16

Immunologic Diseases of the Eye

Munir M. Iqbal, MD, and William G. Hodge, MD, MPH, PhD, FRCSC

Ocular manifestations are a common feature of immunologic diseases even though, paradoxically, the eye is also a site of immune privilege. The propensity for immunologic disease to affect the eye derives from a number of factors, including the highly vascular nature of the uvea, the tendency for immune complexes to be deposited in various ocular tissues, and the exposure of the mucous membrane of the conjunctiva to environmental allergens.

Immunologic diseases of the eye can be grossly divided into two major categories: antibody-mediated and cell-mediated diseases. As is the case in other organs, there is ample opportunity for the interaction of these two systems in the eye.

ANTIBODY-DEPENDENT & ANTIBODYMEDIATED DISEASES

Before it can be concluded that a disease of the eye is antibody-dependent, the following criteria must be satisfied:

1.There must be evidence of specific antibody in the patient’s serum or plasma cells.

2.The antigen must be identified and, if feasible, characterized.

3.The same antigen must be shown to produce an immunologic response in the eye of an experimental animal, and the pathologic changes produced in the experimental animal must be similar to those observed in the human disease.

4.It must be possible to produce similar lesions in animals passively sensitized with serum from an affected animal upon challenge with the specific

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antigen.

Unless all of the above criteria are satisfied, the disease may be thought of as possibly antibody-dependent.

In such circumstances, the disease can be regarded as antibody-mediated if only one of the following criteria is met:

1.If antibody to an antigen is present in higher quantities in the ocular fluids than in the serum (after adjustments have been made for the total amounts of immunoglobulins in each fluid).

2.If abnormal accumulations of plasma cells are present in the ocular lesion.

3.If abnormal accumulations of immunoglobulins are present at the site of the disease.

4.If complement is fixed by immunoglobulins at the site of the disease.

5.If an accumulation of eosinophils is present at the site of the disease.

6.If the ocular disease is associated with an inflammatory disease elsewhere in the body for which antibody dependency has been proved or strongly suggested.

ALLERGIC EYE DISEASE (SEE ALSO CHAPTER 5)

Allergic conjunctivitis (AC) is characterized by conjunctival edema, along with one or more of pruritus, conjunctival hyperemia, chemosis, tearing, and a burning sensation, following exposure to an offending allergen. In severe cases, due to a compromise in the tear film, photophobia and blurred vision can be present. AC is classified as seasonal allergic (hay fever) conjunctivitis (SAC) (usually following exposure to pollen) or perennial allergic conjunctivitis (PAC) (usually following exposure to dust mites, mold, animal dander and occupational allergens).

Pathogenesis

AC is one of the few inflammatory eye disorders for which antibody dependence definitely has been established. It is a form of atopic disease with an implied hereditary susceptibility. Immunoglobulin (Ig) E (reaginic antibody) is attached

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to mast cells lying beneath the conjunctival epithelium. Binding of the offending antigen to corresponding IgE triggers the release of vasoactive substances, principally leukotrienes and histamine, resulting in vasodilation and chemosis.

Diagnosis

Diagnosis is usually clinical, but it can be confirmed by a high proportion of eosinophils in Giemsa-stained scrapings of conjunctival epithelium. Skin test with a causative allergen produces wheal and flare of an immediate (type 1) hypersensitivity response. Serum and tear fluid can be analyzed for specific IgE, total IgE, and cytokines.

Treatment

In addition to prevention of exposure to relevant allergens and other ocular surface irritants and nonpharmacologic management with lubricants and cold compresses, treatment of AC is quite variable and depends on severity and persistence. For mild cases, topical antihistamines or mast cell stabilizers are recommended. In moderate or persistent cases, dual action topical agents consisting of both antihistamines and mast cell stabilizers are indicated. In severe or particularly persistent cases, topical steroids for short duration and dual action agents are indicated, although steroids are seldom used in practice.

Allergen-specific immunotherapy can produce shortand long-term improvement of symptoms and is indicated in severe, persistent cases, as well as in patients who have simultaneous rhinoconjunctivitis. Patients are dosed either sublingually or subcutaneously with gradually increasing doses of suspected allergens, with attenuation of allergen-specific type 2 T-cell response being the probable mechanism of action.

Other forms of treatment are discussed in Chapter 5.

ATOPIC KERATOCONJUNCTIVITIS AND VERNAL KERATOCONJUNCTIVITIS

Atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC) are manifestations of atopy. Both, but especially AKC, ultimately result in

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structural modifications of the lids and conjunctiva.

