Ophthalmologic manifestations of rheumatic diseases

Ophthalmologic Manifestations of Rheumatic Diseases Fayad Hamideh and Pamela E. Prete Objectives: Detailed review of the manifestations of eye involvement in the context of rheumatic diseases. Methods: An OVID Medline search of the rheumatology and ophthalmology English literature related to the eye manifestations of human rheumatic diseases from 1966 to the present was conducted by the authors. Results: Analysis of 300 recent and consecutive rheumatology consultations from a large Veterans Administration Healthcare System shows that 4% are referred for eye manifestations of suspected rheumatic diseases, most commonly, anterior uveitis and keratoconjunctivitis sicca (KCS). Ocular involvement is common in the rheumatic diseases but varies among the different disorders. A literature review indicated that the most common ocular manifestations of rheumatic diseases include keratoconjunctivitis sicca, anterior uveitis, and scleritis. The most serious eye complications of the inherited connective tissue disorders are lens involvement with cataract formation or subluxation. The most significant side effects of the drugs used to treat rheumatic diseases are the maculopathy associated with anti-malarial agents and cataracts and glaucoma associated with corticosteroid use. Although many of the eye manifestations are easily recognizable, consultation with an ophthalmologist is usually necessary for optimal treatment and prevention of complications. Conclusions: The rheumatologist, in coordination with the ophthalmologist, can play a major role in detecting and managing the eye involvement in his patients to save this important sense. Understanding the varied manifestations of eye disease will permit the rheumatologist to better evaluate the activity of the rheumatic disease. Semin Arthritis Rheum 30:217-241. Copyright © 2001 by W.B. Saunders Company INDEX WORDS: eye; rheumatic diseases; connective tissue diseases; uveitis; Sjogren’s syndrome; Reiter’s disease; Behcet’s syndrome; antirheumatic agents. T HE EYE is an especially sensitive barometer for the onset of, or reactivation of, autoimmune phenomena in many of the rheumatic diseases. Understanding the ocular manifestations of rheumatic disease is critically important for the rheumatologist. Some rheumatology patients may present with obscure signs and symptoms, and ocular manifestations may be the only clue for making a difficult diagnosis. Other patients may present with well-documented rheumatic diseases, and eye findings may add to the severity of their illness. Because many of these ocular complications may result in loss of vision, evaluation by an ophthalmologic specialist is needed. A descriptive analysis of 300 consecutive outpatient rheumatology consultations from a large Veterans Adminis- From the Department of Medicine, University of California, Irvine, Medical Center, Orange, CA, and the Rheumatology Section, VA Long Beach Healthcare System, Long Beach, CA. Fayad Hamideh, MD: Rheumatology Fellow, Department of Medicine, University of California, Irvine, Medical Center, Orange, CA; Pamela E. Prete, MD: Professor of Medicine in Residence, University of California, Irvine, Chief, Rheumatology Section, VA Long Beach Healthcare System, Long Beach, CA. Supported by the Arthritis Foundation of Southern California. Address request reprints to Pamela E. Prete, MD, Chief, Rheumatology Section, VA Long Beach Healthcare System, 5901 E Seventh Street (11-111R), Long Beach, CA 90822. E-mail: [email protected] Copyright © 2001 by W.B. Saunders Company 0049-0172/01/3004-0992$35.00/0 doi:10.1053/sarh.2001.16639 Seminars in Arthritis and Rheumatism, Vol 30, No 4 (February), 2001: pp 217-241 217 218 HAMIDEH AND PRETE Table 1: The Rheumatic Disease Diagnosis Established in 12 Patients Referred to Our Rheumatology Clinic for Eye Manifestations Initial Referring Ophthalmologic Diagnosis Anterior uveitis (9) Amaurosis fugax (1) Sicca syndrome (2) Final Rheumatic Disease Diagnosis Spondyloarthropathies (6) No associated rheumatic disorders (3) No associated rheumatic disorder Sjögren’s syndrome (1) No associated rheumatic disorder (1) NOTE. Of 300 consecutive consultative referrals in a large Veterans Administration Healthcare System Hospital. tration Healthcare System showed that 4% were referred for eye manifestations alone. These consultations for ocular problems and their associated rheumatic diseases are summarized in Table 1. The most common ocular problems in this group were anterior uveitis and keratoconjunctivitis sicca (KCS). METHODS A search of the OVID Medline database by subject pertaining to eye involvement with human rheumatic diseases was performed. All English literature and those articles with English abstracts, from 1966 to the present were reviewed. Ophthalmology textbooks were consulted for clarification of the meaning of some rare syndromes and technical terms that are unknown to most rheumatologists and a glossary was compiled. This review of the literature is presented in three parts. The first part relates to major eye involvement during the course rheumatic disease. The second is eye involvement with heritable connective tissue diseases, and the third deals with toxicities to the eye from the drugs commonly used in rheumatic disease therapy. A review of 300 consecutive outpatient rheumatology clinic referrals from medical and surgical physicians and providers from a large Veterans Administration Healthcare System Hospital whose population is older and predominantly male showed that 12 consultations were for eye problems related to suspected rheumatic diseases. The ocular problems and their associated rheumatic diseases are described in tabular form (Table 1). RESULTS Ophthalmologic Manifestations of Rheumatic Diseases With Significant Eye Involvement During the Course of the Disease Table 2 summarizes the ocular problems and their most frequently associated rheumatic diseases. Table 3 lists the rheumatic disease and their most prominent eye disorders. Behçet’s Disease The most common ocular manifestation is anterior uveitis (also includes acute iritis or iridocyclitis) (1-4), which may present either with or without a hypopyon. Although earlier studies described hypopyon presenting uveitis in as many as 88% of patients, more recent series indicate only 9% (1-4). This decrease most likely represents earlier diagnosis and more aggressive therapy. The most characteristic posterior segment lesion of Behçet’s disease is retinal vasculitis (1-6). The vasculitis is usually bilateral and may involve both veins and arteries, causing arterial occlusion and retinal necrosis. Occasionally, secondary neovascularization and retinal detachment develop. Dinning and Perkins (7) found that 81% of retinal vasculitis in Behçet’s disease were bilateral at 1 year, and 93% were bilateral at 2 years. In their series, neovascularization developed in 17% of patients. Neuro-ophthalmic lesions caused by vascular involvement by Behçet’s disease have been described, including cranial nerve palsies, papilledema, and ischemic optic neuropathy (8,9). The prognosis of the eye disease in Behçet’s disease is poor, with most patients losing all or part OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES 219 Table 2: Ocular Disorders and Their Frequently Associated Rheumatic Diseases Ocular Disorder Dry eyes (sicca syndrome) Uveitis Acute anterior uveitis Chronic anterior uveitis Panuveitis Scleritis Keratitis Non-necrotizing corneal melt Necrotizing keratitis Retinal vasculopathy Microvasculopathy Diffuse vaso-occlusive disease Optic nerve disease Ischemic optic neuropathy Rheumatic Disease Rheumatoid arthritis37 Systemic lupus erythematosus135 Scleroderma166 Primary Sjögren’s syndrome15 Spondyloarthropathies82 Behcet’s disease2 Inflammatory bowel disease90 Inflammatory bowel disease90 Relapsing polychondritis20 Behcet’s disease2 Rheumatoid arthritis42 Vasculitis, especially Wegener’s granulomatosis205 Inflammatory bowel disease92 Relapsing polychondritis20 Sjogren’s syndrome15 Rheumatoid arthritis41 Rheumatoid arthritis48 Vasculitis255 Systemic lupus erythematosus144 Systemic lupus erythematosus144 Antiphospholipid antibody syndrome159 Behcet’s disease2 Vasculitis, especially giant cell arteritis216 NOTE. References are denoted by superscript numbers. of their vision within the first 5 years. Ophthalmology consultation is required for this disease. In a series described by Mamo (10), 74% of patients with Behcet’s disease had a final vision of 20/200 or worse. Of the 25 eyes that deteriorated, the decline in vision was rapid, averaging 3.6 years. The use of immunosuppressive and disease-modifying drugs such as azathioprine and especially cyclosporin for ocular Behçet’s has improved the prognosis and is essential. Systemic corticosteroids may delay the progress of the ocular disease, but they do not alter its ultimate outcome (11). Sjögren’s Disease Keratoconjunctivitis sicca (dry eyes) is the hallmark sign of Sjögren’s syndrome. Sicca syndrome is defined as KCS and xerostomia without any extraglandular disease. The initial pathologic changes seen in the lacrimal glands in KCS include small foci of acinar degeneration, followed by lymphocyte and plasma cell infiltration around secretory ducts and acinar epithelium. With time, functional lacrimal glandular tissue is replaced with connective tissue (12). This disorder is most often documented by an abnormal Schirmer’s test that shows decreased tear production, and damage to the ocular surface demonstrated by rose bengal staining. This condition produces a disturbance of tear film physiology with potentially serious sightthreatening complications. Sjögren originally described KCS and xerostomia in patients with rheumatoid arthritis (RA) (13). 