illustrations of nonocular manifestations of reactive arthritis.
CLINICAL PRESENTATION A bilateral papillary conjunctivitis with mucopurulent discharge is the most common ocular finding in reactive arthritis; it has been reported in 30%–60% of patients. The conjunctivitis is self-limited, lasting for days to weeks. Some patients present more often with episcleritis rather than with conjunctivitis. Mild nongranulomatous iritis has been reported to occur in 3%–12% of patients. Various forms of keratitis—including diffuse punctate epithelial erosions, superficial or deep focal infiltrates, or superficial or deep vascularization—may occur in rare cases. Reactive arthritis should be considered in any case of chronic, nonfollicular, mucopurulent conjunctivitis with negative cultures.
MANAGEMENT Treatment is mainly palliative. Corneal infiltrates and vascularization often respond to topical corticosteroids. Systemic antibiotic treatment of the related infection, if any, may be beneficial. Occasionally, the intraocular (uveitic) component of the disease can be very severe and require systemic immune suppression; see BCSC Section 9, Intraocular Inflammation and Uveitis.
Cogan Syndrome
PATHOGENESIS Cogan syndrome is an autoimmune disorder, the etiology of which is obscure. However, the disease shares some clinicopathologic features with polyarteritis nodosa.
CLINICAL PRESENTATION Cogan syndrome produces stromal keratitis, vertigo, and hearing loss and typically occurs in young adults, the majority of whom had an upper respiratory tract infection 1–2 weeks before the onset of ocular or vestibuloauditory symptoms. The earliest corneal findings are bilateral faint white subepithelial infiltrates similar to those occurring in viral keratoconjunctivitis but located in the peripheral cornea. Multifocal nodular infiltrates may develop in the posterior cornea later in the course of this condition. Some patients develop a systemic vasculitis that presents as polyarteritis nodosa.
LABORATORY EVALUATION When the cause of stromal keratitis is not apparent, a VDRL or RPR test and FTA-ABS or MHA-TP are performed (VDRL and RPR tests may become nonreactive in congenital syphilis). Other infectious syndromes should also be considered. Because there are no specific laboratory findings, Cogan syndrome is essentially a diagnosis of exclusion.
MANAGEMENT The acute keratitis of Cogan syndrome is treated with frequent topical corticosteroids. It is important to treat this condition promptly because the ocular and vestibular changes can proceed rapidly, and deafness is more likely if the condition is not treated early. Oral corticosteroids are recommended for the vestibuloauditory symptoms, because this treatment enhances the long-term prognosis and recovery of normal hearing. Cytotoxic agents may also have a therapeutic role but are reserved for severe and unresponsive cases.
Gluth MB, Baratz KH, Matteson EL, Driscoll CL. Cogan syndrome: a retrospective review of 60 patients throughout a half century. Mayo Clin Proc. 2006;81(4):483–488.
Marginal Corneal Infiltrates Associated With Blepharoconjunctivitis
PATHOGENESIS The limbus plays an important role in immune-mediated corneal disorders. As reviewed in Chapter 6, the limbus has a population of antigen-presenting cells (APCs) that constitutively express MHC class II antigens and are capable of efficient mobilization and induction of T-cell responses. Therefore, immune-related corneal changes often occur in a peripheral location
adjacent to the limbus. In addition, because the peripheral cornea is adjacent to the vascularized (posterior) limbus, circulating immune cells, immune complexes, and complement factors tend to deposit adjacent to the terminal capillary loops of the limbal vascular arcades, thereby producing a variety of immune phenomena that manifest in the corneal periphery. Predisposing factors include
blepharoconjunctivitis contact lens wear trauma endophthalmitis
CLINICAL PRESENTATION Marginal infiltrates (also referred to as catarrhal infiltrates) usually occur where the eyelid margins intersect with the corneal surface: the 10-, 2-, 4-, and 8-o’clock positions. Marginal infiltrates in staphylococcal blepharitis are typically gray-white, well circumscribed, and located approximately 1 mm inside the limbus, with a characteristic clear (intervening) zone of cornea between the infiltrate and the limbus (see Chapter 3, Fig 3-14). In chronic disease, superficial blood vessels may cross the clear interval into the area of corneal infiltration. The epithelium overlying marginal infiltrates may be intact, show punctate epithelial erosions, or be ulcerated. Stromal opacification, peripheral corneal thinning, and/or pannus may develop following resolution of the acute marginal infiltrates.