AKC typically begins in the late teens or early twenties, often persisting into the fifth decade of life. It is usually perennial but can have seasonal exacerbations. Symptoms include pruritus, tearing, redness, and burning. There may be severe eczema of the lids and periorbital skin, and the bulbar conjunctiva is hyperemic and thickened. Papillary hypertrophy is often present in the palpebral conjunctiva, particularly inferiorly. Meibomian gland dysfunction and staphylococcal blepharitis are common. Inflammatory mediators and thickening of the lids cause corneal damage including punctate erosions, abrasions, ulcerations, and mucous plaques. There is predisposition to herpes simplex virus keratitis, anterior and posterior subcapsular cataracts, and keratoconus.

VKC characteristically affects children and adolescents and is rare thereafter. It usually occurs in hot, dry climates during the warmer months of the year. Symptoms include severe pruritus, tearing, redness, and frequently photophobia. On examination, there are giant (“cobblestone”) papillae of the tarsal conjunctiva (see Figure 5–10). The keratinized epithelium of the papillae may cause punctate corneal erosions and a large abrasion (shield ulcer), over which a fibrin and mucus-containing plaque may form and require surgical removal. At the limbus, there may be gelatinous infiltration, which often is associated with white accumulations of eosinophils and desquamated epithelial cells (Horner-Trantas dots). Compared to AKC, the papillae are larger, and corneal neovascularization and conjunctival scarring are less common.

Pathogenesis

As well as IgE-mediated mast cell degranulation with release of vasoactive amines, non–IgE-mediated disease processes are active in both AKC and VKC. In VKC, there is heavy papillary infiltration by mononuclear cells and T-cell, eosinophil, and cytokine activity, with type 2 helper T cells being the primary driver. In AKC, there is T-cell activity, with type 1 helper T cells being the primary driver.

Diagnosis

There are large numbers of eosinophils in conjunctival scrapings, but they are more numerous and more often degranulated in VKC than in AKC. There is a type 1 hypersensitivity reaction to skin testing with food extracts, pollens, and various other antigens, but the significance of these reactions is not established.

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Usually the specific inciting antigen is not known.

Treatment

Avoidance or control of known and suspected allergens is beneficial. In AKC, antihistamines and mast cell stabilizers are usually inadequate, and patients often require topical steroid therapy. In VKC, antihistamines and mast cell stabilizers can be quite helpful, with refractory cases requiring topical steroid therapy. In refractory cases, immunomodulators such as cyclosporine and tacrolimus may be beneficial.

Other treatments are discussed in Chapter 5.

JOINT DISEASES AFFECTING THE EYE (SEE ALSO CHAPTERS 5, 7, 15, & 17)

Uveitis and scleritis are the principal ocular manifestations associated with joint diseases. Rheumatoid arthritis may be accompanied by scleritis (see Figures 7– 29 to 7–31), peripheral ulcerative keratitis (see Figure 6–9), or episcleritis (see Figures 7–27 and 7–28) as well as dry eyes (secondary Sjögren’s syndrome).

Juvenile idiopathic arthritis is associated with uveitis (see Figure 7–7). Unilateral or bilateral chronic anterior uveitis that is often clinically silent is associated particularly with the oligoarticular category, which more commonly affects females with positive antinuclear antibodies, and sometimes the rheumatoid factor–negative polyarticular category. Acute, usually unilateral anterior uveitis occurs particularly in the HLA-B27 enthesitis-related category, which is more common in males. Ankylosing spondylitis in adults, which also affects males more frequently than females, may be accompanied by acute anterior uveitis, often with fibrin.

Reactive arthritis affects men more frequently than women. It is triggered by gastrointestinal infection usually with Shigella, Salmonella, or Campylobacter or genitourinary infection particularly with Chlamydia. The first attack of ocular inflammation usually consists of a self-limited papillary conjunctivitis. Subsequent attacks consist of acute iridocyclitis of one or both eyes, occasionally with hypopyon.

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Pathogenesis

Disease activity in rheumatoid arthritis correlates with serum autoantibodies against IgG (rheumatoid factor) and against cyclic citrullinated peptides (CCP) that induce inflammation by several pathways, particularly formation of immune complexes, which is responsible for the occlusive vasculitis that is particularly important in the characteristic necrotizing type of scleritis. Secondary Sjögren’s syndrome is caused by antibody-mediated destruction of acinar cells and lymphocytic infiltration of the lacrimal and salivary glands, resulting in dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia).