220 HAMIDEH AND PRETE Table 3: Rheumatic Diseases and Their Most Common Ocular Disorders Rheumatic Disease Common Ocular Manifestations Behcet’s disease Anterior uveitis,4 retinal vasculitis3 Sjögren’s syndrome Dry eyes13 Relapsing polychondritis Conjunctivitis,20 scleritis,20 uveitis,20 retinal vasculitis20 Rheumatoid arthritis Dry eyes,34 Scleritis40 Marginal corneal ulcers41 Juvenile rheumatoid arthritis Acute anterior uveitis57 Chronic anterior uveitis58 Reiter’s syndrome Conjunctivitis72 Acute anterior uveitis72 Ankylosing spondylitis Acute anterior uveitis77 Inflammatory bowel disease Acute anterior uveitis90 Scleritis92 Systemic lupus erythematosus Eyelid discoid lesions139 Dry eyes135 Retinal vasculitis144 Neuro-ophthalmic lesions152 Scleroderma Eyelid scleroderma168 Conjunctival telangiectasia168 Dry eyes169 Polymyositis and dermatomyositis Heliotrope rash18 Ophthalmoplegia192 Wegener’s granulomatosis Scleritis216 Peripheral keratitis216 Orbital pseudotumor207 Retinal vasculitis207 Neuro-ophthalmic lesions209 Giant cell arteritis Ischemic optic neuropathy,221 amaurosis fugax,221 retinal vasculitis,219 ischemia to the extraocular muscles,219 choroidal ischemia,222 cortical blindness223 Polyarteritis nodosa Hypertensive retinopathy,255 retinal vasculitis,255 neuroophthalmic lesions,255 cranial nerve palsies,245 scleritis,255 marginal corneal ulcers247 Allergic granulomatosis (Churg-Strauss angiitis) Retinal vasculitis258 Neuro-ophthalmic lesions261 Cranial nerve palsies261 Conjunctival granulomata257 Takayasu’s arteritis Retinal arteriovenous anastomoses262 Retinal microaneurysms262 Peripheral retinal ischemia262 Retinal neovascularization264 NOTE. References are denoted by superscript numbers. OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES Subsequently, a distinct group of patients without RA but with a wide variety of extraglandular manifestations, including Raynaud’s phenomenon, purpura, lymphadenopathy, splenomegaly, renal and pulmonary disease in addition to KCS, and xerostomia were described (14-16). Current classification schemes designate this group of patients as having primary Sjögren’s syndrome. These patients have a 40 times greater risk of developing lymphoreticular neoplasms (17). Rosenbaum and Bennett reported a series of patients with primary Sjögren’s syndrome who also developed intermediate anterior uveitis as a main manifestation of the disease (18). Relapsing Polychondritis Ocular manifestations are very frequent in relapsing polychondritis (RP) and occur in 59% of reported patients (19-33). Scleral involvement is the most common ocular manifestation of RP and occurs in 41% of patients (23,24). In RP patients with associated vasculitis, optic nerve involvement and cranial nerve palsies may be seen. Although diffuse anterior scleritis is most frequently observed, all types of scleral inflammation including recurrent episcleritis, necrotizing scleritis, and posterior scleritis have been reported. Uveitis occurs in approximately 25% of RP patients and most often is either an anterior uveitis (iridocyclitis) or a sclerouveitis (25). Keratitis, including marginal corneal ulceration, has been seen in 10% to 15% of RP patients (29). Isaak and co-workers (20) reported retinopathy in 10% of their RP patients, consisting of a few cottonwool spots and intraretinal hemorrhages. Branch retinal vein occlusion, central retinal vein occlusion, and ischemic optic neuropathy have been reported in association with systemic vasculitis in RP. Rheumatoid Arthritis Dry eyes or KCS is the most common ophthalmic manifestation of RA, with a reported prevelance as high as 25% (34-36). Careful slit-lamp examination of these patients shows conjunctival injection, poor tear physiology including poor tear meniscus, early tear film break-up time, with devitalized corneal epithelial cells that stain with rose bengal. Mucus strands attached to the cornea or in the inferior fornix are also frequently seen, with filamentary keratitis often becoming the painful consequence. 221 Secondary Sjögren’s syndrome describes patients with RA or any other identifiable connective tissue disorder, including systemic lupus erythematosus (SLE), diffuse scleroderma (DS), polyarteritis nodosa (PAN), polymyositis, and psoriatic arthritis (PA), who have KCS and xerostomia. A prospective study examining secondary Sjögren’s syndrome in RA concluded that KCS and xerostomia are frequently subclinical in these patients when compared with changes seen on labial salivary gland biopsy specimens, the gold standard for diagnosis. Rose bengal staining was found to be more sensitive in identifying these patients than was either the Schirmer’s test or parotid gland flow rate studies (37). Alexander and co-workers (38,39) have described Sjögren’s patients with ischemic optic neuropathy, presumed to be a consequence of central nervous system vasculitis (38,39). Corneal involvement in RA may be seen rarely in association with episcleritis but more frequently with anterior scleritis. McGavin and others (40-42) found that 43% of RA patients with scleritis had associated corneal involvement. Sclerosing keratitis, which typically occurs adjacent to the inflamed sclera but occasionally in an annular distribution, is characterized by corneal opacification followed by vascularization. The scarring does not disappear with treatment in RA and may progress with recurrences of the scleritis. In stromal keratitis, midstromal opacities are caused by infiltrates and may coalesce. The opacities can be surrounded by a “precipitin” ring, suggesting the involvement of immune complexes. The most severe corneal disease associated with scleritis in RA is keratolysis, in which rapid corneal stromal melting is seen, requiring early referral to ophthalmology for tectonic grafting (41,42). Corneal disease can occur without episcleritis and scleritis. Marginal furrowing, also referred to as limbal guttering, occurs initially in the peripheral cornea but can extend circumferentially, leaving minimal clear central cornea (43,44). Rare reports of central sterile corneal ulceration after either topical or systemic steroid use in RA are found in the literature (45,46). Corneas compromised by inadequate tear film are susceptible to infection, and most cases of bacterial corneal ulcers found in RA patients with secondary Sjögren’s syndrome were caused by gram-positive organisms, particularly Staphylococcus and Streptococcus species (45). 222 Peripheral ulcerative keratitis (PUK) is seen in a number of systemic diseases, including RA. Most commonly, the ulceration is seen inferiorly, leading one to implicate dessication as part of the pathology. Histologically, adjacent conjunctival and episcleral tissues have an abundance of lymphocytes and macrophages. Removal of these inciting mononuclear cells may be the basis for the beneficial effect of conjunctival resection (46). Episcleritis and scleritis are both described in RA patients. Episcleritis is fairly sudden in onset, and patients usually describe discomfort rather than pain. Visual acuity is rarely affected. Attacks last 1 to 2 weeks and are self-limited, but they can be recurrent for years, occurring at intervals of 1 to 3 months. Episcleritis is classified as simple or nodular (47). The incidence of episcleritis in a large group of ambulatory RA patients was 0.17 %, whereas in patients who presented to an ophthalmology clinic with episcleritis, 5.6% had RA (40). The overall prevalence of scleritis in RA patients is reported to range from 0.67 to 6.3%, although as many as 33% of all patients presenting to an ophthalmologist with scleritis may have associated RA (40). Patients with scleritis typically complain of the insidious onset of a deep, boring pain, photophobia, and tearing in a red, tender eye. Scleritis in RA is associated with a more ominous prognosis with regard to ocular morbidity and associated extraarticular manifestations when compared with episcleritis. In general, ophthalmologic consultations should be obtained regularly in RA patients. Watson and Hayreh (47) have proposed a classification of scleritis that includes diffuse anterior scleritis, the most common form of scleritis; nodular scleritis; and necrotizing scleritis, with and without inflammation, which is also called scleromalacia perforans, characterized by severe thinning of the sclera in an otherwise clinically noninflamed, nonpainful eye (47). Uveal prolapse covered by