Ozcura F. Successful treatment of staphylococcus-associated marginal keratitis with topical cyclosporine. Graefes Arch Clin Exp Ophthalmol. 2010;248(7):1049–1050.
Peripheral Ulcerative Keratitis Associated With Systemic Immune-Mediated Diseases
PATHOGENESIS Autoimmune peripheral keratitis may develop in patients who have systemic immunemediated and rheumatic diseases. Peripheral ulcerative keratitis (PUK) occurs most often in association with rheumatoid arthritis but may also be seen in Wegener granulomatosis, systemic lupus erythematosus, polyarteritis nodosa, ulcerative colitis, relapsing polychondritis, and other inflammatory diseases such as rosacea (Table 7-3). Biopsy of conjunctival tissue adjacent to marginal corneal disease—though not a standard diagnostic procedure—typically shows evidence of immunemediated vaso-occlusive disease.
Central corneal melting in the setting of systemic collagen-vascular disease may be due to a different mechanism associated with a T-lymphocyte infiltration.
Table 7-3
CLINICAL PRESENTATION A history of connective tissue disease is often (but not invariably) present, although in some patients the ocular finding of peripheral corneal infiltration or frank stromal melting may be the first sign of the underlying systemic illness. Autoimmune PUK generally correlates with exacerbations of systemic disease activity. Follow-up of these patients reveals that if they are treated inadequately, a high proportion may suffer severe disease-related morbidity. The term keratolysis refers to the significant (and often rapid) stromal melting seen in some cases of immune-mediated PUK associated with systemic autoimmunity.
Although autoimmune PUK can sometimes be bilateral and extensive, it is usually unilateral and limited to 1 sector of the peripheral cornea (Fig 7-17). The initial lesions appear in a zone within 2 mm of the limbus and are accompanied by varying degrees of vaso-occlusion of the adjacent limbal vascular networks. In most cases, the epithelium is absent in the affected area and the underlying stroma thinned; however, if the disease is detected early, epithelial involvement may be patchy and the stroma still of near-normal thickness. Ulceration may or may not be associated with a significant cellular infiltrate in the corneal stroma, and the adjacent conjunctiva can be minimally or severely inflamed.
Figure 7-17 Peripheral ulcerative keratitis associated with rheumatoid disease.
MANAGEMENT The goal of therapy is to provide local supportive measures to decrease melting. This is
achieved through maneuvers intended to (1) improve wetting, (2) promote epithelialization, and (3) suppress the systemic immune-mediated inflammation.
Maintaining enhanced lubrication of the surface is very important: first, because many rheumatoid patients have KCS as a manifestation of their secondary Sjögren syndrome; and second, because lubrication may help in diluting the effect of inflammatory cytokines in the preocular tear film. Melting will stop or slow appreciably if the epithelium can be made to heal by means of lubricants, patching, or a bandage soft contact lens. A number of topical collagenase inhibitors—such as sodium citrate 10%, acetylcysteine solution 20%, medroxyprogesterone 1%, and systemic collagenase inhibitors, such as tetracyclines (eg, doxycycline)—are of potential value. Topical cyclosporine has been shown to be potentially effective in patients with central melting that is probably due to a T-cell– mediated process rather than occlusive vasculitis.
Topical corticosteroids, which also inhibit collagenase function, can have variable effects. In general, if the cornea has thinned significantly, topical corticosteroid therapy should be used with caution. Excision or recession of adjacent limbal conjunctiva (as has been advocated for Mooren ulcer; see the following section) is often followed by healing of the ulcer, presumably because the procedure eliminates a source of inflammatory cells and collagenolytic enzymes.
Definitive management often cannot be achieved by local measures alone and requires institution or escalation of systemic treatment, including immunosuppressive therapy with oral prednisone, cytotoxic agents such as cyclophosphamide, or immunomodulatory agents such as methotrexate or cyclosporine. Biologic agents such as infliximab have reportedly been used with some success in more severe cases. Patients with severe, rapid melting may require intravenous therapy with highdose cyclophosphamide, with or without corticosteroid therapy. Threatened perforation should be treated with temporizing measures such as cyanoacrylate glue and bandage contact lens placement until systemic therapy has been initiated, because lamellar and penetrating grafts are also susceptible to melting. Sometimes multiple tectonic grafts are required to preserve the globe while the systemic therapy is being adjusted. Once the underlying disease process has been controlled, reconstructive keratoplasty can be performed (see Chapter 15). Although conjunctival flaps can be very helpful in controlling the stromal melting in difficult-to-manage microbial keratitis, they are probably best avoided in immune-mediated disease. Bringing the conjunctival vasculature even closer to the area of corneal disease could accelerate melting.