Intraocular inflammation in the seronegative arthropathies is strongly associated with human leukocyte antigen B27 (HLA-B27). Other HLA associations with ophthalmic disease are listed in Table 16–1. Such associations may be causative or coincidental.

Table 16–1. Examples of Human Leukocyte Antigens (HLA) Associated with Ophthalmic Diseases

Diagnosis

Detection of rheumatoid factor and targeted HLA testing may be diagnostic. HLA-B27 is strongly associated with axial spondyloarthritis, including ankylosing spondylitis, and sacroiliitis.

OTHER ANTIBODY-MEDIATED EYE DISEASES (SEE ALSO CHAPTERS 5 & 15)

Systemic lupus erythematosus is a chronic autoimmune disease associated with antinuclear and anti–double-stranded DNA antibodies with inflammatory and

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vascular consequences that affect a wide variety of organs. There are many ocular manifestations, of which secondary Sjögren’s syndrome is most common, and retinal (see Figure 15–5), choroidal, and optic nerve disease are most likely to cause reduction of vision and be associated with nonocular especially cerebrovascular disease. Antiphospholipid antibodies may contribute to pathogenesis.

Mucous membrane (ocular cicatricial) pemphigoid is associated with antibodies to a component of conjunctival basement membrane, provably a protein of hemidesmosomes. It is characterized by subepithelial bullae with chronic conjunctivitis resulting in scarring, symblepharon (see Figure 5–17), contraction of the fornices, and tear deficiency. The end result is bilateral conjunctival and corneal keratinization. Disease control requires systemic immunosuppression. Local treatment includes topical lubricants, lacrimal punctual occlusion, eyelid surgery for trichiasis, and end-stage disease keratoprosthesis.

CELL-MEDIATED DISEASES (SEE ALSO CHAPTERS 7 & 15)

This group of diseases is associated with cell-mediated immunity or delayed hypersensitivity and characterized by infiltration of mononuclear cells, principally lymphocytes and macrophages. The antigenic stimulus may be chronic infection such as tuberculosis, leprosy, toxoplasmosis, and herpes zoster. Such infections are often associated with delayed skin test reactivity following the intradermal injection of an extract of the organism. The granulomatous diseases of the eye are less well understood. They are thought to represent cellmediated, possibly autoimmune processes, but the antigenic stimuli have not been identified.

SARCOIDOSIS

Ocular sarcoidosis is characterized by a panuveitis with occasional inflammatory involvement of the optic nerve, conjunctiva, choroid, and retinal veins (see

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Figure 15–21).

Pathogenesis & Diagnosis

Sarcoidosis is an inflammatory disease of unknown etiology. The presence of macrophages and giant cells suggests phagocytosis of particulate matter, which may be the result of mycobacterial infection. Definitive diagnosis requires identification of noncaseating granulomas for which there is no other cause and thus require biopsy, usually lymph node, skin, or pulmonary, including bronchoalveolar lavage. Pulmonary disease, typically bilateral hilar lymphadenopathy, raised serum angiotensin-converting enzyme (SACE), negative tuberculin (Mantoux or Heaf) test, and positive gallium scan are diagnostic pointers.

Treatment

See Chapter 15.

SYMPATHETIC OPHTHALMIA & VOGT-KOYANAGI- HARADA DISEASE

These are uncommon autoimmune diseases affecting pigmented structures of the eye and skin.

Clinical Features

Sympathetic ophthalmia causes bilateral granulomatous uveitis weeks to months (usually within 1 year) following accidental or surgical ocular trauma. Patients usually present with floaters and painless reduction of vision. The typical findings in both the exciting (traumatized) eye and the sympathizing eye are bilateral anterior uveitis with mutton fat keratic precipitates, moderate to severe vitritis, and choroiditis that may manifest as yellow-white nodular lesions under the retinal pigment epithelium (Dalen-Fuchs nodules). Sometimes papillitis and glaucoma occur. There may be vitiligo (depigmentation of the skin) and poliosis (whitening of the hair and eyelashes).

Vogt-Koyanagi-Harada (VKH) disease affects many organs besides the

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eyes. There is a (meningeal) prodromal stage, during which there may be headache, neck stiffness, encephalopathy, focal neurologic signs and cerebrospinal fluid lymphocytosis, and tinnitus, vertigo, and sensorineural hearing loss. Within a few days, there is bilateral granulomatous panuveitis with choroiditis including Dalen-Fuchs nodules, optic disk edema, and sometimes exudative retinal detachment. Subsequently, there may be vitiligo, poliosis, and alopecia (see Figure 15–33).

