement in erythema multiforme, this does not usually result in ulceration, scarring, symblepharon, or corneal pannus formation.⁷⁰ It may do so, however, with corneal erosions and all the other consequences described for SJS.^93,94

The acute and chronic therapy for the ocular involvement in TEN is identical to that described above for SJS.