Ocular surface immune-mediated diseases encompass a diverse spectrum of pathologies. Aberrant activation of the innate and adaptive immune responses underlies their immunopathogenesis. The conjunctiva is part of the secretory immune system and contains conjunctiva-associated lymphoid tissue. Inflammation of the conjunctiva may occur secondary to inciting exposures or as a manifestation of systemic mucocutaneous disease. The cornea uniquely lacks blood or lymph vasculature. This accounts for both its immune privilege and susceptibility to infection and inflammation not found elsewhere in the body.
Key points
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Immune-mediated diseases of the ocular surface comprise a wide array of pathologies. Their immunopathogenesis is mediated by aberrant activation of both the innate and adaptive immune responses.
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The conjunctiva contains conjunctiva-associated lymphoid tissue, and inflammation may occur secondary to inciting exposures or as a manifestation of systemic mucocutaneous disease.
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The cornea lacks blood or lymph vasculature, accounting for both its immune privilege and susceptibility to infection and inflammation not found elsewhere.
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Discrimination between episcleritis and scleritis is exceptionally important as management, prognosis, and complications vastly differ.
Ocular surface immune-mediated diseases encompass a diverse spectrum of pathologies. Aberrant activation of the innate and adaptive immune responses underlies their immunopathogenesis.
Conjunctiva
The conjunctiva is the transparent, lubricating mucous membrane covering the outer surface of the eye. It is part of the secretory immune system and contains conjunctiva-associated lymphoid tissue, including innate immune cells and goblet cells interspersed within stratified squamous epithelium [ ].
Seasonal allergic conjunctivitis and perennial allergic conjunctivitis
Seasonal allergic conjunctivitis (SAC) is an acute bilateral conjunctivitis caused by hypersensitivity to outdoor allergens, worse in spring to fall. Symptoms include itching, eyelid swelling, conjunctival hyperemia, chemosis ( Fig. 1 ), and mucoid discharge, which improve after allergen removal. In contrast, perennial allergic conjunctivitis (PAC) is a chronic bilateral conjunctivitis secondary to indoor airborne antigens, with no seasonal predilection. The symptoms of PAC are less severe compared to SAC [ ]. Both entities affect both sexes and have high prevalence, affecting 15% to 40% of the population, with greater than 50% reporting daily symptoms and 70% reporting severe symptoms [ , ].
SAC and PAC are caused by Type I IgE-dependent hypersensitivity reactions (HSRs) to airborne antigens [ ]. In sensitized individuals, allergen exposure leads to allergen-specific IgE binding to conjunctival mast cells and downstream release of inflammatory mediators, including histamine, leukotrienes, and prostaglandins [ ].
Diagnosis is clinical, inclusive of careful history and thorough evaluation of signs and symptoms ( Table 1 ). With the identification of a trigger, no further testing is required. In severe cases, clinicians should refer to an allergist for skin testing and consideration of allergen-specific immunotherapy [ ].
| Seasonal/Perennial Allergic Conjunctivitis | Vernal Keratoconjunctivitis | Atopic Keratoconjunctivitis | |
|---|---|---|---|
| Mechanism | Type I HSR | Type I and Type IV HSR | Type I and Type IV HSR |
| Disease course | Seasonal (spring–early fall) and/or perennial | Spring and summer > perennial in warm climates | Perennial with intermittent exacerbations |
| Demographics | Males = Females All ages | Males > females Age: School age or puberty | Males > Females Age: Peak 20–50 y |
| Risk factors | Outdoor allergens : Pollen and grass. Indoor allergens : Dust, mites, mold, adhesives, metals, paints, latex, and pet dander. |
| Family or personal history of atopic dermatitis, eczema, asthma, urticaria |
| Symptoms | Severe itching Epiphora +/− mucoid discharge Redness | Itching Epiphora Mucoid discharge, copious, worse in AM Photophobia Foreign body sensation | Severe itching Epiphora Clear discharge Photophobia |
| Clinical Signs | |||
| Eyelids | Edema | Edema, upper eyelid No eyelid margin involvement | Panda eyes Dennie–Morgan lines Severe : Eyelid margin keratinization, blepharitis, madarosis, ectropion/entropion/ptosis |