conjunctiva alone is not an uncommon finding in scleromalacia perforans. Frank perforation without trauma is rare. Inflammatory necrotizing scleritis is usually associated with widespread visceral involvement in RA. Necrotizing scleritis or PUK, when not treated with systemic immunosuppression, is associated with high mortality (40,47-49). The ophthalmologist and rheumatologist should collaborate in the urgent and long-term care of these RA patients. HAMIDEH AND PRETE Posterior scleritis in RA is often misdiagnosed because it may present as severe orbital pain, with proptosis, limited extraocular movements, and uveitis (50). Not infrequently, only minimal orbital discomfort is present. Decrease in visual acuity is dependent on retinal and choroidal involvement. Ultrasonography is often required to confirm the diagnosis in RA patients. Although topical medications may provide symptomatic relief, systemic therapy is required to halt the progression of scleritis. Verhoeff and King (51) in 1938 were the first to describe episcleral nodules in RA. Histologically, episcleral nodules resemble subcutaneous rheumatoid nodules. They are usually bilateral and tend to develop during the active phase of the disease. The nodules are quite tender but respond very well to systemic corticosteroid therapy. These nodules may easily be confused with pseudorheumatoid nodules, which occur in children and young adults without any rheumatic disease. Histologically, they are necrobiotic granulomata, which regress spontaneously (52). The orbital apex syndrome (which includes internal and external ophthalmoplegia, ptosis, decreased corneal sensation, and decreased vision resulting from orbital rheumatoid nodules) also has been described (53). Brown’s syndrome, consisting of an inability to elevate the eye when it is in adduction, occurs occasionally in RA secondary to inflammation of the bursa between the orbital trochlea and the superior oblique tendon (54). Venous stasis retinopathy has been described in RA as part of a hyperviscosity syndrome secondary to polyclonal gammopathy (55). Cranial nerve palsies and geniculocortical blindness also have been reported (56). Juvenile Chronic Arthritis (JCA) The incidence of uveitis in juvenile chronic arthritis (JCA) is estimated to be about 21%, ranging from 1% to 6% of the patients in the systemiconset group, 7% to 14% of those with polyarticular onset, and 78% to 91% of patients with pauciarticular-onset JCA (57,58). Girls with JCA carry a distinctly higher risk of uveitis than do boys (59,60). In one study, in which 86% of the patients were girls, girls were found to have, on average, a 4-year earlier onset, and a significantly longer duration of active disease than boys (61). In the uveitis of JCA, there is no relationship between OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES joint inflammation and the presence or exacerbation of intraocular inflammation. Children with JCA and uveitis usually do not have a positive rheumatoid factor and are seronegative as indicated by both latex and agglutination titer testing (62). The presence of circulating antinuclear antibodies (ANA) and uveitis in JCA patients is well known and necessitates frequent ophthalmologic consultation. ANA prevalence ranges from 71% to 93%, with titer being unrelated to the severity of eye involvement (57,63). In the study by Dana et al (61), 82% of the eyes and 89% of JCA children, had at least one complication related to their uveitis: cataracts (70%), band keratopathy (64%), clinical or angiographic macular edema (32%), vitreous haze (25%), glaucomatous optic neuropathy (21%), or hypotony (17%). Band keratopathy is caused by the accumulation of calcium hydroxyapatite in the subepithelial space and Bowman’s membrane, which is located in the anterior part of the cornea. It usually appears in the periphery of the cornea at the level of the interpalpebral cornea and progresses centrally, finally involving the visual axis. Prolonged topical and systemic steroid treatment, as well as the inflammatory status of the eye, may lead to the formation of cataracts in 28% to 31% of JCA children (64-66). Glaucoma in children with JCA may be attributable either to the administration of steroid drops or more often to the inflammatory status of the eye. The overall incidence of glaucoma in JCA patients varies from 14% to 22% (67,68). The visual prognosis of secondary glaucoma in children with JCA is poor, with 35% of patients having no light perception (69). Macular edema appears to be an underestimated complication of JCA; it may be secondary to the inflammatory status of the eye or to cataract surgery, and it can reduce visual acuity, in addition to other complications (61). Diagnosis may be made clinically by the fundal examination and is usually identified by fluorescein angiograms, but these may be difficult to achieve in young children. Vitreous haze is the consequence of the presence of cellular inflammatory cells in the vitreous humor (61). Vision is reduced in direct proportion to the density of cells, and this complication may require special treatment. Hypotony of the eye is thought to be secondary to the hypoactivity of the ciliary body (secreting the aqueous humour) and is usually found in eyes that have longstanding 223 chronic inflammation or that have had multiple operations. Rarely, other complications may occur, such as the formation of epiretinal membranes, tractional or reghmatogeneous (ripping-related) retinal detachment, disc neovascularization (70), or the acquired Brown’s syndrome (71). Reiter’s Disease Inflammatory eye lesions form a classic part of the clinical picture of Reiter’s syndrome and may be unilateral or bilateral. Conjunctivitis with sterile discharge is the most frequent manifestation. It usually subsides but may progress to episcleritis, keratitis, or even corneal ulcerations (72,73). Acute uveitis, especially anterior uveitis (iridocyclitis), also is common. The ocular lesions may be the first or the only manifestation of this reactive arthritis, which is associated with HLA-B27, and have a strong tendency to recur (74). Ankylosing Spondylitis Acute anterior uveitis is the most common extraskeletal involvement in patients with ankylosing spondylitis (AS), occurring in 25% to 40% of patients at some time in the disease course (75-80). It is relatively more common in HLA-B27–positive (81,82) than HLA-B27–negative patients with AS, who usually have higher rates of circulating plasma immune complexes (83). There is little correlation between the activity of AS and the development of acute anterior uveitis. The acute anterior uveitis is related to AS itself and not because both are associated with HLA-B27. Thus, it is 11 times more prevalent in AS patients than in HLA-B27–positive relatives without AS. This uveitis is virtually always unilateral and has a strong tendency to recur, not infrequently in the contralateral eye. It is rare for both eyes to be clinically involved during the same attack, and such bilateral involvement, even in an individual with AS, should stimulate a search either for an alternative cause or for underlying Reiter’s syndrome. Individual attacks of uveitis usually subside within 2 to 3 months, without any sequelae. Residual visual impairment is rare; it may occur if treatment is inadequate or delayed. Occasionally, acute iritis may be the presenting symptom that draws attention to the diagnosis of AS or related spondyloarthropathy (75,84). As in AS itself, the uveitis is seen more frequently in men, but there is some indication that it may be increased during preg- 224 nancy. In one study, it was seen in 10 of 50 pregnant women with AS (85). Juvenile Ankylosing Spondylitis (JAS) Acute anterior uveitis occurs in 5% to 10% of the juvenile ankylosing spondylitis (JAS) patients (86). In Kanski and Shun-Shin’s study (69), which included 340 children with anterior uveitis, 14% had JAS. Involvement in boys is 90% of cases. Patients are negative for serum rheumatoid factor and ANA but are HLA B27 positive. Three distinct presentations of JAS have been described: most of the patients presented with back pain (the lumbrosacral spine or the sacroiliac joints); 25% presented with peripheral asymmetric pauciarticular inflammation; and the smallest group (3%) were those with acute anterior uveitis. Calabro (87) reported that 25% of JAS patients developed acute anterior uveitis, but none developed chronic progressive anterior uveitis of JCA. Ocular inflammation in patients with HLA B27 arthropathies and AS have acute self-limiting uveitis resolving within weeks of onset and responding well to local treatment. Recurrence is common in JAS, but permanent visual loss, as in JCA, is rare (87-89). The inflammation is usually unilateral at presentation, but in most of the patients, during the course of the illness, both eyes are involved (88). Inflammatory Bowel Disease (IBD) and Arthritis Acute anterior uveitis is the most common ocular manifestation in inflammatory bowel disease (IBD) (90). It is associated with HLA-B27 and with axial involvement (91). Conjunctivitis and episcleritis