REVIEW

RULA A. HAJJ-ALI, MD CAREEN LOWDER, MD, PhD BRIAN F. MANDELL, MD, PhD CME Department of Rheumatic and Immunologic Cole Eye Institute, The Cleveland Clinic Foundation Vice-Chairman of Medicine for Educational Affairs; CREDIT Disease, Center for Vasculitis Care and Department of Rheumatic and Immunologic Research, The Cleveland Clinic Foundation Diseases, Center for Vasculitis Care and Research, The Cleveland Clinic Foundation; Editor-in-Chief, Cleveland Clinic Journal of Medicine

Uveitis in the internist’s office: Are a patient’s eye symptoms serious?

■ ABSTRACT ATIENTS OFTEN PRESENT to the office P with vague eye symptoms, such as pho- is an inflammatory process that may affect one or tophobia, , or “.” In most cases several specific areas of the eye. But when a patient the symptoms are minor and do not reflect a presents to an internist with eye symptoms, be it serious problem. But in some cases, those , “floaters,” or red eye, the diagnosis is not symptoms indicate the more serious, vision- always clear. If the diagnosis of uveitis is made, internists threatening condition of uveitis (intraocular must search for an underlying cause, such as infection or inflammation). an autoimmune disease. Diagnosis of uveitis is challenging, and its diagnosis and treatment are best handled col- ■ KEY POINTS laboratively with an ophthalmologist. Once uveitis is diagnosed, physicians must Many systemic and regional diseases can cause ocular determine whether it is caused by infection or inflammation. It is critical to rule out infectious disease as is a sign of an underlying condition. the cause of uveitis, because giving immunosuppressive This article covers the causes of uveitis, therapy to someone with infective uveitis can be how to approach its diagnosis, and recommen- disastrous. dations for managing it. ■ UVEITIS IS INFLAMMATION Infectious causes of uveitis include , AT ANY SITE , herpes simplex virus, , and . The constitutes the middle portion of the eye between the and . Systemic inflammatory causes include , However, uveitis now commonly refers to juvenile idiopathic arthritis, inflammatory bowel disease, intraocular inflammation at any site. and HLA-B27-associated diseases, especially ankylosing The anterior uveal tract consists of the spondylitis and reactive arthritis. . The is the intermediate area connecting the iris to the posterior uveal por- If the cause of uveitis is not infectious, treatment includes tions of the (FIGURE 1). Anterior uveitis , given either topically, by periocular refers to inflammation of the iris (iritis) or both iris and ciliary body (iridocyclitis). injection, or systemically. Immunosuppressive therapy Inflammation of the ciliary body is termed may be required to limit steroid use. cyclitis, pars planitis, or . Posterior uveitis includes vitritis, choroidi- tis, , , or retinochoroidi- tis. Panuveitis or diffuse uveitis is the term used

This paper discusses therapies that are not approved by the US Food and Drug Administration for when there is both anterior and posterior the use under discussion. uveitis.

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Terms used in the text Cells and flare—findings on slit lamp examination: Uveitis—inflammation of the uveal tract cells imply the presence of leukocytes within the ante- (iris, ciliary body, choroid) rior, posterior, or vitreous chambers; flare represents increased protein in the intraocular fluids

Synechiae—inflammatory Vitritis—Inflammation within adhesions between the iris and the vitreous cavity (anterior synechiae) or the iris and (posterior Posterior synechiae) chamber Vitreous chamber Lens Uveal tract Cornea Iris Ciliary Retina body Choroid Anterior Retinitis/retinochoroiditis— chamber inflammation of the retina (retinitis) with or without contiguous choroidal inflammation (retinochoroiditis)

Iritis/cyclitis/iridocyclitis— inflammation of the iris (iritis), ciliary Choroiditis/chorioretinitis—inflammation body (cyclitis) or both (iridocyclitis) involving the choroid primarily (choroiditis), with or without contiguous involvement of CCF the retina (chorioretinitis) ©2005 FIGURE 1. Schematic figure of the different structures of the eye.

