Rheumatology

Uveitis

Does this patient have uveitis?

Uveitis is defined as inflammation of the uveal tract including the iris, ciliary body, and choroid. Uveitis is classified by anatomical location which correlates with etiology and affects treatment as well as prognosis (see Figure 1). Anterior uveitis, also known as iritis or iridocyclitis, is inflammation predominantly affecting the iris, ciliary body, and anterior chamber. Intermediate uveitis, previously termed, pars planitis, is inflammation of the vitreous and peripheral retina. Posterior uveitis is inflammation of the retina and/or choroid; and panuveitis is inflammation in all three areas.

Figure 1.

Ocular Anatomy. Uveitis is classified based on location within the eye. Location directly affects the etiology, treatment, and prognosis. Anterior uveitis involves the anterior chamber, iris, and aqueous humor. Intermediate uveitis involves the vitreous humor and peripheral retina. Posterior uveitis involves the retina and/or choroid. Panuveitis is inflammation in all three locations.

The signs and symptoms of uveitis vary depending on the portion of the uveal tract involved and whether the inflammation began suddenly or insidiously. Acute anterior uveitis usually causes redness, pain, and photophobia. Eye redness alone could also be due to other diseases such as conjunctivitis, episcleritis, scleritis, keratitis, or acute closed angle glaucoma. Examination by biomicroscopy (slit lamp ophthalmoscope) is critical in distinguishing these possibilities. Patients who have pain or a change in visual acuity should be evaluated by an ophthalmologist. Persistent redness also merits referral.

Uveitis affecting the posterior segment of the eye without the anterior component may be more insidious, presenting with flashes, floaters, or blurry vision, without pain or redness. However, it is important to note that the differential diagnosis for the symptoms aforementioned includes many more common, non-uveitic ocular conditions, and thus, diagnosis requires the evaluation by an experienced ophthalmologist.

Scleritis and episcleritis are distinct inflammatory conditions affecting, respectively, the eye wall, or sclera, or the thin tissue overlying the sclera, the episclera. Differentiating between the two is important for prognosis and treatment considerations. Scleritis tends to be intensely painful, cause diffuse or localized redness often with tenderness and a bluish hue, with generally preserved visual acuity. Episcleritis is characterized by irritative symptoms, similar to a viral or allergic conjunctivitis. About 40% of patients with scleritis have an associated systemic disease such as rheumatoid arthritis, granulomatosis with polyangiitis, inflammatory bowel disease, polychondritis, spondyloarthritis, Behçet’s disease, or other forms of systemic vasculitis.

Inflammation within ocular tissues is difficult to discern on a non-ophthalmologic clinical examination. Depending on the anatomical part of the eye that is involved in inflammation, various examination techniques, requiring a slit lamp or indirect ophthalmoscope, are required to diagnose uveitis. This may involve, for instance, visualizing leukocytes in a fluid adjacent to a uveal structure, i.e. white blood cells in the aqueous or vitreous humors. Uveitis could also be diagnosed by identifying an infiltrate in the retina or choroid when performing a dilated fundus examination. Imaging modalities such as optical coherence tomography (OCT), fundus fluorescein angiography, and autofluorescence are helping us understand what specific ocular structures are involved in uveitis, but are best obtained and interpreted by an experienced ophthalmologist.

Rheumatologists need to be knowledgeable about uveitis for the following reasons: 1) ophthalmologists may refer patients with uveitis to determine if a systemic, immune-mediated disease is associated with the eye inflammation; 2) many patients who have a known inflammatory joint disease may develop uveitis (common examples include ankylosing spondylitis, reactive arthritis, juvenile idiopathic arthritis, psoriatic arthritis, inflammatory bowel disease, sarcoidosis, and Behçet’s disease); 3) some patients with uveitis require systemic immunosuppression that is best managed in collaboration with a rheumatologist (see below).

What tests to perform?

The differential diagnosis of uveitis is extensive and includes systemic immune-mediated diseases (for example: ankylosing spondylitis, Crohn’s disease, sarcoidosis, juvenile idiopathic arthritis, Behçet’s disease); infections (such as herpes simplex, tuberculosis, syphilis); ophthalmic syndromes (such as intermediate uveitis with pars plana exudates, birdshot choroidopathy, acute multifocal placoid pigmentary epitheliopathy); or masquerade syndromes (such as lymphoma, leukemia, retinal detachment) (see Table I).

Table I.

Common Forms of Uveitis and Their Characteristic Presentation

Many diagnoses are suggested by the history. Behçet’s disease is a good example of a disease that can be associated with uveitis affecting the anterior chamber or the retina, but it is diagnosed based on the systemic disease criteria. Other diagnoses are indicated by the exam. For example, herpes simplex often causes characteristic corneal changes but can rarely cause retinitis instead; toxoplasmosis causes a characteristic chorioretinal lesion with overlying leukocytes; birdshot choroidopathy is defined by characteristic yellowish ill-defined chorioretinal lesions.