are other rare ocular manifestations occurring in IBD and are characterized by a red eye without pain and photophobia. Acute anterior uveitis is the ocular manifestation most commonly associated with Crohn’s disease, occurring in 3% to 11% (90,92) of patients. It is acute in onset, unilateral, and transient, but recurrences are common. Conjunctivitis and episcleritis also are described. The dermatologic and ocular manifestations of ulcerative colitis are comparable to those seen in Crohn’s disease but are less common. Acute anterior uveitis and conjunctivitis occur in approximately 5% to 30% of enterogenic reactive arthritis cases (93,94) and are usually self-limited. The uveitis frequently is associated with attacks of arthritis but subsequently can follow an independent course (95). HAMIDEH AND PRETE Progressive dementia and ophthalmoparesis are relatively common in Whipple’s disease. Oculomasticatory myorhythmia, a pendular convergence nystagmus with co-contraction of muscles of mastication, has been described. Keratitis, uveitis, vitreous opacities, retinal hemorrhage, cottonwool spots, optic disc edema, and choroidal folds have been reported in Whipple’s disease (96-102). Psoriatic Arthritis Ocular signs occur in approximately 10% of cases of psoriasis (103). Such complications are seen twice as frequently in men as in women and may be the only manifestation of the disease (104). The eyelids are frequently involved, and if the scaling process affects the bases of the lashes, the eyelid margins may become swollen, erythematous, and scaly (105). Granulating lesions of the palpebral and bulbar conjunctiva and vascular infiltration of the cornea may appear (104,106). Wright and Reed (107) reported a significant association between psoriatic arthritis and the ocular involvement in psoriasis in a series of 11 patients with psoriatic arthritis (107). Juvenile Psoriatic Arthritis (JPsA) The percentage of children with juvenile psoriatic arthropathy (JPsA) and anterior uveitis varies from 8% to 14% (108,109). A total of 80% of Shore and Ansell’s JPsA patients with uveitis were ANA positive and presented at an early stage as pauciarticular disease (108). Dermatologic symptoms usually develop after a few years (110). There appears to be a predilection in girls for eye disease in JPsA. The affliction is usually bilateral and may lead to cataract formation. Lyme Disease In Lyme disease, the eye is spared during the localized infection (111). Steere reported conjunctivitis and photophobia in 11% of patients with early Lyme disease (112) and considered this a manifestation of stage 2 disseminated disease (113,114). Other ocular manifestations of disseminated disease include intraocular inflammation (iridocyclitis/uveitis) (115,116), panophthalmitis (117), and choroiditis (118), macular edema (119), optic disc edema (119,120), optic neuritis (121123), and optic atrophy (124). The ophthalmologic manifestations of stage 3 (persistent infection) Lyme disease include stromal OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES keratitis (125-131), episcleritis (128,132), orbital myositis (133), and cortical blindness (134). Stromal keratitis is characterized by multiple nebular opacities with indistinct borders at varying levels of the stroma. Stromal edema and neovascularization can be present (126,127). Stromal keratitis may occur earlier in the disease than has been reported, because patients may be asymptomatic. Systemic lupus erythematosus (SLE). KCS with or without xerostomia is the most common ocular manifestation of systemic lupus erythematosus (SLE), occurring in approximately 25% of patients (135,136). Conjunctivitis, episcleritis, and interstitial keratitis are rare (137-140). Diffuse anterior or nodular scleritis can be the presenting manifestation of SLE (141,142), and rheumatologists should consider the diagnosis of SLE in patients with scleritis (143). Necrotizing scleritis is uncommon in SLE compared with RA and other immunologic disorders. Discoid lupus can occur on the eyelids, appearing very much like chronic blepharitis. Retinal involvement in SLE is common, second only to KCS. A prospective clinical study showed that 88% of patients with lupus retinopathy had active systemic disease, and SLE patients with retinopathy had a significantly decreased survival compared with those without retinopathy (144). The classic finding in lupus retinopathy is the cottonwool spot, which has been correlated with avascular zones on fluorescein angiography (145). Severe visual loss is not usually seen, and the retinopathy improves with treatment of the underlying disease. Far fewer patients with lupus retinopathy develop severe retinal vasculitis that can progress to proliferative retinopathy that has a worse visual prognosis (146-148). The underlying process is characterized by diffuse arteriolar occlusion with extensive capillary nonperfusion; retinal neovascularization may result. The severe retinopathy in this group of patients is typically associated with active systemic disease and with central nervous system lupus in particular. However, some patients develop proliferative retinopathy with quiescent systemic disease (146,149). Choroidopathy is much less common in SLE compared with retinopathy. Jabs and colleagues (150) described six lupus patients with multifocal serous elevation of the retinal pigmented epithelium (RPE) and sensory retina (150). Control of systemic disease in three of these patients resulted 225 in improvement of their serous detachments. Finally, Matsuo and associates (151) reported two additional cases of lupus with multifocal RPE and serous retinal detachments (151), one of whom had deposits of immune complexes in Bruch’s membrane. Retrochiasmal visual problems in lupus include geniculocalcarine blindness, homonymous hemianopsia, visual hallucinations, and transient amaurosis. Painful ophthalmoplegia that reversed with systemic steroids has been described in SLE (152). Diplopia as a transient phenomenon, often with vertigo, can be seen, and unilateral internuclear ophthalmoplegia (INO) is well known in SLE. However, bilateral INO, characteristic of multiple sclerosis with lesions of both medial longitudinal fasciculi, has also been described in SLE (153,154). Orbital myositis manifesting with proptosis and pain with external ocular movements occurs infrequently (155,156). Episcleritis, widespread RPE changes, and capillary tortuosity have been reported in drug-induced lupus caused by hydralazine (157). Lupus Anticoagulants, Antiphospholipid Antibodies There are many problems in patients with lupus and lupus anticoagulants, primarily retinal and neuroophthalmologic in nature. Independent studies have shown the presence of lupus anticoagulants in patients with retinopathy in a higher proportion than in the general SLE population (144,158-160). Lupus anticoagulants also have been associated with central retinal vein occlusion in SLE and in otherwise healthy adults without any immunologic diseases (158). Optic neuritis (161163) and ischemic optic neuropathy (159,164) also have been reported. Optic nerve (161) and chiasmal lesions (165) have been seen, along with spinal cord disease in SLE. A mistaken diagnosis of multiple sclerosis is frequently made in these cases of lupus neuropathy because of similar clinical presentations, which occur typically in young women. Not infrequently, involvement of the visual system may be the manifesting sign of SLE. Ocular inflammatory problems such as uveitis or scleritis may precede diagnosable SLE by 5 or more years. The patient may be ANA-positive at the time of initial evaluation and may have extraocular signs or symptoms such as Raynaud’s phenomenon, alopecia, arthralgias, 226 or recurrent aphthous ulcers. These individuals must be considered “lupus suspects” and should be restudied annually. In general, eye manifestations in SLE patients require ophthalmologic consultation for diagnosis and treatment. Fibromyalgia There is no documented ocular disease in fibromyalgia. However, many patients report multiple seemingly unrelated somatic symptoms, such as dizziness, difficulty concentrating, dry eyes and dry mouth, palpitations, and sensitivity to foods, medications, and allergens. Diffuse Scleroderma KCS, with or without xerostomia, is probably the most frequent ocular finding in DS (166-169). Most patients have progressive conjunctival pouch (forniceal) foreshortening from subepithelial fibrosis (169,170), which is not surprising in a disease characterized by mucosal subepithelial fibrosis. Other conjunctival findings include vascular congestion, telangiectasia, varicosities, intravascular sludging, and loss of fine vessels (168,171). Corneal involvement is rare (172-174). Ophthalmoscopic manifestations of DS include retinal hemorrhages, retinal and optic nerve head edema, hard exudates, cottonwool spots with or without cytoid bodies, and venous thrombosis (168,174-178) and are more typical of advanced disease. One third to one half of DS patients had choroidal vascular abnormalities characterized by areas of delayed choroidal perfusion (179) and