Immunol Allergy Clin N Am

28 (2008) 119–136

Ocular Manifestations of Blistering

Diseases

Samih Elchahal, MDa, Eric R. Kavosh, MDb,

David S. Chu, MDa,*

aInstitute of Ophthalmology and Visual Science, UMDNJ–New Jersey Medical School, Doctors O ce Center, 90 Bergen Street, Suite 1600, Newark, NJ 07103, USA bDepartment of Medicine, UMDNJ–New Jersey Medical School, University Hospital, 150 Bergen Street, UH-1248, Newark, NJ 07103, USA

Autoimmune blistering diseases with ocular-surface manifestations belong to a group of systemic entities characterized by autoantibodies against the epithelial basement membrane zone (BMZ) of conjunctiva. The specific tissue components targeted by these autoantibodies and the characteristic patterns of mucocutaneous involvement di erentiate these diseases. The autoimmune activity in mucous membrane pemphigoid (MMP), linear immunoglobulin A disease (LAD), and epidermolysis bullosa acquisita (EBA) occurs at a subepithelial location, whereas ocular pemphigus vulgaris (OPV) exhibits intraepithelial activity.

Mucous membrane pemphigoid

Clinical features

MMP is an idiopathic systemic disorder that manifests on the eyes primarily through scarring of the conjunctiva in a progressive, chronic nature. This condition, characterized by antibody tissue–specific antigen-mediated (type-2 hypersensitivity) reaction, is rare, with estimates in the ophthalmic population ranging from 1 in 8000 to 1 in 46,000 [1,2]. Typical presentation involves a patient in the fifth or sixth decade of life who has bilateral ocular and mucocutaneous lesions, although the disease can present at other times.

* Corresponding author.

E-mail address: chuda@umdnj.edu (D.S. Chu).

0889-8561/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2007.12.002 immunology.theclinics.com

No racial or geographic predispositions have been found; however, women are estimated as being 1.5 to 5 times more frequently a ected than men [3]. Several human leukocyte antigens (HLAs) including HLA-DR2, HLADR4, and HLA-DQw7 (DQB1*0301) have been associated with creating increased susceptibility to the disease [4–6].

The diagnosis of MMP should be considered in patients who present with blistering, erosive, scarring conjunctivitis, with or without other associated mucocutaneous involvement. Although these lesions may be found on initial examination, the disease typically presents insidiously, with nonspecific complaints of bilateral red eyes, itching, burning, foreign-body sensation, or tearingdall of which are common symptoms and findings of chronic conjunctivitis. The disease is usually bilateral; however, asymmetrical presentation is not uncommon. Slit-lamp examination may reveal papillary conjunctivitis associated with di use conjunctival hyperemia, followed by formation of subconjunctival bullae, which may rupture, leading to ulceration and pseudomembrane formation [1,2]. Fibrosis and retraction of subepithelial tissue leads to fornix foreshortening and flattening of the plica semilunaris (medial fold of redundant conjunctival that allows for unrestricted eye movement) and caruncle. Patients who have advanced disease exhibit symblepharon (conjunctival adhesions) formationda sign typically seen inferiorly firstdor ankyloblepharon (lid adhesions) involving the lateral canthi [7]. Entropion (eyelid inversion), lagophthalmos (incomplete eyelid closure), and lash metaplasia including distichiasis (eyelash growth arising from meibomian glands) and trichiasis (misdirected eyelash growth, usually toward the globe) may follow (Figs. 1 and 2) [1]. Patients commonly complain of dry eye symptoms, the etiology of which involves all three components of the tear film (mucin, aqueous, and lipid) because scarring destroys conjunctival goblet cells and obstructs lacrimal gland ductules and meibomian gland orifices. Eyelid involvement thus contributes to tear film dysfunction to create the keratopathy observed in MMP. In addition,

Fig. 1. A 70-year-old white woman who has MMP exhibits madarosis, entropion, and ocular surface inflammation.

Fig. 2. One-year later, the patient in Fig. 1 exhibits active disease with progression of ocular surface disease.

depletion of limbal stem cells (perilimbal basal epithelial cells that replete the corneal epithelial cell layers through continuous proliferation) plays a recognized role in the development of vision-threatening keratopathy, presenting initially as small epithelial defects and ultimately as large corneal ulcerations with resultant total corneal surface keratinization and vascularization [8,9]. If bilateral, the associated corneal opacification may lead to blindness.

The di erential diagnosis of MMP includes other autoimmune bullous diseases, including LAD, EBA, and OPV, chronic atopic keratoconjunctivitis, rosacea, scleroderma, paraneoplastic pemphigus, and scarring secondary to ocular trauma or irradiation. It is important that the clinician also consider drug-induced MMP, which occurs as a side e ect of certain topically administered medications including several antiglaucoma medications such as pilocarpine hydrochloride, timolol maleate (Timoptic), epinephrine, echothiophate iodide, and medication preservatives such as benzalkonium chloride [10–12]. Drug-induced MMP can present similarly but has several di erentiating characteristics including the lack of cutaneous lesions in the topical drug-induced form, and disease that does not progress after the causal medication has been discontinued [13].

Diagnostic studies

Histologic examination of the conjunctiva in MMP shows epithelial metaplasia as conjunctival squamous keratinization, parakeratosis, and scarcity of goblet cells. Subepithelial blister formation is constituted by a mixed dermal infiltrate of neutrophils, monocytes, macrophages, lymphocytes, and eosinophils [14,15]. Acute disease exacerbation is marked by neutrophilic and eosinophilic stromal infiltration, excessive mucous presence in the inferior fornix, and increased fibroblast and mast cell activity and proliferation [16,17]. Disruption of the BMZ includes redundancy and variation of basal laminar thickness, increased desmosome concentration, and

disorganized collagen fibrils. The ensuing cicatrization yields an end result of conjunctival fibrosis [16,17].

