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Chapter 13 Ocular Findings in Rheumatic and Connective Tissue Disorders

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 13 Ocular Findings in Rheumatic and Connective Tissue Disorders

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Scott S. Weissman and Stephen E. Bloomfield

Rheumatoid arthritis
Juvenile rheumatoid arthritis (JRA)
Ankylosing spondylitis (AS)
Reiter's syndrome
Enteropathic arthropathy
Systemic lupus erythematosus
Temporal arteritis (TA) and polymyalgia rheumatica (PMR)
Polyarteritis nodosa
Wegener's granulomatosis
Polymyositis and dermatomyositis
Scleroderma

The eye and its associated orbital structures may exhibit pathologic changes in patients afflicted with many connective tissue or collagen diseases. In certain inflammatory joint diseases, such as rheumatoid arthritis (RA), there is a similarity in the pathologic processes occurring in the joints and the eye. Inflammation in the conjunctiva and sclera seems to be somewhat analogous to that occurring in the synovium and cartilage, where uncontrolled and relentless immunologically-mediated inflammation in either organ results in its destruction. For the purposes of classifying the ocular manifestations of collagen disease, it is convenient to conceptualize the eye anatomically as a structure consisting of three concentric spheres or coats: an outer collagen coat, or scleral shell; a middle vascular coat, known as the uveal tract ; and the inner, retinal layer. Each of the various collagen diseases shows a characteristic pattern involving one or more of these structures. For example:

1. The outer collagen or corneoscleral layer becomes involved with RA, and a scleritis results.
2. The middle or uveal coat is more often involved with the seronegative spondyloarthropathies, such as ankylosing spondylitis or juvenile arthritis, and iridocyclitis develops.
3. The inner, retinal layer is involved in systemic lupus erythematosus (SLE), so that a characteristic retinal vasculitis, retinopathy, or choroidopathy results. In the following sections, the ocular manifestations found in each of the rheumatic diseases is considered .

I. Rheumatoid arthritis. The most characteristic and potentially serious ocular manifestation of RA is inflammation of the sclera, cornea, or both. The most common manifestation of RA is keratoconjunctivitis sicca.

1. Scleritis. The clinical spectrum of scleritis may range from a mild, localized, superficial episcleritis to a dramatically painful, necrotizing scleritis with dire prognostic systemic implications.

   The various types of scleritis are probably different manifestations of a single pathologic process, which appears similar to that operating in the joints. An immune complex vasculitis in the sclera appears to be responsible for the inflammatory process. The specific clinical entity produced depends on the site, depth, and extent of the pathologic process.