■ CLASSIFICATION OF UVEITIS rize by etiology should be made (see below),4 ie: •An infectious disease Uveitis is classified according to its: •A localized specific ocular disease •Anatomic location (anterior, intermedi- •A specific systemic inflammatory disease ate, or posterior) •A masquerade syndrome (eg, intraocular • Laterality (unilateral or bilateral) tumors). •Onset (acute or insidious) •Duration (self-limited, chronic, or recurrent) ■ DIFFERENT PATTERNS • Size and distribution of keratic precipi- IN DIFFERENT POPULATIONS tates (“granulomatous” or “nongranulo- matous”) seen by slit lamp examination. Different patterns of uveitis are associated Biopsy of these inflammatory precipi- with different ages, genders, and races, mainly tates is rarely performed, but older because of disease associations. pathological studies permit the current For example, chronic anterior uveitis is labeling of the deposits as granulomatous associated with pauciarticular juvenile or nongranulomatous on the basis of rheumatoid arthritis, and it is more common their magnified (not biopsied) appear- in young girls. Acute anterior uveitis, associat- ance. ed with ankylosing spondylitis, is more com- This classification helps the ophthalmolo- mon in men and boys and is an important gist develop a differential diagnosis.4,5 Although cause of uveitis in the United States and the many cases are idiopathic, an attempt to catego- United Kingdom.

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Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. TABLE 1 Features of anterior uveitis that differentiate it from other common causes of red eye No discharge No itching Redness affecting primarily the limbus (FIGURE 2) Poorly reactive Irregularity of the pupil Pain and photophobia Family history of uveitis

FIGURE 2. Congestion of the limbus In Caucasians, in whom the prevalence of (the junction between the cornea and the uveitis is approximately 17 cases per 100,000 sclera) in anterior uveitis. and the peak ages are between 20 and 50 years,1 anterior uveitis is the most common ■ SYMPTOMS DEPEND ON SITE pattern.2 In contrast, in Japanese people, pos- terior uveitis accounts for most cases and is a The symptoms of uveitis depend on the site of manifestation of Behçet syndrome or Vogt- involvement. Koyanagi-Harada syndrome.3–5 Ocular sar- Acute anterior uveitis frequently causes coidosis is more common in African pain and photophobia associated with ciliary Americans, while Behçet disease is much injection. This is the typical pattern in more common in Asians and in people of patients with HLA-B27-associated iridocy- Middle Eastern descent.2 clitis. Initially, vision may or may not be affected. ■ IS THIS UVEITIS? Insidious anterior uveitis. If the onset is insidious (eg, in pauciarticular juvenile idio- The first question the internist must answer is pathic arthritis), patients may experience no Uveitis may whether a patient with eye symptoms has symptoms, despite inflammation and intraoc- precede the uveitis and should be referred to an ophthal- ular damage, until scarring, loss of vision, and mologist. occur. full-blown Many patients with anterior uveitis Posterior uveitis causes “floaters” and expression of have a red eye, but other causes of a red eye hazy vision. Redness and pain are not usual that should be distinguished from uveitis features of isolated posterior uveitis, although systemic include corneal inflammation (), a dull ache may be present. Involvement of disease conjunctival inflammation (), the retina may produce blind spots or flashing blood vessel inflammation in the episclera lights (a major warning sign). or sclera ( and , respec- tively), or acute closed-angle . ■ CAUSES OF UVEITIS: TABLE 1 summarizes the signs and symptoms INFECTIOUS DISEASES that help in recognizing anterior uveitis. Patients with posterior uveitis are more Although infection is an uncommon cause of likely to be pain-free but with visual changes uveitis, it is critical to rule out infection such as floaters. The new onset of significant because giving immunosuppressive therapy to floaters, especially with any haziness of vision, someone with infective uveitis can be disas- warrants referral to an ophthalmologist. trous. The diagnosis of uveitis is confirmed by Infectious uveitis can occur in immuno- slit lamp examination, which can demon- compromised or healthy people. It is usually strate inflammatory cells and the flare that recognized by specific findings on ophthalmo- results from protein extravasations from logic examination in an immunocompromised inflamed blood vessels into the anterior or patient—or after uveitis does not respond to posterior chambers. anti-inflammatory therapy.

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FIGURE 4. Cytomegalovirus retinitis. Note the characterisitic retinitis that progresses along the nerve fiber layer (arrows).