Pathogenesis

In both diseases, there is a T-cell–mediated granulomatous inflammation. In sympathetic ophthalmia, the stimulus is exposure of intraocular antigens by the ocular trauma. In VKH, one or more antigens related to melanin are the stimulus, and the disease typically occurs in heavily pigmented individuals such as Hispanics and Japanese. Both conditions are associated with certain HLA types (Table 16–1).

Diagnosis

Both conditions are diagnosed primarily on clinical features. On fundus fluorescein angiography, pinpoint leakage at the level of the retinal pigment epithelium is typical. On ultrasonography, particularly in VKH, there is choroidal thickening. Treatment of both conditions is immunosuppression.

OTHER CELL-MEDIATED EYE DISEASES (SEE ALSO CHAPTER 15)

Giant cell arteritis is a large-vessel vasculitis with a predilection for the branches of the carotid arteries, particularly the (superficial) temporal artery, and for the vertebral arteries. It presents in individuals older than 50 years and typically with temporal headache, scalp tenderness, jaw claudication, malaise, weight loss, and polymyalgia rheumatica. Ocular complications include anterior ischemic optic neuropathy and central retinal artery occlusion and, without prompt treatment, a risk of progression to complete blindness. Initial diagnosis is primarily clinical supplemented by raised erythrocyte sedimentation rate and C- reactive protein. Temporal artery biopsy showing chronic inflammation

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sometimes with giant cells and typically with fragmentation of the internal elastic lamina is conclusive. Varicella-zoster virus or other infection may be a trigger.

Polyarteritis nodosa is a necrotizing arteritis of medium and small arteries. It can affect both the anterior and posterior segments of the eye and cause neurologic disease with ophthalmic manifestations (see Figure 15–28).

Granulomatosis with polyangiitis (Wegener’s granulomatosis) is a systemic vasculitis predominantly affecting small to medium vessels. There is necrotizing granulomatous inflammation, usually involving the respiratory tract and commonly affecting the kidneys. Ophthalmic involvement usually consists of peripheral ulcerative keratitis and scleritis, but retinal vasculitis can occur (see Figure 15–29). The presence of cytoplasmic pattern of antineutrophil cytoplasmic antibodies (C-ANCA) is helpful in making the diagnosis.

Behçet’s disease has an uncertain place in the classification of immunologic disorders. It is characterized by recurrent iridocyclitis with hypopyon (see Figure 15–31) and occlusive vasculitis of branch retinal veins. Although it has many of the features of a delayed hypersensitivity disease, dramatic alterations of serum complement levels at the very beginning of an attack suggest an immune complex disorder. Furthermore, high levels of circulating immune complexes have recently been detected in patients with this disease. Most patients with ocular symptoms are positive for HLA-B51 and of eastern Mediterranean or Southeast Asian ancestry.

Contact dermatitis, which may affect the eyelids, represents a significant, although minor, disease caused by delayed hypersensitivity. Topical medications such as brimonidine and atropine, eye drop preservatives, perfumed cosmetics, materials contained in plastic spectacle frames, and other locally applied agents may act as the sensitizing hapten. The lower lid is more extensively involved than the upper lid when the sensitizing agent is applied in drop form (Figure 16– 1). There is an erythematous and vesicular rash with pruritus.

Figure 16–1. Periocular contact dermatitis due to delayed hypersensitivity reaction to eye drops.

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Epidermal necrolysis, which encompasses Stevens-Johnson syndrome and toxic epidermal necrolysis, is most commonly incited by drugs such as allopurinol and carbamazepine. It may lead to conjunctival and corneal scarring. Disease manifestations result from keratinocyte apoptosis, which probably is due to immune-mediated cytotoxicity. Certain subtypes are associated with HLA types (Table 16–1).

Phlyctenular keratoconjunctivitis (see Figure 5–14) represents a delayed hypersensitivity response to certain microbial antigens, principally those of

Mycobacterium tuberculosis and Staphylococcus aureus (see also Chapters 5 and 6).

CORNEAL TRANSPLANTATION AND GRAFT REJECTION

Reduction of vision due to central corneal disease may be suitable for a corneal graft that, depending on the extent of disease, may be achieved by penetrating keratoplasty (PKP), in which the full thickness of the cornea is replaced (see Figure 6–13); anterior lamellar keratoplasty, in which part of the anterior portion is replaced; or endothelial keratoplasty, in which only the endothelium is replaced.