   1. The incidence of scleritis in RA is about 5%; thus, scleritis will develop in one of every 20 patients in the rheumatology clinic during the evolution of their disease. Also of interest is the incidence of RA in patients who consult an ophthalmologist and are given a diagnosis of scleritis. The incidence of RA in patients with scleritis is approximately 33%. Therefore, every scleritis patient in an ophthalmology clinic should be evaluated for arthritis.
   2. Prognosis for life and sight. The prognostic significance of rheumatoid scleritis is dramatically illustrated by a study in which 45% of patients with scleritis died within 5 years of being given the diagnosis, compared with 18% of a matched control sample of RA patients without scleritis. In mild forms of scleral inflammation, such as local or generalized episcleritis, the swelling and inflammatory process is superficial, although painful, and it is usually easy to control with topical medications and resolves without serious sequelae. Deep scleritis, however, is one of the few severely painful eye problems, has serious prognostic implications for sight and life, and requires systemic, often long- term treatment with one of several antiinflammatory agents . In necrotizing scleritis, the most dramatic and destructive form of scleritis, a scleral vessel is suddenly occluded, causing an avascular patch (sequestrum) that eventually dissolves and exposes the underlying uveal tissue. Necrosis occurring slowly over time and without inflammation is called necrotizing scleritis without inflammation; it is referred to in the older classic literature as scleromalacia perforans. Necrotizing scleritis represents the eye changes of the malignant phase of a systemic tissue disorder and usually occurs in patients who have manifested the advanced stages of the disease. It is also seen in polyarteritis nodosa, Wegener's granulomatosis, and SLE. Scleritis itself has serious ocular complications other than the production of a scleral defect; it can result in keratitis, cataracts, uveitis, and glaucoma.
   3. Treatment. Because of the depth and severity of the inflammatory process in scleritis, long-term (years) systemic antiinflammatory agents are required. Those that have been reported to be effective include indomethacin, diflunisal, corticosteroids, azathioprine, cyclophosphamide, and cyclosporin A. In the most severe and sight- threatening cases, cyclophosphamide along with intravenous corticosteroids must be used. With the latter two drugs, the clinician is in the unenviable position of balancing toxic treatments versus a destructive disease.
2. Corneal complications. Corneal manifestations associated with RA are serious problems whose importance and occurrence are not generally appreciated. Corneal involvement may accompany inflammation of the adjacent sclera or may occur in the absence of any other ocular complications. One form is the development of peripheral ulcers or furrows at or near the limbus (limbal guttering), frequently occurring in the absence of significant inflammation. These ulcers may be nonprogressive or go on to cause marked thinning and perforation of the cornea. Central corneal ulcers and perforations can be seen in clinically quiet eyes. These patients are usually in an advanced stage of their disease and are often on maintenance doses of systemic corticosteroid drugs.
3. Sicca syndrome (keratoconjunctivitis sicca) (see Chapter 29). Keratoconjunctivitis sicca is one of the most common ocular manifestations of RA. It also occurs with several of the other collagen diseases and as an isolated entity. The syndrome as originally described by Sj gren consists of dry eye, dry mouth, and arthritis. Today, the term has come to be used to describe patients with joint disease and a dry eye. The xerostomia may or may not be present.
   1. Signs and symptoms. The symptoms that patients complain of are a foreign-body sensation or a feeling of something (sand or lashes) in their eyes. The clinical spectrum of a patient with keratoconjunctivitis sicca may vary from symptoms only, with very few signs seen by the ophthalmologist, to mild signs consisting of punctate erosions on the inferior half of the cornea, with or without filaments that consist of a mixture of surface cells and mucus. There is one particularly devastating variation in which corneal infiltration and necrosis sometimes develop, leading to possible corneal perforation. Fortunately, this is quite rare.
   2. Treatment of a dry eye consists of keeping the eye moist and clean with a minimum number of drugs and devices, as these treatment methods have their own complications. The eye can be kept moist with tear replacements and by decreasing evaporation through the use of moist- chamber glasses or contact lenses.
      1. The first line of defense is replacement of tear volume through the use of artificial tears. This works best when combined with nightly eyelash lavage with baby shampoo to clean off accumulated debris that the compromised tear film cannot handle. Variable success has been reported with artificial tear inserts , such as Lacriserts.
      2. Another simple expedient is the use of moist-chamber glasses, which are an extension of the glasses frame. Clear plastic extends to the face, trapping any moisture produced and thereby decreasing evaporation.
      3. More severe cases require more aggressive treatments, all of which have inherent risks. Occlusion of the punctum can reduce the drainage of tears but should only be used if less than 3 mm of wetting is noted on Schirmer's test. Therapeutic soft contact lenses are extremely useful when foreign-body symptoms are so extensive that patients cannot keep their eyes open . This is also the case when filaments develop in a dry eye.

         The filaments, as mentioned, consist of mixtures of desiccated, loose, surface epithelial cells combined with mucus, which is produced in greater quantities in these patients. The problem with contact lenses in patients with dry eyes is the possible development of corneal infections.