Huerva V, Sanchez MC, Traveset A, Jurjo C, Ruiz A. Rituximab for peripheral ulcerative keratitis with Wegener granulomatosis. Cornea. 2010;29(6):708–710.
Kaçmaz RO, Kempen JH, Newcomb C, et al. Cyclosporine for ocular inflammatory diseases. Ophthalmology. 2010;117(3):576–584.
Perez VL, Azar DT, Foster CS. Sterile corneal melting and necrotizing scleritis after cataract surgery in patients with rheumatoid arthritis and collagen vascular disease. Semin Ophthalmol. 2002;17(3-4):124–130.
Pham M, Chow CC, Badawi D, Tu EY. Use of infliximab in the treatment of peripheral ulcerative keratitis in Crohn disease. Am J Ophthalmol. 2011;152(2):183–188.e2.
Tarabishy AB, Schulte M, Papaliodis GN, Hoffman GS. Wegener’s granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic disease. Surv Ophthalmol. 2010;55(5):429–444.
Mooren Ulcer
PATHOGENESIS Although the etiology of Mooren ulcer is unknown, evidence is mounting that autoimmunity plays a key role. The following have been found in patients with Mooren ulcer:
abnormal T-suppressor cell function increased level of IgA
increased concentration of plasma cells and lymphocytes in the conjunctiva adjacent to the
ulcerated areas
increased CD4+/CD8+ and B7-2+/APC ratios as well as increased vascular cell adhesion molecule 1, very late antigen 4, and intercellular adhesion molecule 1 in the vascular endothelium of conjunctival vessels
tissue-fixed immunoglobulins and complement in the conjunctival epithelium and peripheral cornea
A significant number of resident cells in Mooren ulcer specimens express MHC class II antigens, a reflection of the degree of immune-mediated inflammation in the tissue. It has been suggested that autoreactivity to a cornea-specific antigen may play a role in the pathogenesis of this disorder, and humoral and cell-mediated immune mechanisms may be involved in the initiation and perpetuation of corneal destruction. The proximity of the ulcerative lesion to the limbus probably has pathophysiologic importance (as discussed earlier, in the section on PUK), because resection or recession of the limbal conjunctiva can often have a beneficial therapeutic effect.
Although the cause of Mooren ulcer is unknown, precipitating factors include accidental trauma, surgery, or exposure to parasitic infection. The latter is of considerable importance, as the incidence of Mooren ulcer is particularly high in areas where parasitic (eg, helminthic) infections are endemic. The principal hypotheses are that inflammation associated with previous injury or infection may alter the expression of corneal or conjunctival antigens (to which autoantibodies are then produced) or that cross-reactivity occurs between the immune effectors generated in response to infection and corneal autoantigens. The simultaneous presence of multiple types of inflammatory cells, adhesion molecules, and costimulatory molecules in Mooren ulcer conjunctiva suggests that their interaction may contribute to a sustained immune activation as at least part of the pathogenic mechanism of this disorder. By definition, Mooren ulcer is of unknown cause. Cases of PUK due to known local (eg, rosacea) or systemic (eg, rheumatoid arthritis) diseases should not be called Mooren ulcer.
CLINICAL PRESENTATION Mooren ulcer is a chronic, progressive, painful, idiopathic ulceration of the peripheral corneal stroma and epithelium. Typically, the ulcer starts in the periphery of the cornea and spreads circumferentially and then centripetally, with a leading undermined edge of deepithelialized tissue (Fig 7-18). Slower ulceration proceeds toward the sclera. The eye is inflamed and pain can be intense, with photophobia and tearing. Perforation may occur with minor trauma or during secondary infection. Extensive vascularization and fibrosis of the cornea may occur.
Figure 7-18 Mooren ulcer. (Courtesy of Vincent P. deLuise, MD.)
In some patients, it may be very difficult to distinguish Mooren ulcer from idiopathic PUK. An