late hyperfluorescence, which was attributed to the retinal pigment epithelial layer (180). All of the histologic findings support the general concept that the primary injury in scleroderma is to the vascular endothelium (175,181). Diffuse scleroderma frequently involves the eyelids and periorbital tissues. Periorbital edema has been described (182-184) and is usually followed by fibrosis or atrophy, but swelling alone may occasionally persist for months (168). The most frequent ocular manifestation is the fibrotic change seen in the lids, resulting in an indurated, “woody” appearence (168). Patients often complain of stiff and taut lids, and the progressive blepharophimosis can be dramatic. Lid telangiectasia may occur (168), and eyelashes may be lost (168,169). Exposure keratitis secondary to the fibrotic lid changes may occur; cicatricial ectropion HAMIDEH AND PRETE is rare (185). Orbital involvement in scleroderma is limited to the extraocular muscles. Both localized scleroderma (coup de sabre) (186-188) and DS (189) have been associated with ocular myopathy, most notably affecting the superior rectus muscle. Other findings associated with scleroderma include iritis, iris sectoral atrophy (190), iris transillumination defects (168), heterochromia (182), and pupillary sphincter dysfunction (191). However, cataract, vitreous frosting, and raised intraocular pressure are probably not related to scleroderma as reported by others (168,169). Inflammatory Muscle Disease The most common ocular manifestation of patients with inflammatory muscle disease is the heliotrope rash affecting the eyelids. Occasionally ophthalmoplegia caused by involvement of the extraocular muscles by myositis may be seen, but ocular and facial muscle weakness are rare (189,192). Cottonwool spots on the retina occasionally have been seen in association with polymyositis and dermatomyositis (193-202). Most of these reports are in children with dermatomyositis, and this association may be attributable to the vasculitic nature of the disease in children (194200). However, retinal microangiopathy also has been reported in an occasional dermatomyositis patient without demonstrable systemic vasculitis (201). Vasculitis—Wegener’s Granulomatosis The ocular manifestations of vasculitis fall into two general categories: scleritis, and vasculitismediated damage to the retina, optic nerve, or cranial nerves (203). Although these eye lesions may occur with any of the vasculitides, the frequency and the pattern of ocular involvement is dependent on the size and pattern of blood vessels involved by a given type of vasculitis. Thus, ocular manifestations are very common in Wegener’s granulomatosis, which frequently involves the small to medium vessels of the head and neck, occurring in approximately half of the patients (204-212). Orbital disease is common in Wegener’s, often presenting as an extension of the granulomatous inflammation from the sinus into the orbit (213,214). Orbital cellulitis may occur as a sinus superinfection that extends into the orbit. Dacryocystitis may develop as a consequence of obstruction of the nasolacrimal drainage apparatus OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES from the involved nasal mucosa. Scleritis also is common and may be of any type. Marginal corneal ulcers are often seen in association with the scleritis (necrotizing sclerokeratitis) (205-209). Retinal vascular and optic nerve lesions occur in 10% to 18% of patients with ocular involvement from Wegener’s granulomatosis (207). A retinopathy consisting of cottonwool spots with or without intraretinal hemorrhages is more common, but retinal arterial occlusion, ischemic optic neuropathy, optic disc vasculitis, and even retinal vasculitis, have been reported. In patients with retinal vasculitis, neovascularization, vitreous hemorrhage, and rubeotic glaucoma may develop (205-209,215). Giant Cell Arteritis Ischemic optic neuropathy is the most common cause of visual loss in giant cell arteritis (GCA), occurring in 36% of patients, but more recent studies series reported less visual loss because of earlier disease recognition and corticosteroid therapy use (216-224). The characteristic clinical features of ischemic optic neuropathy are a painless, sudden loss of vision, loss of color vision, and the characteristic altitudinal visual field defect. Amaurosis fugax has been reported in 2% to 19% of patients with GCA and is an indication for immediate corticosteroid therapy (225). Diplopia caused by ophthalmoplegia occurs in approximately 12% of patients with GCA, and is attributable to ischemia of the extraocular muscles (225-229). Other ocular complications include the ocular ischemic syndrome, hypotony, choroidal ischemia, and cortical blindness (216,230-232). Polyarteritis Nodosa Although polyarteritis nodosa generally involves visceral vessels, ocular involvement occurs in 10% to 20% of patients (233-255). Older series reporting more ocular disease did not distinguish between polyarteritis nodosa and other forms of vasculitis. The most common ocular manifestations of polyarteritis nodosa are related to the vascular disease and include hypertensive retinopathy in patients with renal disease, retinopathy from the vasculitis itself, retinal arterial occlusive disease, central lesions resulting in visual loss (such as visual field deficits), cranial nerve palsies, scleritis, and marginal corneal ulceration. Any type of scleritis can occur, although the anterior or necrotizing type is more common than posterior 227 scleritis. Choroidal ischemia with serous detachments of the retina also has been reported (251). Churg-Strauss Allergic Granulomatosis In addition to the vasculitis-related ocular complications, such as scleritis and neuro-ophthalmologic lesions, seen in polyarteritis nodosa, conjunctival granulomas may be seen in patients with Churg-Strauss allergic granulomatosis (256-261). Takayasu’s Arteritis In 1908, Takayasu, an ophthalmologist, described unusual retinal arteriovenous anastomoses in a young woman (262). Two other ophthalmologists, Oonishi and Kagoshima, separately and simultaneously reported the association of the retinal vascular pattern with a radial pulse deficit. The most characteristic ocular findings of Takayasus arteritis are retinal arteriovenous anastomoses. These lesions generally are seen around the disc and in the midperiphery, and are thought to be due to ocular ischemia from narrowing of the carotid and vertebral arteries (263). These retinal changes are best demonstrated by fluorescein angiography. The earliest findings are small vessel dilation and microaneurysm formation. Long-standing and more severe ischemia may result in peripheral retinal nonperfusion, neovascularization, and consequent vitreous hemorrhage (264). Cogan’s Syndrome Cogan’s syndrome consists of nonsyphilitic interstitial keratitis with characteristically patchy, bilateral vascularization of the middle and deep corneal stroma, associated with vestibular-auditory symptoms, such as hearing loss, dysacousia, or vertigo. Cogan’s syndrome in its atypical form can be associated with orbital inflammation, which may be bilateral or unilateral (265-272). This form of the disease is not necessarily associated with any corneal pathology, but rather the presence of hearing loss, vertigo, tinnitus, scleritis, chemosis, and conjunctival injection, mild iritis, eyelid edema, and proptosis. Painful interstitial keratitis may develop after orbital inflammation occurs. Kawasaki Disease Kawasaki disease, also called mucocutaneous lymph node syndrome (273), has conjunctival hyperemia in 95% of cases. Burns and co-workers (274) found evidence of anterior uveitis by slit- 228 lamp examination in 66% of patients examined after the onset of fever; bilateral involvement was present in 97% of those affected (274). Other ocular manifestations of Kawasaki disease include punctate keratitis, subconjunctival hemorrhage, optic disk edema, and vitreous opacities (275). Blau Syndrome Blau syndrome comprises granulomatous arthritis, iritis, and rash, in the absence of pulmonary manifestations and the presence of a negative Kveim-Siltzbach skin test (276-278). It is an autosomal-dominant trait with variable expressivity and onset in childhood. Cinca Syndrome Chronic inflammatory neurologic, cutaneous, and arthritis syndrome is a recently defined condition presenting most often at birth with rash, progressive arthritis, fever, chronic meningitis as well as sensory organ involvement including deafness and eye manifestations (279,280). The ocular manifestations have been recently categorized and include chronic perilimbic redness, corneal infiltration, anterior uveitis without the complications associated with JCA, and optic neuropathy leading to visual impairment in 25% of cases (279). HAMIDEH AND PRETE Corneal sarcoidosis may be either interstitial keratitis or localized stromal opacification secondary to endothelial decompensation in areas where keratic precipitates once were present (286,287). The sclera rarely may be a site of activity in sarcoidosis. Granulomatous scleritis, a localized