4. Differential diagnosis of red eye. These diagnostic possibilities hold for all the collagen diseases but are presented in this section because RA is the most common underlying entity and is associated with the greatest number of possible causes of a red eye.
   1. Scleritis, either local or general. Pain is usually present.
   2. Keratitis sicca results in the eyes becoming irritated from lack of a normal tear volume to lubricate and protect the surface.
   3. Conjunctivitis occurs secondary to a tear volume deficit, which deprives the eye of its natural protection against infection.
   4. Iridocyclitis usually occurs acutely in seronegative spondyloarthropathies, with light sensitivity, a miotic pupil on the affected side, and a peripupillary red ring (ciliary flush). A more chronic iridocyclitis, with a white and quiet external appearance, is more typical of children with juvenile rheumatoid arthritis (JRA).
   5. Glaucoma, secondary either to scleritis and inflammation of the trabecular meshwork or to corticosteroid therapy .
   6. Herpetic keratitis, complicating immunosuppressive drug regimens used to treat this group of patients.

II. Juvenile rheumatoid arthritis (JRA) is sufficiently different in its ocular manifestations to warrant consideration as a separate entity. Adult RA affects the outer collagenous coat of the eye, producing scleritis, whereas in JRA, inflammation of the middle coat or a uveitis is the classic ocular complication. The uveitis in JRA is an insidious inflammation of the anterior uveal tract (iridocyclitis). Scleral inflammation in JRA is rare.

1. The incidence of uveitis in JRA is approximately 10%, and uveitis is more common in patients with pauciarticular involvement than with polyarticular disease. The uveitis usually develops after the arthritis but may precede it by many years.
2. Signs and symptoms. Acute iridocyclitis usually manifests with redness, pain, photophobia, and tearing , but the low-grade, chronic iridocyclitis of JRA may be asymptomatic, which makes it a particularly dangerous problem because extensive ocular disease may occur before the condition is recognized or show no correlation with joint inflammation. The most common sequela of iridocyclitis is the deposition of calcium beneath the corneal epithelium, causing band keratopathy. Band keratopathy is a nonspecific condition that develops after any longstanding inflammation. Chronic iridocyclitis also produces cataracts and secondary glaucoma. This chronic form of iridocyclitis can be unrelenting and have a progressive downhill course that leads to visual loss. The treatment itself, which consists of topical or systemic corticosteroid therapy, can result in glaucoma and cataracts.

III. Ankylosing spondylitis (AS). Iridocyclitis is so common in AS that it might be regarded as a clinical feature rather than a complication of the disease. Iridocyclitis occurs at some point in the life of almost all these patients and may be the presenting feature, antedating the joint symptoms by as much as 12 years or occurring when the disease is entirely quiescent. The iridocyclitis tends to affect one eye at a time and is generally fulminant in onset. In 20% of patients, it is the most disabling feature of the disease, because of both its severity and the frequent recurrences.

In addition to anterior uveitis being found in a large number of patients with AS, spondylarthropathy is found in a significant percentage of patients presenting to an ophthalmologist with iritis. Young men with iridocyclitis should be investigated for signs and symptoms relating to AS. There is a striking association of this disease with the presence of the histocompatibility antigen HLA-B27, which is found in only 5% to 8% of controls but in approximately 90% of white patients with AS.

IV. Reiter's syndrome. The classic diagnostic triad of Reiter's syndrome includes non-gonococcal urethritis, arthritis, and conjunctivitis. The ocular findings may be the presenting feature of this disease, although they usually follow the other symptoms. Conjunctivitis, part of the classic triad , is the most common ocular manifestation of the disease. It is usually mild and presents with some burning and tearing. Among the connective tissue diseases, Reiter's syndrome and psoriatic arthropathy are the only conditions in which conjunctivitis is a complication. Anterior uveitis occurs in 8% to 40% of patients with this entity. It is more common with recurrent disease than in the initial stage of illness . Reiter's syndrome also shows an association with the HLA-B27 antigen.