FIGURE 3. Toxoplasmosis. Note the focal of systemic cytomegalovirus infection, or by area of retiniitis (white arrows) adjacent to polymerase chain reaction studies of vitreous scar area (black arrrow). fluid. Other herpesviruses that can cause Parasitic infection: toxoplasmosis retinitis include herpes simplex and herpes Toxoplasmosis is a common cause of zoster. Herpes simplex retinitis usually occurs retinochoroiditis (posterior uveitis) in normal in immunosuppressed patients or in patients and immunosuppressed patients,6 accounting who are congenitally infected. A unique form for as many as 25% of cases of posterior uveitis of rapidly progressive necrotizing retinitis can in the United States. Retinitis is usually occur in normal hosts as a result of various Inappropriate prominent.7 Most cases of acute toxoplasmic herpes infections and is known as the acute use of immuno- retinochoroiditis in adults are believed to be retinal necrosis syndrome.11,12 This is associat- reactivations of congenital infection. ed with visual loss and can be identified by an suppressive Toxoplasmosis is diagnosed by observing a ophthalmologist. It warrants immediate high- therapy in focal active area of retinitis adjacent to a dose antiviral therapy. chorioretinal scar (FIGURE 3), with supportive infectious serologic testing. The finding of antitoxoplas- Bacterial and treponemal diseases uveitis can be mic antibodies helps in the diagnosis but is Tuberculosis was once the most frequent disastrous not sufficient to confirm active disease, since cause of choroiditis. Now it is found in fewer seropositivity is very common in the general than 1% of all cases of uveitis in the United population.8 States.13,14 It should be considered as the cause of uveitis in a patient with active sys- Viral infections temic tuberculosis. Cytomegalovirus infection can cause pos- Syphilis can cause anterior or posterior terior uveitis (retinitis) in immunocompro- uveitis, usually during the secondary or ter- mised people. Patients with acquired immuno- tiary stages of infection.15 deficiency syndrome are the most susceptible, Anterior syphilitic uveitis typically pre- especially those with CD4 cell counts lower sents as acute unilateral iritis or iridocyclitis than 50 cells/mL.9 The incidence has decreased with involvement of the contralateral eye in in the United States since highly active anti- half of cases (a pattern not generally found in retroviral therapy has become available.10 HLA-B27-associated uveitis—see below). The infection is bilateral in 50% of cases. Posterior syphilitic uveitis can present as dif- The diagnosis is made by recognizing the fuse or localized choroiditis or chorioretinitis, characteristic retinitis that progresses along most often in patients with human immun- the nerve fiber layers (FIGURE 4) in the setting odeficiency virus infection. Half of all cases