form of nodular scleritis, also may be seen (288). Acute sarcoid iridocyclitis occurs, and chronic iridocyclitis frequently is associated with cystoid macular edema. Patients tend to be older and present with blurred vision and floating spots (281). Keratic precipitates, posterior and anterior synechiae, and vitreous cells all may be present. Small exudates near retinal veins, termed “candle wax drippings” (en taches de bougie), may be present in sarcoidosis (281,289). Neovascularization may occur. Choroidal granulomas may be small and multiple or single and very large resembling a choroidal tumor. Chronic cystoid macular edema may cause decreased vision in patients with long-standing sarcoid uveitis. The optic nerve may be involved with disc neovascularization, disc edema in chronic inflammation, or with granuloma formation within the optic nerve. Ophthalmologic Manifestations of Heriditary Connective Tissue Diseases Sarcoidosis Metabolic Disease Uveitis is the most common and most serious form of intraocular involvement in sarcoidosis (281,282). Uveitis in sarcoidosis may be granulomatous or nongranulomatous, acute or chronic, localized or diffuse. Acute iritis presents most often in women, between the ages 20 and 30 years, with pain, redness, and photophobia (281). Iris nodules on the pupillary border (known as Koeppe nodules) or in the midstroma (known as Busacca nodules) may be present (283,284). Any part of the globe or ocular adnexa also may be involved. The skin of the lids may have sarcoid nodules. Conjunctival sarcoidosis appears as discrete yellowish nodules usually less than 2 mm in diameter. Although these nodules may occur on the tarsal conjunctiva and in the fornices, they also may be present on the bulbar conjunctiva or on the conjunctiva overlying the lacrimal gland. Lacrimal gland enlargement or dacryoadenitis is an early finding in sarcoidosis, but it is the initial manifestation of the disease in approximately 1% of patients (285). Gout and alkaptonuria. Tophi can occur in different parts of the eye in chronic gout. In alkaptonuria (ochronosis), no eye disease occurs, and the characteristic pigmentation of the sclera is rarely seen before the age 20 years. The deposition of ochronotic pigment in the eye usually is visible at the insertion of the rectus muscle, but it may be more diffuse, involving the conjunctiva and cornea (290). Marfan’s syndrome. In Marfan’s syndrome, the principal lenticular anomaly is ectopia lentis. This is found in most patients; it is usually bilateral and commonly occurs as superior or supernasal displacement, presumably because of poor zonular attachments (291). Myopia, ptosis, megalocornea, and blue sclera all have been reported frequently in patients with Marfan’s syndrome (292). Strabismus likewise is extremely common, but its presence alone does not suggest the diagnosis (293). The anterior segment structures exhibit both subtle and gross changes, some of which (especially in combination) are OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES strongly suggestive of Marfan’s syndrome. The anterior chamber angle exhibits an immature ciliary body with hypoplasia of the muscular elements, a broad trabecular meshwork, and an inconspicuous Schwalbe’s line (the circular line between corneal endothelium and trabecular meshwork). Transillumination shows that the iris has a posterior insertion on the ciliary body, the processes of which extend radially behind the iris much more than usual. The iris tends to show no circumferential ridges, few crypts, and, occasionally, iris root cysts, whereas iridodonesis occurs when the lens is subluxed. One peculiar abnormality is hypoplasia of the iris dilator muscle; this causes the pupil to remain small even in response to mydriatic drops. Hypopigmentation of the iris pigment epithelium has been described (291,294,295). Spherophakia and cataract formation also occur in Marfan’s syndrome. Various types of retinal degeneration may be seen, including myopic and lattice degeneration and vitreous traction syndromes in the peripheral retina. Both retinal detachment and peripheral pigmentary retinopathy are common. Glaucoma complicating Marfan’s syndrome may arise by any one of several mechanisms, including direct pupillary block from anterior lens dislocation, lens luxation into the anterior chamber, and upward or downward lens dislocation resulting in crowding of the anterior chamber angle by mechanical movement of the iris. Ehlers-Danlos syndrome. Multiple ocular abnormalities have been described in association with Ehlers-Danlos syndrome, especially with the ocular form or form VI, the most common of which is marked epicanthal folds (296,297). Angioid streaks and associated macular pigmentary degeneration occur in patients with this disease alone or in combination with pseudoxanthoma elasticum (298). Other eye findings include strabismus, blue fragile sclerae with spontaneous perforation of the globe, microcornea, keratoconus, ectopia lentis, epicanthal folds, strabismus, microcornea/microphthalmos, severe myopia, and familial retinal detachment (290,299-304). Osteogenesis imperfecta. Ocular findings in osteogenesis imperfecta are varied, but the most prominent and well-recognized finding is the blueish coloration of the sclera caused by increased translucency allowing the uveal pigment to shine through. Whether patients with blue scleras and no 229 other findings of osteogenesis imperfecta really have the disease or not is a philosophic question. In pathologic examination, both the cornea and sclera are reduced in thickness by 50% to 75%, and megalocornea and keratoconus have been described coincidentally (305). Hypermetropia, zonular cataracts, posterior embryotoxon (a band of corneal opacity, similar in appearance to arcus senilis, sometimes seen in the newborn), and retrobulbar neuritis also have been irregularly reported, whereas glaucoma occurs even less frequently. A common finding is the appearance of a Saturn ring, which is a comparative whitening of the paralimbal sclera that occurs as a result of the lack of pigmented uvea behind the sclera. Optic atrophy may be attributable to bony compression of the nerve or may develop secondary to chronic papilledema. Paget’s disease of bone. The ocular findings associated with Paget’s disease are of two principal types: (1) the intrinsic disorders of the eye associated with osteitis deformans; and (2) the effects on the eye produced by the bone disease when it encroaches on nerves and blood vessels (306). Primary ocular manifestations of Paget’s disease most commonly include choroidal sclerosis and angioid streaks. The precise percentage of patients in whom these manifestations occur has not been determined, but both are seen frequently enough that their presence should not be considered unusual. Choroidal sclerosis is of the senile diffuse type, and the angioid streaks appear much the same as they do in certain other associated conditions such as pseudoxanthoma elasticum, sickle cell disease, Ehlers-Danlos syndrome, and familial hyperphosphatemia. Only in Paget’s disease and pseudoxanthoma elasticum is it common to find these angioid streaks progressing to disciform degeneration with severe loss of central vision (307). Cataract formation may be seen in patients with Paget’s disease, but this may be nothing more than coincidence in an aging population. Bony compression of nerves in Paget’s disease results in much higher ocular morbidity than does intraocular disease (308). Spasm of the seventh nerve may develop bilaterally, with associated painful blepharospasm. There may be trigeminal neuralgia, which may be similar to any form of tic and which may be associated with lacrimation and a red eye. Extraocular muscle palsies are seen; these may result from compression of nerves in 230 various cranial foramens, or, in the case of the trochlear nerve, bony deformity of the trochlea may cause a mechanical limitation of superior oblique function. Visual loss caused by optic nerve compression may progress slowly and insidiously, causing bizarre visual field defects and eventually result in optic atrophy (309). Rarely, extensive orbital involvement by Paget’s disease may cause an increase in orbital venous pressure with a resultant increase in intraocular pressure. Osteopetrosis. Signs and symptoms referable to the eyes in osteopetrosis are principally a result of bony abnormalities about the eyes and orbit. Ophthalmoplegia, especially of the third and fourth nerves, as well as nystagmus of inconsistent type, are commonly observed (310,311). Exophthalmos occurs as a result of bone disease in the orbit. Optic atrophy is potentially the most serious of the ocular complications. It may be caused by direct bony compression of the optic nerve, secondary to chronic papilledema, or by optic nerve involvement by infection in patients with chronic meningitis (usually secondary to chronic osteomyelitis). Fibrous dysplasia—Albright’s disease. The eye signs in fibrous dysplasia of bone and Albright’s disease are of three general classes, which are all referable to changes in the bony