V. Enteropathic arthropathy is the form of polyarthritis associated with inflammatory bowel disease, including ulcerative colitis and Crohn's disease. Ocular findings associated with these entities involve mainly the uveal tract and manifest as an iridocyclitis. Scleritis has also been reported. The incidence of ocular findings in enteropathic arthropathy, however, is less than in the more common arthritis syndromes.

VI. Systemic lupus erythematosus, unlike some of the other connective tissue disorders, can involve almost every structure in the eye. The inner eye is rarely involved in RA, and the outer eye is rarely involved in the seronegative arthritides.

These distinctions can be clinically important, because if a fundus lesion or an anterior uveitis is seen in a patient with scleritis, it is likely that the disease syndrome is related to SLE. The fundus changes involve the inner retinal layer through an immune complex-mediated occlusive vasculitis.

1. The most common retinal findings are cotton-wool spots, retinal hemorrhages, and edema of the disk and surrounding retina . Similar changes can result from the associated hypertension seen in SLE patients with nephritis. The findings associated with vasculitis are sometimes called lupus retinopathy.
2. Anterior segment involvement may take the form of conjunctivitis, sicca syndrome, or scleritis. Ptosis and proptosis have been reported secondary to myositis of the extraocular muscles . Drug-induced SLE can also be associated with ocular manifestations.

VII. Temporal arteritis (TA) and polymyalgia rheumatica (PMR). Temporal arteritis, also known as giant- cell or cranial arteritis, can result in sudden, dramatic, and disastrous loss of vision. Polymyalgia rheumatica is included in this section because a small percentage of PMR patients have occult TA and 50% of TA patients have PMR. The two disorders are parts of a single disease spectrum.

1. Temporal arteritis. Ocular manifestations may occur in 30% of patients and are among the most serious consequences of this illness. Ocular complications occur usually several weeks to months after the onset of systemic symptoms but may also occur years later or develop first in the absence of systemic signs, a situation referred to as occult temporal arteritis. Inflammation of the ophthalmic, central retinal, or posterior ciliary arteries is responsible for the various ocular problems.
   1. The most frequent and disastrous problem is the sudden, irreversible loss of vision caused by inflammation either in the central retinal artery, which is the terminal branch of the ophthalmic artery, or in the posterior ciliary arteries, which supply the optic nerve; the latter situation can result in an ischemic optic neuritis. An altitudinal visual field deficit is characteristic of optic nerve inflammation in temporal arteritis.
   2. Diplopia also occurs from involvement of the posterior ciliary arteries, which supply the extraocular muscles.
   3. When several of the extraocular muscles are involved, the syndrome of anterior segment necrosis may occur, which essentially is ischemia of the front of the eye that results in uveitis, iris necrosis, and scleritis.
   4. Treatment, which must be instituted rapidly , consists of systemic corticosteroids in doses sufficient to suppress the clinical and laboratory evidence ( especially the erythrocyte sedimentation rate) of disease activity. Any visual symptoms must be treated aggressively, at times with prednisone doses over 100 mg/day or intravenously with 500 “1000 mg of Solumedrol. In some cases, vision is lost despite massive doses of systemic antiinflammatory medication . Unfortunately, bilateral blindness may occur in up to 25% of patients with temporal arteritis. The purpose of treatment is really prevention. Improvement of visual acuity in an involved eye after steroid therapy has begun is only rarely noted.
2. Polymyalgia rheumatica is the descriptive term coined by Barber in 1957 for the syndrome consisting of pain and stiffness in the shoulder and pelvic girdles in elderly patients, an associated high erythrocyte sedimentation rate, and a prompt and dramatic clinical response to modest doses of systemic prednisone, in the range of 10 to 15 mg/d. The importance of recognizing this entity lies in the fact that, in some patients, it is an occult pattern of temporal arteritis.