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Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. of syphilitic posterior uveitis are also bilater- favorable prognosis.21 Periodic remissions and al. Uveitis due to secondary syphilis often exacerbations are typical. cannot be distinguished from other causes of uveitis on the basis of the ocular manifesta- ■ CAUSES OF UVEITIS: tions. SYSTEMIC INFLAMMATORY DISEASES Other, rare causes of bacterial and spiro- chetal uveitis include leprosy, leptospirosis, HLA-B27-associated diseases cat scratch disease, , and Anterior uveitis is associated with the histo- Whipple disease. compatibility antigen HLA-B27. In the United States and England, where HLA-B27 ■ CAUSES OF UVEITIS: is relatively common (prevalence 4%–10%), LOCALIZED OCULAR DISEASES from 30% to 70% of patients with acute ante- rior uveitis have this antigen.22,23 Some inflammatory diseases that are confined Only half of patients with HLA-B27 and to the eye, without systemic associations, anterior uveitis have an associated systemic manifest as uveitis. Patients may present to disease such as ankylosing spondylitis, psori- their internist, but the specific diagnosis is atic arthritis, reactive arthritis, or inflamma- generally recognized by an ophthalmologist tory bowel disease. Of patients with ankylos- on the basis of special features on examination ing spondylitis, 90% have HLA-B27; in or by history. reactive arthritis the prevalence is 60%. A Sympathetic ophthalmia is inflammation patient with ankylosing spondylitis or Reiter of the “sympathizing” eye that results from syndrome has a 20% to 30% chance of penetrating trauma or surgery in the con- developing iritis during the course of the dis- tralateral (“exciting”) eye. It is thought to be ease.24 due to an immune response against an ocular HLA-B27-associated uveitis is character- antigen that is exposed after the trauma.16 ized by the acute onset of unilateral iridocycli- Early enucleation of the exciting eye improves tis with redness and photophobia. With treat- the visual outcome in the sympathizing eye; ment, the prognosis is good, and the inflam- Trauma to use of systemic corticosteroids and other mation usually resolves within 2 to 4 months, one eye immunosuppressant agents has also improved which permits therapy to be discontinued. the prognosis. Recurrences are frequent, however, and may can cause Birdshot choroidopathy is a bilateral pos- occur unilaterally in the contralateral eye (a uveitis in terior uveitis characterized by yellowish spots “flip-flop”pattern). Some patients develop disseminated throughout the fundus at the synechiae (scarring). the other level of the retinal pigment epithelium or Iritis as a complication of either psoriatic choroid. Also noted are disc edema and or inflammatory bowel disease is less common, numerous inflammatory cells in the vitreous less well characterized, and less frequently and choroid in a birdshot appearance. associated with HLA-B27. Around 7% of Most patients are women in middle age patients with psoriatic arthritis develop (mean age 50). The disease is strongly associ- uveitis, as do fewer than 5% with inflammato- ated with HLA-A29 antigen: about 80% to ry bowel disease.25 Iritis associated with ulcer- 90% of patients are positive for HLA-A29, ative colitis is frequently unilateral and sud- compared with 7% of the general popula- den in onset, but the uveitis associated with tion.19,20 Crohn disease is much more variable and is Pars planitis is an idiopathic inflamma- frequently bilateral, posterior, insidious in tion of the of the ciliary body, the onset, and chronic in duration.26 portion of the eye between the iris and the choroid. It is known as “intermediate uveitis” Sarcoidosis when it is associated with a systemic disease To the internist, sarcoidosis is a chronic mul- such as or sarcoidosis.17,18 tisystem disease characterized by lung infil- Vision is usually affected, but about half of trates, hilar adenopathy, and lesions of the eye patients have a mild inflammation and a and skin. may be the initial or only

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manifestation, and it can affect all ocular •A pauciarticular onset with involvement structures. of four joints or fewer Sarcoidosis accounts for fewer than 6% of • Spondylitis, often with an initial peripher- cases of anterior uveitis.27,28 Sarcoidosis-relat- al arthritis. ed uveitis is bilateral in 80% of cases; approx- Uveitis is common in juvenile idiopath- imately 85% of cases are anterior and 25% are ic arthritis: the prevalence can reach 20% in posterior (10% are both).29,30 Anterior sar- children with pauciarticular onset and 5% coidosis-related uveitis is an iridocyclitis char- with polyarticular onset. It is extremely rare acterized on slit-lamp examination by large in the form with systemic onset. Most often, “mutton-fat” keratic precipitates. The iridocy- it occurs in young girls who have early-onset clitis can be chronic, bilateral, and recurrent pauciarticular disease, frequently with a pos- and may lead to posterior synechiae forma- itive antinuclear antibody test. However, a tion. Posterior uveitis can be accompanied by recent study suggests that despite the classic involvement of the retinal vessels, the central teaching, antinuclear antibody positivity nervous system, or both.30 may not predict uveitis risk in patients with Occasionally, sarcoid uveitis presents pauciarticular juvenile idiopathic arthri- acutely with parotitis, fever, and facial nerve tis.31 palsy (uveoparotid fever). Asymptomatic Uveitis is usually asymptomatic and lacrimal gland enlargement is common and often presents within 5 years of the onset of may provide a clue to the underlying dis- juvenile idiopathic arthritis. An insidious, ease. bilateral iridocyclitis, it is often completely The diagnosis of ocular sarcoidosis is asymptomatic until complications and loss of strongly supported by the finding of sterile vision develop.32 noncaseating granulomas on biopsy of an Reports from the 1970s described visual affected organ, most commonly the lungs or loss in 66% of patients and blindness in up to lymph nodes. Conjunctival biopsy in patients 38%.33,34 Early detection by regular eye suspected of having ocular sarcoidosis may screening every 3 to 4 months has dramatical- Uveitis is occasionally be worthwhile; the yield is ly decreased the rate of to common in increased by biopsy of clinically abnormal tis- 16%.32,35 sue. Computed tomography of the lungs is Children with spondylitis may develop juvenile superior to chest radiography in demonstrat- acutely painful recurrent anterior uveitis, sim- idiopathic ing adenopathy. The angiotensin-converting- ilar to adults with HLA-B27-associated enzyme level is a nonspecific test and should uveitis. arthritis not be used diagnostically. Ophthalmologists often make the diagno- Behçet disease sis of ocular sarcoidosis on the basis of the Behçet disease, most commonly seen in the clinical appearance and pattern of the inflam- Mediterranean and eastern rim of Asia, is matory disease, after excluding alternative characterized by recurrent orogenital ulcers, diagnoses, in the absence of systemic findings. uveitis, thrombosis, vasculitis, and cuta- How often this pattern “evolves” into systemic neous manifestations. Uveitis, a dominant sarcoidosis is unknown. feature of the disease, occurs in 80% of patients.36 Juvenile idiopathic arthritis Uveitis in Behçet disease typically is Juvenile idiopathic arthritis is a group of chronic and bilateral, and can be anterior or inflammatory arthritides affecting children posterior or both. The inflammatory response younger than 16 years. It can present in four in the anterior chamber may be so brisk as to different modes: elicit a visible meniscus of inflammatory •A systemic onset characterized by fever, cells, termed (FIGURE 5). Blindness polyarthritis, rash, adenopathy, and leuko- can result from a relentlessly progressive cytosis occlusive that often does •A polyarticular onset in which more than not respond to aggressive immunosuppressive four joints are involved therapy.37