Diagnosis of an autoimmune bullous disease is confirmed through immunofluorescent and immunoperoxidase laboratory techniques on conjunctival tissue biopsy samples. Perilesional skin biopsies are also diagnostically helpful because direct immunofluorescence testing exhibits characteristic linear immunoglobulin and complement (C3) deposition along conjunctival, buccal, or cutaneous tissue basement membranes in most cases [18–20]. A higher frequency of association is found in mucosal lesions compared with cutaneous lesions and with the immunoglobulin (Ig)G class of immunoglobulins over IgA and IgM, although sole IgA presence has also been documented [21,22]. Purely ocular MMP exhibits immune deposition in the upper lamina lucida, whereas mucocutaneous involvement is characterized by deposition in the lower lamina lucida and lamina densa [23–26]. Circulating autoantibodies used in indirect immunoelectron microscopy demonstrate regularly clustered lower lamina lucida and lamina densa immunostaining [27]. In addition, the sensitivity of detecting immune deposits increases from between 50% and 52% with immunofluorescence alone to 83% when labeled immunoperoxidase is used [21]. Various autoantibody targets have been described, including the beta 4 integrin subunit and laminin-5, suggesting that the clinical diagnosis of MMP encompasses various pathophysiologic disease entities [28–32]. Support for the antigenic role played by the beta 4 integrin subunit as a feature of MMP has been shown, with demonstrated presence of autoantibodies whose circulating levels may correspond to clinical disease improvement with intravenous immunoglobulin (IVIG) treatment [33,34].

Disease course and treatment

The course of MMP is variable among patients. Some experience limited disease and mild ocular scarring that remits following treatment, others follow an intermittent course, and approximately one third of patients experience chronic, progressive disease with only partial response to treatment, necessitating lifelong follow-up [35–37]. A multimodal approach to treatment is preferred to optimize patient response and minimize permanent disease sequelae.

Topical corticosteroids such as triamcinolone acetonide, fluocinonide, or clobetasol propionate may be used for limited acute and early-stage cases that present with ocular or oral lesions, although topical treatment alone is not adequately e ective in stopping MMP progression [38]. Posterior lid margin conjunctival keratinization may respond to topical retinoid treatment [32]. When progressive conjunctival cicatrization is present, subconjunctival mitomycin C or steroid injection may be e cacious as a temporizing measure to slow disease progression [39].

In most cases, systemic treatment is required for acute exacerbations and chronic disease. In mild or moderate cases of MMP, first-line systemic treatment involves long-term use of immunoregulatory chemotherapy such as

dapsone, unless the patient has a history of glucose-6-phosphate dehydrogenase deficiency or drug intolerance [35,36]. In contraindicated cases or in those who do not have adequate response to dapsone, cytotoxic agents such as mycophenolate mofetil (Cellcept), sulfasalazine, methotrexate, or azathioprine (Imuran) are used for suppression of conjunctival inflammatory activity and prevention of progressive cicatrization [35,36,40–43]. Persistent inflammation should prompt transition to treatment with cyclophosphamide (Cytoxan) [35,36]. In severe or extensive cases, cyclophosphamide treatment may be used along with a rapid systemic prednisone taper [35,36]. Monotherapy with systemic steroids should be avoided because they are not as e ective as other immunosuppressive therapies and are associated with significant systemic toxicity when used at required doses [35,36]. In addition, disease relapse with tapering of steroid treatment supports their use as adjunct rather than sole treatment agents in patients refractory to immunosuppressive drug therapy. Immunosuppressive treatment should be continued for at least 1 year beyond the resolution of the episode of active inflammation, and patients should be routinely monitored for known side e ects while on systemic immunosuppressive medications [35,36]. Additional immunosuppressive agents with exhibited e cacy include infliximab, daclizumab, and rituxamab [44,45]. Although IVIG therapy can be used in refractory cases or treatment-intolerant patients, it is also playing an increasing role as a primary systemic treatment of MMP. Increasing evidence shows that IVIG therapy can result in a decrease in circulating autoantibody against B4 through the treatment course [37,44–50]. IVIG is usually administered in dosages of approximately 2 to 3 g/kg per cycle, with each cycle lasting 3 to 5 consecutive days each month. Clinical improvement and disease remission has been shown to continue with increased time between cycles and a gradual tapering of IVIG [33]. On average, patients who had successful halting of disease progression had received an average of 32 cycles over 35 months [51]. The e cacy of IVIG at halting disease progression in patients unresponsive to traditional immunosuppressive treatments and its ability to avoid the limiting side e ects of other agents have encouraged its use as a primary treatment for refractory disease.

To minimize disease reactivation or progression, surgical techniques should be preempted by medical control of inflammation and supplanted with perioperative systemic corticosteroids in patients because reconstructive surgery will be successful only with proper control of disease activity [1,52]. Nonpharmacologic options include therapeutic interventions to protect and maintain the ocular surface and address any eyelid or conjunctival cicatrization present [1,2,52,53]. In cases of advanced corneal keratinization or ulceration, one may perform amniotic membrane grafting, penetrating keratoplasty (PKP), or limbal stem cell transplantation (LSCT) to restore ocular surface integrity and to regain useful vision to a functionally blind eye, although surrounding host tissue disease can limit long-term success of these techniques [54,55]. As limbal stem cell deficiency is thought to be present in