| Conjunctiva | Mild papillary reaction Hyperemia Chemosis | Palpebral : Giant papillae, cobblestoning of superior tarsal conjunctiva Limbal : Limbal nodules, Horner–Trantas dots | Small-medium papillae inferior tarsal conjunctiva Hyperemia Chemosis Severe : Subepithelial fibrosis, cicatrization, symblepharon |
| Cornea | None | Punctate keratopathy KCN Severe: Shield ulcer, LSCD | Punctate keratopathy KCN HSK Severe : LSCD, peripheral ulcerative keratopathy, scarring with vascularization and opacification |
| Lens | None | None | Posterior or anterior subcapsular cataracts |
| Management | |||
| Conservative | Allergen avoidance/elimination Cold compresses Preservative-free artificial tears | ||
| Medical a | Antihistamines Mast-cell stabilizers Steroids, pulsed | Mild/moderate : Antihistamines, mast-cell stabilizers, NSAIDs, or Steroids pulsed Severe : Above ± cyclosporine, tacrolimus, pulsed oral steroids | Mild/moderate : Antihistamines, mast-cell stabilizers, NSAIDs, or steroids pulsed Severe : Above ± cyclosporine, tacrolimus, systemic immunosuppression |
| Procedural/Surgical | None | Supratarsal subconjunctival steroid injection Corneal plaque peeling/wiping | None |
Patients should be counseled to avoid triggers. The removal of antigens via washing linens and clothing or vacuuming the home can decrease chronic exposure. The first-line management includes frequent artificial tears and cool compresses. Topical antihistamines and mast-cell stabilizer eye drops treat the allergic mediators, and oral antihistamines may help with concurrent systemic allergic symptoms. Low-potency topical steroid drops can be effective for short-term treatments [ , ].
Vernal keratoconjunctivitis
Vernal keratoconjunctivitis (VKC) is a bilateral chronic inflammatory disorder of the conjunctiva and cornea, most commonly affecting male prepubertal children [ , ]. VKC is a severe but self-limited disease, usually subsiding by 20 years of age, with only 6% of patients developing vision-threatening complications [ ]. There are 2 forms of VKC, though presentation can overlap.
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Palpebral : Diffuse papillary hypertrophy more prominent in the upper tarsal conjunctiva which may evolve into cobblestone-like giant papillae ( Fig. 2 ) surrounded by mucous strings [ , ]; bulbar hyperemia and chemosis may be present.
Fig. 2
Upper tarsal giant papillae in VKC.
( Courtesy of Dr S. Orlin, MD, Philadelphia, PA.)
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Limbal : Perilimbal lymphocytic infiltrates coalesced into nodules ( Fig. 3 ), and Horner–Trantas dots comprised necrotic eosinophils, neutrophils, and mast cells [ , ].
Fig. 3
Perilimbal lymphocytic infiltrates in VKC.
( Courtesy of Dr S. Orlin, MD, Philadelphia, PA.)
The primary symptoms of VKC include itching, redness, epiphora, mucous discharge, photophobia, and foreign body sensation [ , ]. Corneal findings include punctate keratopathy that may evolve into a shield ulcer ( Fig. 4 ); leading to pannus formation and/or permanent corneal scarring [ ]. Severe disease also may be associated with keratoconus, amblyopia, and limbal stem cell deficiency [ ].
VKC is mediated by Type I (IgE-dependent) and Type IV (lymphocyte-mediated) immune pathogenic mechanisms. While tarsal papillae have fibroblasts and epithelial cells, limbal papillae may be due to inflammatory infiltrates; conjunctival scrapings have shown eosinophilic infiltration, mast cells, inflammatory cytokines IL-6 and IL-8, and growth factors [ , ].
Clinical diagnosis is made via careful history to identify triggers and thorough examination (see Table 1 ).
Management is based on disease severity
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Mild : Allergen avoidance, environmental control, cool compresses, preservative-free artificial tears, and topical antihistamines [ ].
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Moderate : Addition of topical mast-cell stabilizers and short courses of topical nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids [ ].
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Severe disease : Addition of steroid-sparing agents including topical cyclosporine or tacrolimus [ ]. Biologics such as omalizumab have been used [ ]. Oral steroids may be pulsed with topical anti-inflammatories, weighed against possible concurrent side effects [ ]. The procedural management of shield ulcers includes supratarsal subconjunctival steroid injection, peeling/wiping of the corneal plaque, placement of amniotic membrane, and/or bandage contact lens [ ].