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Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Vogt-Koyanagi-Harada syndrome Vogt-Koyanagi-Harada syndrome is a pre- sumed autoimmune disease that can cause bilateral panuveitis and acute serous . It is one of the leading causes of uveitis in Japan.38 Other manifestations include alopecia, peliosis (whitening of patch- es of hair), sterile meningitis, and eighth cra- nial nerve disease.

Other systemic causes Other causes of uveitis include tubulointersti- FIGURE 5. Hypopyon in Behçet disease tial nephritis,39 Kawasaki disease,40 multiple (can also be seen in anterior uveitis of sclerosis,18,41 relapsing polychondritis,42 other causes). Sjögren syndrome,43 Wegener granulomato- sis,44 drug or hypersensitivity reactions,45 and lar edema, observed most commonly in Lyme disease.46 Uveitis is rarely associated patients with sarcoidosis, intermediate uveitis, with rheumatoid arthritis or systemic lupus birdshot chorioretinopathy, and retinal vas- erythematosus. culitis. Glaucoma may occur if the inflammatory ■ MASQUERADE SYNDROMES cells and debris clog the trabecular meshwork or from posterior synechiae. A number of noninfectious processes can be Retinal detachment occurs in patients mistaken for an inflammatory process and can with posterior, intermediate, or diffuse uveitis. mimic uveitis. These “masquerade syndromes” It is believed that aggressive reduction of include non-Hodgkin lymphoma, leukemia, all inflammation will prevent most delayed , and retinoblastoma. sequelae of uveitis. These are often suspected when there is poor Cataracts can response to anti-inflammatory agents that are ■ APPROACH TO PATIENTS WITH UVEITIS be due to given to treat assumed uveitis. Lymphomas must be considered when When uveitis is diagnosed, potential causes inflammation— uveitis presents at an older age. They are typ- should be considered. A specific diagnosis for or anti- ically of B-cell origin and confined to the eye uveitis can be found in approximately 70% of and the central nervous system.47 cases, and a systemic disease is associated with inflammatory Other masquerade syndromes include uveitis in up to half.48–50 Infection should be treatment uveal melanoma and metastatic lesions of considered when uveitis develops in an breast, lung, or renal origin. immunocompromised patient, or when uveitis fails to respond to anti-inflammatory therapy. ■ COMPLICATIONS OF UVEITIS The active participation of the internist in the evaluation and management of immunosup- The major sight-threatening complications of pression in patients with uveitis is extremely uveitis are cataracts; glaucoma; cystoid macu- helpful. lar edema; retinal detachment; subretinal, retinal, and neovascularization; If this is uveitis, and . is it associated with systemic disease? Cataracts occur in patients with uveitis as The most helpful tools in the initial search for a direct result of inflammation—as well as associated systemic diseases are the patient’s treatment of the inflammation with cortico- history and the general physical examination, steroids. Uveitis may lead to anterior and pos- coupled with the information given by the terior synechiae which can impede aqueous ophthalmologist about the ocular pattern of outflow and cause glaucoma. Permanent loss the inflammation. TABLE 2 summarizes systemic of vision can occur with long-standing macu- conditions and their common associated ocu-