About 30% of patients with uveitis are said to have “idiopathic” disease, which means that it is not readily classified into a diagnostic niche. Our routine is to screen all patients with idiopathic uveitis with a chest x-ray (to look for sarcoidosis or tuberculosis) and a serological test for syphilis. Serologic screening for additional diseases that rarely cause uveitis, such as Lyme disease or systemic lupus erythematosus, often leads to inaccurate diagnosis and needless expense. Opportunistic infections can occur in the eye in immunosuppressed individuals, and patients who have risk factors for HIV infection should be tested for this virus. Testing for tuberculosis exposure is reserved primarily for patients who have a risk factor for TB such as homelessness, HIV positivity, or living in an endemic environment. Many forms of uveitis have a characteristic pattern.

A patient with unilateral or alternating (flip flopping from one eye to the other but not active in both eyes simultaneously), recurrent, acute anterior uveitis (AAU) should be checked for HLA-B27, as studies have demonstrated that approximately 50% of cases of AAU are associated with a positive HLA-B27. The SENTINEL and DUET studies each found that a high percentage of patients with acute anterior uveitis have axial spondyloarthritis without realizing this. Axial spondyloarthritis is more common among those patients who are HLA B27+, but it also occurs frequently among those who are B27 -. A child with bilateral, sudden onset, anterior uveitis should be screened with a urinalysis and urine b2microglobulin level to determine whether or not they have tubulointerstitial nephritis and uveitis syndrome (TINU). Juvenile idiopathic arthritis associated uveitis is minimally symptomatic. These patients, especially the high risk anti-nuclear antibody positive, rheumatoid factor negative, pauciarticular subset must be screened regularly by an ophthalmologist. A complete blood count and metabolic panel rarely help with the differential diagnosis, but might be useful in the monitoring of systemic therapy.

Rarely, an elderly patient with chronic uveitis that is difficult to manage with immunosuppressive therapy may, in fact, have intraocular lymphoma, which can masquerade as uveitis. If this is suspected, prompt referral and a magnetic resonance imaging (MRI) of the brain +/- lumbar puncture should be considered.

How should patients with uveitis be managed?

The treatment of uveitis depends on the cause, the location within the uveal tract, and the severity. Management should either be the responsibility of an eye care professional or be undertaken as a collaboration between an internist, such as a rheumatologist, and an ophthalmologist. Most patients with uveitis do not require systemic medication. The mainstay of treatment for anterior uveitis that is not associated with active systemic disease is topical corticosteroid drops or a local depot of steroids in or around the eye if inflammation is severe.

Patients with posterior segment-involving uveitis can consider systemic immunosuppression, which may be indicated once an infection or malignancy has been ruled out. Indications for immunosuppression include: 1) topical and local therapy have failed; 2) the inflammation is active; and 3) the severity is interfering with activities of daily living. Usually, all criteria should be met. A rheumatologist may not be able to judge the activity of the inflammation. Furthermore, macular scarring, optic nerve damage, or cataract may be the cause of visual loss that does not respond to immunosuppression. Consequently, frequent communication between the ophthalmologist and the consultant is required.

The selection of treatment for different diagnoses is vast and beyond the scope of this chapter. A useful review is provided at the conclusion of the chapter, and a simplified treatment algorithm is shown in Figure 2. Some of the options for immunosuppression include oral or intravenous corticosteroids, methotrexate, mycophenolate, azathioprine, cyclosporine, tacrolimus, and biologics such as adalimumab or infliximab. Among these therapies, only adalimumab has been approved by government regulatory agencies for intermediate, posterior or panuveitis. In most instances, the use of adalimumab should only be considered if antimetabolite and corticosteroid therapy have failed. Local therapies with periocular or intravitreal steroids, delivered in an office setting or via surgically implanted devices, are also commonly used. Additional approaches such as intravitreally injected sirolimus are being studied.

Figure 2.

Uveitis Treatment Algorithm. Effective treatment of uveitis requires accurate localization of the inflammation source and potential etiology. Often, anterior uveitis responds well to topical therapy alone while posterior uveitis requires systemic or local steroids. Should immunomodulatory agents be required, they are often combined (i.e. anti-metabolite and calcineurin antagonist) or different agents trialed prior to instituting a biologic response modifier. Unilateral disease is commonly treated locally.

What happens to patients with uveitis?

Some forms of uveitis such as that associated with ankylosing spondylitis tend to be severe but self-limited in duration. If treated, resolution generally occurs within two months and vision usually returns to baseline. Other forms of uveitis such as pars planitis or that associated with juvenile idiopathic arthritis follow a chronic course, sometimes over decades.

The uveitis with Behçet’s disease is recurrent and frequently leads to blindness when it is not treated. Generally, uveitis involving the posterior segment of the eye more commonly leads to irreversible vision loss compared to that involving just the anterior segment, and often requires chronic immunosuppressive therapy. Complications of chronic uveitis can include cataract, glaucoma, cystoid macular edema, hypotony, retinal detachment or scarring, or optic nerve damage.

How to utilize team care?

As noted above, an ophthalmologist should be involved in the management of all patients with uveitis.

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