Atopic keratoconjunctivitis
Atopic keratoconjunctivitis (AKC) is a bilateral chronic disease affecting the eyelids, conjunctiva, and cornea, occurring mostly in men aged 20 to 50 years [ , ]. The disease is strongly associated with a personal or family history of atopic disease such as dermatitis, eczema, asthma, or urticaria [ , ]. Symptoms include chronic itching and watery discharge, exacerbated by cold weather [ ]. Eyelid findings may include panda eyes (eyelid eczema with lid hyperpigmentation), Dennie–Morgan lines (eyelid edema with horizontal lid creases), and Hertoghe’s sign (absence of lateral end of eyebrows) [ ]. Advanced/chronic disease causing keratinization of the eyelid margins may lead to madarosis and eyelid deformities. Conjunctival signs include hyperemia, chemosis, papillae in inferior tarsal conjunctiva, and cicatrization and symblepharon formation with forniceal shortening. Corneal findings vary from superficial punctate keratitis to corneal scarring, pannus, and limbal stem cell deficiency. Patients may be predisposed to infections such as Staphylococcus aureus blepharoconjunctivitis and herpes simplex keratitis [ ].
AKC is caused by both Type I (IgE-mediated) and Type IV (lymphocyte-mediated) immune reactions with the predominant participation of T-cells (especially Th1-cells) that produce chemotaxis and stimulate eosinophil production. Eosinophils initiate cytokine production, heightening the inflammatory response.
Clinical diagnosis is made via careful history and thorough examination.
Conservative treatment is the same as for VKC. Similar treatments for VKC may be implemented such as topical cyclosporine, topical tacrolimus, or pulsed topical corticosteroids (see Table 1 ).Treatment with antibiotics and antivirals should be implemented as appropriate. In severe cases, one should consider referral to rheumatology for consideration of systemic immunosuppression.
Stevens–Johnson syndrome/toxic epidermal necrolysis
Stevens–Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN), are acute, life-threatening inflammatory disorders. They affect the skin and mucous membranes of people of all ages and may be precipitated by drugs. Implicated medications include antiepileptics, most commonly carbamazepine, antibiotics, most commonly sulfonamides, nonsteroidal anti-inflammatory drugs, and more [ , ]. Presentation includes skin tenderness and erythema, followed by cutaneous and mucosal sloughing, and possible ophthalmic manifestations, as ocular involvement in SJS/TEN, seen in greater than 50% of patients [ ].
Two phases of ophthalmic involvement occur
Acute stage : Extensive eyelid margin ulceration, conjunctival hyperemia, mucopurulent or pseudomembranous conjunctivitis, corneal punctate erosions, epithelial defects, and/or ulcers, episcleritis, and iritis [ ].
Chronic stage : Entropion, trichiasis, conjunctival scarring ( Fig. 5 ), symblepharon ( Fig. 6 ) and ankyloblepharon, severe dry eye, limbal stem cell deficiency, corneal neovascularization, keratinization, ulceration, and scarring and/or globe perforation [ ].
SJS/TEN are considered Type IV HSRs involving triggering of a T-cell-mediated cytotoxic reaction to drug antigens.
Diagnosis is clinical with appropriate history, dermatologic evaluation, and ophthalmologic examination.
No universally accepted treatment regimen exists for SJS/TEN. In the acute phase, treatment measures are important to prevent long-term ocular complications; this includes frequent use of preservative-free artificial tears, removal of pseudomembranes, lysis of symblepharon using a glass rod or symblepharon ring, topical antibiotics, and topical cycloplegics [ , ]. While treatment with steroids remains controversial, topical corticosteroids to prevent scar formation are an accepted modality in acute SJS/TEN [ , ]. Patients should undergo frequent ophthalmic follow-up examinations to ensure the best outcome [ ].
Mucous membrane pemphigoid
Mucous membrane pemphigoid (MMP) encompasses a group of blistering immune-mediated mucocutaneous diseases. Ocular cicatricial pemphigoid (OCP) is a subtype of MMP that features a chronic, relapsing–remitting bilateral conjunctivitis, affecting 60% to 70% of patients with MMP. Those with ocular involvement have a worse prognosis than those with skin/oral mucosa involvement alone. The disease affects women more than men in 2:1 ratio, and patients aged 60 to 80 years [ , ].
Early signs include diffuse hyperemia, papillary reaction, dry eye syndrome, trichiasis, and keratoconjunctivitis sicca (KCS). Four disease stages have been described: subepithelial fibrosis (stage I), shortened fornices (stage II), symblepharon formation (stage III), and keratinization (stage IV) ( Fig. 7 ) [ ].