orbit. The most potentially serious change is loss of vision caused by compression of the optic nerve within the optic canal. This is easily diagnosed and localized with radiologic techniques; it occurs when the sphenoid bone is involved (312). The second category of ocular anomaly is proptosis, which, like decreased vision, may be the presenting sign of fibrous dysplasia (313). The direction of the proptosis is dependent on which of the orbital bones is involved and usually is away from the mass. Because the tumors may arise from any bone, including the sides of the orbit, the displacement of the globe may be lateral as well as forward. Lateral displacement of the globe is a very unusual finding in most other orbital tumors. The sequelae of proptosis, such as corneal exposure and chemosis, are found when the displacement is severe. The final common ocular finding is a disturbance in motility, which occurs for obvious reasons (314). It should be emphasized that the monostotic form of the disease often shows a predilection for the bones of the orbit. The absence of generalized findings should not dissuade the clinician from the diagnosis of fibrous dysplasia. HAMIDEH AND PRETE Stickler’s syndrome. A familial form of osteoarthritis with prominent ocular involvement is Stickler’s syndrome (hereditary arthro-ophthalmopathy). This syndrome is a relatively common autosomal-dominant disease (1 in 10,000) characterized by vitreous degeneration, retinal detachment, and premature degenerative joint disease (315,316). Patients are usually highly myopic, and many have peripheral perivascular pigmentary changes (but normal electroretinograms). Cataracts and open-angle glaucoma may develop. Vitreous degeneration is usual (317-319). The gravity of this condition lies in the malignant retinal detachment that may occur; the prognosis for repair of these detachments is poor (320). Kneist’s dysplasia. Kneist’s dysplasia is a rare autosomal dominant disorder characterized by shortening of the trunk and limbs, flattening of the face and bridge of the nose, protruberance of the eye globes, and severe joint abnormalities (321). The joints are usually large at birth and continue to enlarge during childhood and early adolescence. Most affected individuals develop severe premature degenerative joint disease, particularly involving the knees and hips. The articular cartilage is soft and has decreased resilience. Ocular abnormalities (myopia, retinal detachment and cataract) and deafness may be seen (321). Ophthalmologic Manifestations as Side Effects of Medications Used to Treat Rheumatic Diseases Table 4 summarizes the ocular side effects from drugs used to treat rheumatic diseases. Nonsteroidal Anti-inflammatory Drugs The systemic side effects of nonsteroidal antiinflammatory drugs are much more common than ocular side effects. There have been reports of whorl keratopathy (322) and possibly optic nerve toxicity with the use of indomethacin. Ocular side effects, including blurred vision without more serious vision-threatening side effects, diplopia, and toxic amblyopia (323), occur with the use of ibuprofen and naproxen but appear to be less common with the use of sulindac and tolmetin. Antimalarial Drugs Corneal deposition is seen with anti-malarial drugs (more commonly with chloroquine than hydroxychloroquine), does not appear to be related to OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES 231 Table 4: Ocular Side Effects of Rheumatic Drugs Drugs Ocular Side Effects NSAIDs Whorl keratopathy326 Optic neuropathy (possible toxicity)327 Photosensitivity326 Nystagmus (toxic effect)327 Retinal or subconjunctival hemorrhage327 Corticosteroids PSC (associated frequently with systemic steroids)334 Glaucoma (more frequently with topical steroids)336 Gold salts Corneal/lens deposits (over 1.5 g/Kg dose)339 Chloroquine/Hydroxychloroquine Toxic maculopathy and retinopathy329 Whorl keratopathy331 Toxic neuropathy332 Methotrexate Punctate keratopathy342 D-penicillamine Optic neuropathy344 NOTE. References are denoted by superscript numbers. Abbreviations: PSC, posterior subcapsular cataracts; NSAID, nonsteroid anti-inflammatory drug. dosage, and is seen within the first month after initiating treatment (324). Toxic retinopathy occurs in 13% to 40% of patients taking quinoline drugs (325-328). The classic bullseye retinopathy occurs with both medications, although less frequently with hydroxycloroquine. The incidence of retinopathy increases with higher cumulative dosages (greater than 8g/kg) (325). The medication has a predilection for pigmented tissues and accumulates in uveal tissue. One of the early ophthalmoscopic signs is pigmentary disruption of the macula (particularly in a circular pattern) and loss of the foveal reflex. These retinal signs may be difficult to distinguish from age-related maculopathy, and may be attributed to the latter in an aging patient. Cruess et al (326) found color photos to be as sensitive or more sensitive in detecting the pigment disruption associated with quinoline toxic retinopathy. Serial color testing should be performed, and Ishihara plates with appropriate lighting are the preferred method (326). Vision loss will develop if toxic maculopathy occurs. Cessation of the drug allows pigmented tissues to release bound drug but not immediately, contributing to maculopathy progression after discontinuing the drug. Electroretinography and electrooculography are used to follow chloroquine toxicity, which primarily affects the retinal pigment epithelium. However, the elec- trooculogram is abnormal in 20% of RA patients not using chloroquine (329). Corticosteroids The correlation between steroid use and posterior subcapsular cataracts (PSC) is well documented (330,331). This occurs with both topically applied and orally administered steroids. PSC development is related to the duration, dosage, and patient susceptibility. PSC occurs more frequently with oral administration compared with topical administration, more potent as opposed to less potent steroid, and long-term as compared with short-term usage. The secondary open angle glaucoma that occurs with steroid use is more frequently seen with topical than oral administration (332). Gold Salts Gold salts cause chrysiasis (red-purple deposits of gold), which is found histologically throughout the body, including the eye. Ocular chrysiasis is seen in 97% of patients receiving a cumulative parenteral dosage greater than 1,000 mg/kg (333335). Gold deposits can be seen in the eyelid, conjunctiva, corneal stroma, anterior lens, and retina. Reversal of the tissue deposition occurs after drug cessation (as early as 6 months). There is no 232 HAMIDEH AND PRETE need to discontinue treatment when chrysiasis is found. Tierney reports that tissues with gold deposits are at risk for developing hypersensitivity reactions, which is not unreasonable given the altered immunologic systems associated with rheumatic disease (336). Kincaid et al (337) observed RA patients with corneal chrysiasis, inflammation, and marginal ulceration. However, it is difficult to establish a causal relationship between gold deposition and inflammation. The keratitis and marginal ulceration may be manifestations of the underlying RA pathologic process and not related to the corneal deposits. Gold salts have been implicated as a cause of the Miller Fisher syndrome, characterized by bilateral external ophthalmoplegia, generalized areflexia, and ataxia (338). Methotrexate Tear levels of methotrexate are equivalent to serum levels as early as 48 hours after the initiation of therapy (339). Diffuse irritation of the cornea, conjunctiva and eyelids occur commonly. Ocular lubricants without preservatives are beneficial. 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GLOSSARY age-related maculopathy (ARM): A common macular degeneration beginning with drusen of the macula and pigment disruption and sometimes leading to severe loss of central vision. amaurosis fugax: Transient blindness that may result from transient ischemia due to carotid artery insufficiency, retinal artery embolus, or centrifugal force (visual blackout in flight). amblyopia: An ancient word meaning “impaired vision.” It is associated with poor vision in one eye without detectable cause. More recently, It has become almost synonymous with suppression amblyopia. angioid streaks: Breaks in Bruch’s membrane visible in the peripapillary fundus oculi, and sometimes mistaken for choroidal vessels. aqueous humor: The watery fluid that fills the anterior and 240 posterior chambers of the eye; it is secreted by the ciliary processes within the posterior chambers. band-shaped keratopathy: A horizontal, gray, interpalpebral opacity of the cornea that begins at the periphery and progresses centrally. It occurs with hypercalcemia, chronic iridocyclitis, and Still’s disease. Calcium is deposited in the subepithelial space and Bowman’s membrane. blepharitis: Inflammation of the eyelids. blepharoptosis, blepharoptosia: Drooping of the upper eyelid. blepharospasm, blepharospasmus: Involuntary spasmodic contraction of the orbicularis oculi muscle. It