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TABLE 2 Systemic conditions and their associated ocular pattern of inflammation

SYSTEMIC DISEASE PATTERN OF UVEITIS

Ankylosing spondylitis Acute unilateral anterior uveitis; may “flip-flop” between eyes Reactive arthritis Acute unilateral anterior uveitis Inflammatory bowel disease Acute unilateral anterior uveitis* Juvenile idiopathic Chronic insidious bilateral uveitis pauciarticular arthritis Sarcoidosis Chronic insidious bilateral anterior or posterior uveitis, retinal involvement Behçet syndrome Chronic insidious bilateral anterior or posterior uveitis Vogt-Koyanagi-Harada syndrome Chronic insidious bilateral anterior or posterior uveitis, retinal detachment

*Uveitis associated with Crohn disease may be bilateral, posterior, insidious in onset, and chronic in duration

lar pattern of inflammation. mate clinical value of routine spine or sacroil- Once the inflammation is localized to iac radiographs in the absence of axial symp- either anterior or posterior segment, and the toms is not established.53 onset (acute or insidious) and the symmetry HLA typing can occasionally help deter- The new onset (unilateral or bilateral) have been established, mine the prognosis of anterior uveitis. of floaters and clues from the history and physical examination HLA-B27 is associated with both can direct the diagnosis and workup (TABLE 3). spondyloarthropathy and isolated anterior hazy vision uveitis. Seventy-one percent of patients with warrants Are there specific considerations acute-onset unilateral “nongranulomatous” in the uveitis workup? (the ophthalmologic term based on the slit- referral to an The diagnostic evaluation of patients with lamp appearance of the eye) anterior uveitis ophthalmologist uveitis should be tailored to fit the history and are HLA-B27-positive.54 HLA typing is not physical findings. Chest radiography, computed indicated if a patient presents with acute uni- tomography, or both are mandatory when pul- lateral uveitis and the diagnosis of spondy- monary symptoms are elicited. However, imag- loarthropathy is already established, howev- ing can still be considered if there are no pul- er. HLA-B27 testing is also not helpful when monary symptoms and if a cause of uveitis is not the uveitis is posterior or bilateral, since in obvious, since thoracic sarcoidosis is frequently this setting the relation to HLA-B27 is not asymptomatic. This approach has not been clear. demonstrated to influence outcomes in patients Testing may be most useful when a patient with otherwise asymptomatic sarcoidosis, how- presents with acute unilateral anterior uveitis ever. without a clear explanation by history and Symptoms of spondyloarthropathy may be physical examination. In such cases, detecting atypical in female patients, and radiographic HLA-B27 would direct the diagnosis away evaluation of the sacroiliac joints can be help- from sarcoidosis or syphilis and would suggest ful if this diagnosis is considered.51 A normal that the disease is likely to respond to inter- sacroiliac radiograph does not exclude spondy- mittent local therapy with steroid drops, loarthropathy, since radiographs may be nor- although it will likely recur.24 mal early in the disease.52 However, the ulti- Typing for HLA-A29 strongly supports the

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POSSIBLE DIAGNOSE CLUES WORKUP