Except in the rare instance of exchanging tissue between the two eyes of the same individual (autograft), corneal transplantation is an allograft with the attendant risk of graft rejection. However, due to various factors that limit exposure to the foreign antigens and the immunological response to them, corneal allograft generates a relatively weak immune response. Even though tissue matching for HLA antigens and systemic immunosuppression are not routinely used, 1-year graft survival for PKP is at least 85%, and in low-risk cases, 5-year survival is over 90%. In contrast, in high-risk cases, such as inflamed or vascularized recipient corneas, 5-year survival is around 55%. The antigens responsible for the vast majority of the immune response are located on the endothelium. Whenever possible, corneal graft surgery is limited to anterior lamellar keratoplasty to minimize the immunogenicity of the graft tissue and the likelihood of rejection.

Both humoral and cellular mechanisms have been implicated in corneal graft rejection. It is likely that early graft rejection (2–4 weeks from surgery) is cell-

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mediated. Cytotoxic lymphocytes are present at the limbus and in the corneal stroma, and in vivo phase microscopy has shown them attacking donor endothelial cells, but CD8 T-cell knockout mice can mount a vigorous rejection response, with predominance of delayed-type hypersensitivity inflammatory cells, so cytotoxic T cells may not be required. Lymphocytes mediating rejection generally move inward from the periphery of the cornea, forming a “rejection line” that may be seen on the endothelium or the epithelium as they move centrally. The donor cornea becomes edematous as the endothelium becomes increasingly compromised.

Late rejection of a corneal graft may occur weeks to months after surgery and may be antibody-mediated, since cytotoxic antibodies have been isolated from the serum of patients with a history of multiple graft reactions in vascularized corneal beds. These antibody reactions are complement-dependent and attract polymorphonuclear leukocytes, which can form dense rings in the cornea at the sites of maximum deposition of immune complexes.

Treatment

The mainstay of the treatment of corneal graft reactions is intensive topical corticosteroid therapy. Epithelial and stromal damage often is reversible. Due to its lack of regenerative capability, endothelial damage is likely to be irreversible, leading to graft failure such that endothelial rejection requires more aggressive and prolonged treatment. In severe endothelial graft rejections, systemic steroids may be indicated. Systemic and topical cyclosporine or tacrolimus also are effective in preventing and treating graft rejection.

For patients known to be high risk for rejection (eg, corneal neovascularization, prior graft rejection, young age, prior anterior segment surgery, active inflammation, and herpes simplex virus keratitis), especially if the other eye has little or no visual potential, matching for histocompatibility (HLA) and blood group (ABO) antigens and pretreatment with immunosuppressants such as azathioprine, cyclosporine, or mycophenolate mofetil may be undertaken.

IMMUNOTHERAPY

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While in many cases the initiators of ocular inflammatory diseases are still unknown, the components of the inflammatory response are increasingly understood. Of paramount importance in many systemic and ocular inflammatory conditions are T-cell–mediated immune reactions and cytokines.

Immunosuppressants

These include antimetabolites (azathioprine, methotrexate, and mycophenolate mofetil), T-cell inhibitors (cyclosporine and tacrolimus), and alkylating agents (cyclophosphamide and chlorambucil). The treating physician must be familiar with the ocular and systemic side effects of these medications, which are discussed in Chapter 15.

Biologic Response Modifiers

The biologic response modifiers (biologics) most frequently used for ophthalmic disease are the anti–vascular endothelial growth factor (VEGF) agents for choroidal neovascularization, such as in age-related macular degeneration, and for retinal vascular disease, such as diabetic retinopathy. For inflammatory diseases, a wide range of agents have been shown to be beneficial (Table 16–2).

Table 16–2. Examples of Biologic Response Modifiers (Biologics) for Ocular Disease

Modes of Delivery

In order to enhance anti-inflammatory effect on the eye and to minimize systemic side effects, alternative modes of delivery of these agents (apart from oral or intravenous) have also been studied. A topical anti–tumor necrosis factor α antibody, ESBA105, is being investigated for its feasibility in treating ocular inflammation. Intraocular methotrexate has shown vision improvement and

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reduction of macular edema in uveitic patients. Sustained implants of immunosuppressants, as well as intraocular viral and nonviral gene therapies that deliver anticytokine agents, are being investigated in animal studies.

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