may occur in isolation or be associated with other dystonic contractions of facial, jaw, or neck muscles. Often it is initiated or aggravated by emotion, fatigue, or drugs. Bowman’s membrane (anterior limiting layer of cornea): Transparent homogeneous acellular layer, 6 to 9 mm thick, lying between the basal lamina of the outer layer of stratified epithelium and the substantia propria of the cornea. It is considered to be a basement membrane. Bruch’s membrane (lamina basalis choroideae): Transparent, nearly structureless inner layer of the choroid in contact with the pigmented layer of the retina. bulbar: Relating to eye bulb. cataract: Loss of transparency of the lens of the eye or its capsule. chemosis: Edema of the bulbar conjunctiva, forming a swelling around the cornea. choroid: The middle vascular tunic of the eye lying between the retina and the sclera. choroiditis: Inflammation of the choroid. choroidopathy: Noninflammatory degeneration of the choroid. chrysiasis: Slate-gray discoloration of the skin and sclera resulting from deposition of gold together with increased melanin formation. ciliary body: A thickened portion of the vascular tunic of the eye between the choroid and the iris. It consists of three parts or zones; orbiculus ciliaris, corona ciliaris, and ciliary muscle. conjunctiva: The mucous membrane investing the anterior surface of the eyeball and the posterior surface of the lids. conjunctivitis: Inflammation of the conjunctiva. corpus vitreum (vitreous body): A transparent jelly-like substance filling the interior of the eyeball behind the lens of the eye. It is composed of a delicate network (vitreous stroma) enclosing in its meshes a watery fluid (vitreous humor). cortical blindness: Loss of sight caused by an organic lesion in the visual cortex. cotton-wool patches: White, fuzzy areas on the surface of the retina (accumulations of cellular organelles) caused by damage (usually infarction) of the retinal fiber layer. cyclitis: Inflammation of the ciliary body. dacryocystitis: Inflammation of the lacrimal sac. Descemet’s membrane (posterior limiting layer of cornea): A transparent homogeneous acellular layer between the substantia propria and the endothelial layer of the cornea. It is considered to be a highly developed basement membrane. diplopia: The condition in which a single object is perceived as two objects. ectopia lentis: displacement of the lens of the eye. embryotoxon: Congenital opacity of the periphery of the cornea, a feature of osteogenesis imperfecta. HAMIDEH AND PRETE en tache de bougie (mutton-fat) keratic precipitates: Coalescent precipitates, forming small plaques that gradually become more translucent. entropion: The infolding of the margin of an eyelid. episclera: The connective tissue between the sclera and the conjunctiva. episcleral nodule: A small node on the sclera. episcleritis: Inflammation of the episcleral connective tissue. fovea centralis retinae (central retinal fovea): A depression in the center of the macula retinae containing only cones and lacking blood vessels. geniculocalcarine tract (optic radiation): The massive, fanlike fiber system passing from the lateral geniculate body of the thalamus to the visual cortex (striate or calcarine cortex, area 17 of Brodmann). glaucoma: A disease of the eye characterized by increased intraocular pressure, excavation, and atrophy of the optic nerve; produces defects in the field of vision. guttate: Of the shape of, or resembling, a drop, characterizing certain cutaneous lesions. heterochromia: A difference in coloration in two structures that are normally alike in color. homonymous hemianopia: Blindness in the corresponding (right or left) field of vision of each eye. hyperopia (hypermetropia): Longsightedness; that optical condition in which only convergent rays can be brought to focus on the retina. hypopyon: The presence of leukocytes in the anterior chamber of the eye. iridocyclitis: Inflammation of both iris and ciliary body. iridodonesis: Quivering of the iris on eye movement. iris, pl. irides: The anterior division of the vascular tunic of the eye, a diaphragm, perforated in the center (the pupil), attached peripherally to the scleral spur; it is composed of stroma and a double layer of pigmented retinal epithelium from which are derived the sphincter and dilator muscles of the pupil. iritis: Inflammation of the iris. keratitis: Inflammation of the cornea. keratoconjunctivitis sicca (KCS): Keratoconjunctivitis associated with decreased tears, dry eyes. keratoconus: A conical protrusion of the cornea caused by thinning of the stroma; usually bilateral. keratomalacia: Dryness with ulceration and perforation of the cornea, with absence of inflammatory reaction. lacrimal: Relating to the tears, their secretion, the secretory glands, and the drainage apparatus. limbal guttering of cornea: The formation of deep recess or grooves at the margin of the cornea overlapped by the sclera. macular, maculate: Denoting the central retina, especially the macula retinae. myopia: That optical condition in which only rays from a finite distance from the eye focus on the retina. necrotizing scleritis: Fibrinoid degeneration and necrosis of the sclera. neovascularization: Proliferation of blood vessels in tissue not normally containing them, or proliferation of blood vessels of a different kind than usual in tissue. oculomasticatory myorhythmia: A form of hyperkinesia involving the ocular and masticatory muscles in which the tremor rate (2 to 4 per second) is irregular and slower than in OPHTHALMOLOGIC MANIFESTATIONS OF RHEUMATIC DISEASES alternating tremor, with greater frequency and higher voltage of the associated spike potentials in the electromyogram. ophthalmoplegia: Paralysis of one or more of the ocular muscles. ophthalmoparesis: Partial or incomplete paralysis of one or more of the ocular muscles. optic disk: An oval area of the ocular fundus devoid of light receptors where the axons of the retinal ganglion cell converge to form the optic nerve head. orbit: The bony cavity containing the eyeball and its adnexa. It is formed of parts of seven bones: the frontal, maxillary, sphenoid, lacrimal, zygomatic, ethmoid, and palatine bones. panophthalmitis: Purulent inflammation of all layers of the eye. papilledema: Edema of the optic disk, often attributable to increased intracranial pressure. peripheral ulcerative keratitis (PUK): Corneal inflammation at the limbus associated with ulcers. posterior subcapsular cataract (PSC): A cataract involving the cortex at the posterior pole of the lens. proptosis (exophthalmos, exophthalmus): Protrusion of one or both eyeballs. Can be congenital and familial, or caused by pathology, such as a retro-orbital tumor (usually unilateral) or thyroid disease (usually bilateral). retinal pigmented epithelium (RPE): The outer layer of the retina, consisting of pigmented epithelium. retinitis: Inflammation of the retina. retinopathy: Noninflammatory degenerative disease of the retina. retrochiasmal: Behind the decussation or crossing of the two optic nerves. rhegmatogenous retinal detachment: Retinal separation associated with a break, a hole, or a tear in the sensory retina. rubeotic glaucoma: Glaucoma caused by neovascularization of the anterior surface of the iris. Schirmer test: A test for tear production using a strip of filter 241 paper; a measurement of basal and reflex lacrimal gland function. Schwalbe’s ring (anterior limiting ring): The periphery of the cornea marking the termination of Descemet’s membrane and the anterior border of the trabecular meshwork; an important landmark in gonioscopy. scleritis: Inflammation of the sclera. scleromalacia: Degenerative thinning of the sclera, occurring in persons with rheumatoid arthritis and other collagen disorders. scotoma, pl. scotomata: An isolated area of varying size and shape, within the visual field, in which vision is absent or depressed or a blind spot in psychological awareness. slit lamp: A combination of a microscope and a narrow beam of collimated light, used to examine the eye. strabismus: A manifest lack of parallelism of the visual axes of the eyes. sympathetic ophthalmia: A serous or plastic uveitis caused by a perforating wound of the uvea followed by a similar severe reaction in the other eye that may lead to bilateral blindness. trochlea, pl. trochleae: A fibrous loop in the orbit, near the nasal process of the frontal bone, through which passes the tendon of the superior oblique muscle of the eye. uvea (vascular tunic of eye): The vascular, pigmentary, or middle coat of the eye, comprising the choroid, ciliary body, and iris. uveitis, pl. uveitides: Inflammation of the uveal tract: iris, ciliary body, and choroid. Anterior uveitis: Inflammation involving the ciliary body and iris. Posterior uveitis (choroiditis): Inflammation of the choroid. vitreous humor: The fluid component of the vitreous body, with which it is often erroneously equated. vitreitis: Inflammation of the corpus vitreum. xerostomia: Dryness of the mouth, having a varied cause, resulting from diminished or arrested salivary secretion, or asialism.