Spondyloarthropathy Asymmetric peripheral arthritis Sacroiliac radiography Dactylitis, enthesitis HLA-B27 testing if diagnosis Morning back stiffness is unclear Sarcoidosis Cough, dyspnea Chest radiography Lacrimal gland enlargement Computed tomography Parotid gland enlargement Behçet disease Oral or genital ulcers Rule out infectious cause (eg, herpes viruses) Inflammatory bowel disease Gastrointestinal symptoms Colonoscopy Heme-positive stools HIV infection Opportunistic infections HIV testing Malignancy Abnormal white blood cell count CD40 count Cancer therapy Thrombocytopenia

diagnosis of birdshot , a serious is a distinct subspecialty of , chronic chorioretinitis that is usually suggested and a uveitis specialist may need to be con- by the clinical appearance of the retina.19,20 sulted in complex cases. Often, an internist or Antinuclear antibody testing is not rec- rheumatologist manages dosing and monitors ommended in cases of unexplained uveitis, the toxicity of immunotherapy, while an oph- because the test has poor diagnostic value for thalmologist assesses disease activity and ocu- lupus (or any other specific diagnosis) in the lar damage, dictating the need for increased or A positive absence of specific diagnostic concern sug- decreased intensity of therapy. antinuclear gested by the history, laboratory evaluation, or physical examination. A positive antinuclear Treatment of infectious diseases antibody test antibody test in the setting of isolated uveitis Viral infections, particularly cyto- does not does not warrant the diagnosis of systemic megalovirus infection and herpetic acute reti- lupus erythematosus. Some pediatric rheuma- nal necrosis, should be treated very aggres- establish tologists use the antinuclear antibody test in sively with antiviral agents to prevent retinal lupus—or young patients with pauciarticular juvenile damage. anything else inflammatory arthritis to help predict progno- Syphilitic uveitis should be treated as sis, but as noted, this practice has recently neurosyphilis. been questioned.31 Toxoplasma infection is usually treated with Serologic tests for syphilis should be con- the combination of sulfadiazine, pyrimethamine, sidered in patients with unexplained uveitis. and folinic acid. Venereal Disease Research Laboratory (VDRL) testing may be negative but the fluo- therapy rescent treponemal antibody absorption test is Corticosteroids are the mainstay of therapy for usually positive in syphilis-related eye disease.4 noninfectious causes of uveitis; the route This is especially important in patients infect- depends on the location of inflammation, the ed with human immunodefieciency virus. severity, the degree of visual disability, and the presence or absence of systemic disease. ■ TREATMENT IS MULTIDISCIPLINARY Topical corticosteroids are used in anteri- or uveitis but are not recommended in poste- Uveitis is best managed in collaboration with rior uveitis because of poor penetration and an ophthalmologist. Inflammatory eye disease thus limited efficacy. The frequency of doses

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depends on disease severity; hourly applica- and long-term use. Although untreated tion may be needed at first. uveitis can cause cataracts and glaucoma, Topical steroids may worsen viral or other these are also recognized complications of infections and delay the appropriate therapy. steroid therapy. Thus, it is imperative to communicate with an Other immunosuppressive medications ophthalmologist before starting topical corti- used in steroid-dependent or refractory uveitis costeroid therapy. include methotrexate, sulfasalazine, azathio- Periocular corticosteroid injections are prine, cyclosporine, mycophenolate, chloram- used for posterior disease. They have the bucil, and tacrolimus.55–57 Few randomized advantage of achieving high intraocular levels trials of these agents have been performed. of steroids while avoiding the systemic side Recent reports showed promising results with effects of oral corticosteroids. perfora- anti-tumor necrosis factor agents in some tion, , and glaucoma are potential risks. forms of inflammatory uveitis.58–59 Systemic corticosteroid therapy, may be Immunosuppressive medications should effective in controlling anterior uveitis, but is be managed by physicians experienced in their generally reserved for patients with bilateral use, given the wide range of potential toxicity, disease that is refractory to local medication or and in collaboration with an ophthalmologist for those with major ocular disability or retini- skilled in the management of uveitis. tis. Adjunctive therapies, including mydriat- Systemic or topical corticosteroids usual- ic/cycloplegic agents, are used mainly to pre- ly elicit a therapeutic response, but some vent adhesion of the pupillary margins to the inflammatory conditions do not fully anterior lens capsule and to relieve painful cil- respond or require unacceptably high doses iary spasm.

■ REFERENCES

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