VIII. Polyarteritis nodosa

1. Ocular manifestations involve almost every tissue of the eye in this inflammatory disease affecting small and medium- sized arteries. The most common and serious manifestation is scleral keratitis, which is similar to that seen in RA but usually more painful and sharply demarcated. Guttering of the peripheral cornea develops in the limbal region, which may spread circumferentially to form a ring. Bilateral involvement can be present, and the associated pain may be intense . The process may extend centrally to involve much of the cornea, producing extensive scarring, vascularization, and perforation.
2. Clinical syndromes have been described in which polyarteritis nodosa is associated with specific eye and ear findings.
   1. In Cogan's syndrome, an interstitial keratitis (deep corneal haze and vascularization) is associated with audiovestibular disease, characterized by profound deafness, vertigo, and tinnitus.
   2. Another variation is an association of polyarteritis, scleritis, and otitis media. Anterior uveal involvement is manifested as iridocyclitis. The retinopathy of polyarteritis includes retinal vasculitis and changes secondary to coexistent hypertension. A host of ocular signs and symptoms of polyarteritis reflect central nervous system complications.

IX. Wegener's granulomatosis. Ocular and orbital complications are fairly common in Wegener's granulomatosis, the reported incidence being as high as 60%. If the orbit is involved by direct spread of the granuloma from the paranasal sinuses, the patient can have proptosis, limitation of movement of the globe, and a rapid destruction in vision from either involvement of the optic nerve or an exudative retinal detachment secondary to a posterior scleritis. Nasolacrimal duct obstruction may also be the presenting sign.

1. Proptosis, which is a common clinical feature and can be severe, results from invasion of the orbit, and later the sclera, by granulomatous tissue. The sclera becomes infiltrated, and the underlying collagen is attacked by granulation tissue. The histologic picture differs from that usually seen in scleral inflammatory disease in that the invasion is from the outside rather than from foci within the sclera.
2. Other types of scleritis are also seen in which intrascleral inflammation develops first. A particularly painful peripheral ulcerative keratitis or necrotizing scleritis may occur and be the presenting feature of the disease.

X. Polymyositis and dermatomyositis. Polymyositis is an inflammatory disease of striated skeletal muscle. When a characteristic skin rash is present, the term dermatomyositis is used. The most common ocular finding, indeed one of the more characteristic findings of dermatomyositis, is lid discoloration. There is a lilac discoloration of the upper eyelids, often associated with periorbital edema. This violaceous discoloration, called heliotrope rash, is considered pathognomonic.

Other ocular findings have been reported, but none is specific. Extraocular muscle weakness is uncommon and may be caused by the myositis itself or by coexistent myasthenia gravis. In children with dermatomyositis, retinal vasculitis is a relatively common feature.

XI. Scleroderma. The most common ocular manifestation of this chronic disease of connective tissue is involvement of the skin of the lids, which may have secondary effects on the cornea and conjunctiva. The eyelids lose their freedom of movement and become thin, smooth, and shiny. Tightness of the lids may result in only minimally decreased mobility or marked restriction of lid movement. Lid restriction may in turn lead to a severe exposure keratitis, especially when it is combined with a hyposecretion of tears occasionally seen with this disease. Sicca syndrome is a significant feature of scleroderma, as it is with the other connective tissue syndromes.

Bibliography

Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis: effects of systemic immunosuppression . Ophthalmology 1984;91:1253.

Foulks GN. Non-infective inflammation of the anterior segment. Int Ophthalmol Clin 1983;23(1):3.

Gold OH. Ocular manifestations of connective tissue diseases. In: Duane T, ed. Clinical ophthalmology, vol 5. Hagerstown, MD: Harper & Row, 1980:1B.

McGavin OOM, et al. Episcleritis and scleritis: a study of their clinical manifestations and association with rheumatoid arthritis. Br J Ophthalmol 1976;60:192.

Theodore FH, Bloomfield SE, Mondino BJ. Clinical allergy and immunology of the eye. Baltimore: Williams & Wilkins, 1983.

Watson PG, Hazleman BL. The sclera and systemic disorders. London: WB Saunders, 1976.

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Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders