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Anterior uveitis is the most common form of uveitis, with an annual incidence of 8 : 100 000 population, and is the least likely to be referred to a uveitis specialist.
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Although anterior uveitis is usually the most easily managed form, associated complications such as glaucoma may result in severe visual loss.
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Many disorders that can cause a panuveitis, such as sarcoidosis, Behçet’s disease, bacterial endophthalmitis, and ocular malignancies start as an anterior uveitis.
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Diagnostic evaluation should be based on the medical history and clinical examination and used to narrow the differential diagnosis.
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Anterior uveitis is associated with systemic disease in about half of patients. Diagnosis of the underlying condition is important to ensure proper treatment of both the uveitis and the systemic disease.
Anterior uveitis is the most common form of uveitis and the least likely to be referred to a uveitis specialist. The diagnosis of anterior uveitis is based on inflammation limited to the anterior chamber. Because many patients have only a single episode of disease without recurrence or complications, there is a debate on how to evaluate and treat patients with newly diagnosed anterior uveitis. Although anterior uveitis is usually the most easily managed form, associated complications such as glaucoma may result in severe visual loss. In addition, many disorders that can cause a panuveitis, such as sarcoidosis, Behçet’s disease, bacterial endophthalmitis, and ocular malignancies may start as an anterior uveitis. Therefore, the approach to patients with anterior uveitis requires careful thought and planning.
As we learn more about the pathophysiology of uveitis, it is becoming increasingly clear that many forms of uveitis may be triggered by a microbial agent. There are a number of conditions where the line between infectious and noninfectious causes becomes blurred. Therefore, this section is now titled Uveitic Conditions not Caused by Active Infection.
Epidemiology
Anterior uveitis accounts for approximately three-quarters of cases of uveitis, with an annual incidence rate of about eight per 100 000 population. Most cases have no identifiable cause and are classified as idiopathic; however, in some series HLA-B27 is associated with the disease in up to a third of patients.
Clinical description
Anterior uveitis includes diseases previously categorized as both iritis (inflammation of the iris) and iridocyclitis (inflammation of the iris and ciliary body). Patients with anterior uveitis often complain of redness, pain, and photophobia; some are relatively asymptomatic. Tearing may occur, but ocular discharge is rare. Some patients with severe anterior uveitis may also complain of blurred vision. Conjunctival injection is frequently noted on examination. Ciliary flush – conjunctival injection in the perilimbal area, is characteristic of many forms of the disease. Pupillary miosis, posterior synechiae, and dilated iris vessels are common findings in all forms of anterior uveitis. However, sector abnormalities of the iris may suggest herpes zoster ophthalmicus as an underlying cause. The iris may also adhere to the trabecular meshwork, forming peripheral anterior synechiae (PAS). These PAS should be looked for on gonioscopic examination because patients with severe PAS are at increased risk for secondary glaucoma. In addition, patients with severe posterior synechiae – iris adhesions to the lens – can develop pupillary block and may require prophylactic iridectomy.
The major indicators of anterior uveitis are the presence of cells and flare in the anterior chamber. Anterior chamber inflammation is assessed on slit-lamp biomicroscopic examination and is discussed in detail in Chapter 3 . These cells and flare represent extravasated inflammatory cells and protein as a result of a breakdown of the blood–aqueous barrier. A device has been developed that uses laser photometry to objectively assess anterior chamber cells and flare. Guex-Crosier and colleagues used laser flare-cell photometry to demonstrate that blood–aqueous barrier disruption was very pronounced in idiopathic anterior uveitis and acute retinal necrosis, but minimal in patients with toxoplasmosis or Fuchs’ heterochromic cyclitis. These authors suggested that laser flare-cell photometry provides a quantitative and sensitive assessment of anterior segment inflammation and may be useful for the management of patients with uveitis.
Fibrin may accumulate in the anterior chamber and may cause the once-mobile cells that circulate in the aqueous to become frozen. This plasmoid aqueous is a sign of severe anterior uveitis that requires aggressive therapy. Another sign of severe anterior uveitis is a hypopyon composed of layered leukocytes. A hypopyon can be seen in a number of forms of anterior uveitis, but it is frequently associated with Behçet’s disease or infectious endophthalmitis. Anterior uveitis, including some cases with hypopyons, has been described in patients with AIDS who are receiving the drug rifabutin as treatment or prophylaxis for mycobacterial infection. Also, hyphema may occur in patients with anterior uveitis, but it usually resolves without permanent damage.
Inflammatory cells may also collect and adhere to the corneal endothelium and form keratic precipitates. The mechanism appears to involve the expression of cell adhesion molecules that are upregulated in the presence of inflammatory cytokines such as interleukin-1. Large, greasy-appearing keratic precipitates are suggestive of a granulomatous inflammation and may help in determining the cause of the uveitis (see Chapter 4 ). In vivo confocal microscopy of keratic precipitates showed heterogeneous features of KP and may have diagnostic relevance.
During the acute inflammatory episode, the intraocular pressure is often reduced because of ciliary body shutdown and reduced aqueous production. As the inflammation subsides, however, the intraocular pressure may rapidly increase, especially in patients with severe PAS. In some patients it is difficult to determine whether the increased intraocular pressure is a result of underlying inflammation or a steroid response to the corticosteroids used to control the disease. In secondary glaucoma caused by active inflammatory disease, increased corticosteroid therapy will lead to a reduction in intraocular pressure.
Although some of the clinical symptoms and signs of anterior uveitis are specific for certain diseases, most disorders are differentiated by their associated systemic findings. The clinical findings of the common disorders that cause anterior uveitis are summarized in Table 19-1 . Some disorders, such as postsurgical inflammation, infectious uveitis, Behçet’s disease, sarcoidosis, and the masquerade syndromes, are discussed in separate chapters.
| Disease | Age (yr) | Sex | Ocular Redness | HLA-B27 | Systemic Findings | Steroid Response |
|---|---|---|---|---|---|---|
| Idiopathic | Any | Either | Yes | No | None | Yes |
| HLA-B27, ocular only | 15–40 | M > F | Yes | Yes | None | Yes |
| Ankylosing spondylitis | 15–40 | M > F | Yes | Yes | Spondylitis, sacroiliitis | Yes |
| Reactive arthritis | 15–40 | M > F | Yes | Yes | Arthritis, urethritis, mucocutaneous lesions | Yes |
| Juvenile rheumatoid arthritis | 3–16 | F > M | No | No | Pauciarticular arthritis, ANA-positive, RF-negative | Yes |
| Fuchs’ iridocyclitis | Any | Either | No | No | None | Yes/no |
| Posner–Schlossman syndrome | Adult | Either | No | No | None | Yes |
| Schwartz syndrome | Adult | Either | No | No | None | No |
| Ocular ischemia | >50 | Either | Yes | No | Carotid insufficiency | No |
| Kawasaki disease | 1–18 | Either | Yes | No | Skin rash, lymphadenopathy fever, cardiac lesions | Yes |
Idiopathic anterior uveitis
After a thorough medical history and an ocular and general physical examination, almost 50% of patients are found to have an anterior segment inflammation that is not associated with other defined clinical syndromes. This form of anterior uveitis is referred to as idiopathic anterior uveitis. Patients with idiopathic anterior uveitis must not only lack systemic disease associations but also cannot have the HLA-B27 haplotype, which is associated with anterior segment inflammatory disease. In one study, 47% of patients with anterior uveitis had HLA-B27-associated anterior uveitis; however, about one-quarter of these patients also had underlying systemic disorders, including ankylosing spondylitis and Reiter’s syndrome. Nevertheless, the diagnosis of idiopathic anterior uveitis depends greatly on the extent of the evaluation for an underlying condition. Many of the conditions initially diagnosed as idiopathic anterior uveitis are later found to be a specific disorder.
Importantly, one should rule out masquerade syndromes that present with an anterior uveitis (see Chapter 30 ). Conditions, including the presence of intraocular foreign bodies, malignancies including leukemia and lymphoma, and pigment dispersion syndrome, can be misdiagnosed as an idiopathic anterior uveitis. Medications including rifabutin, sulfonamides, topical prostaglandin analogs for glaucoma and ocular hypertension, and vaccines have been associated with anterior uveitis. , Nevertheless, a specific etiology for anterior uveitis cannot be determined in many patients. It has been hypothesized that these patients may have an immune responsiveness that may explain the development of anterior segment inflammation. Patients with a history of acute anterior uveitis but no signs of ocular inflammation at the time of recruitment showed a high innate immune responsiveness compared with control subjects. In a whole blood culture assay, levels of tumor necrosis factor-α and C-reactive protein were significantly higher in patients with a history of anterior uveitis than in control subjects.
Diagnostic workup
A controversial topic in uveitis concerns the diagnostic evaluation of patients with a first episode of anterior uveitis. Some suggest that no evaluation is needed. Others state that a long list of laboratory tests and diagnostic procedures should be ordered. The prudent approach probably lies somewhere in the middle, and, as discussed in Chapter 4 , a complete medical history and thorough examination can help target the workup. For example, if the patient complains of lower back pain, a diagnosis of ankylosing spondylitis is suggested and the evaluation might consist solely of sacroiliac joint films and HLA-B27 testing. Similarly, for a child with anterior uveitis with band keratopathy and a history of arthritis a diagnosis of juvenile rheumatoid arthritis is suggested, and a targeted evaluation consisting of tests for antinuclear antibody (ANA) and rheumatoid factor may suffice.
However, when a thorough history and examination fail to suggest specific diagnoses, what tests should be ordered? We tend to do a limited workup of all patients with anterior uveitis even if it is their first episode. If the uveitis is nongranulomatous, we order a fluorescent treponemal antibody absorption test to rule out syphilis, because this test is both highly sensitive and specific for the disease and because syphilis is treatable, and early treatment can prevent long-term complications. Similarly, we obtain results of a complete blood cell count and urinalysis to rule out an underlying systemic disorder such as connective tissue disease, because the associated renal disease or anemia may be asymptomatic yet warrant therapy. If the inflammation is granulomatous, a number of other disorders are suggested (see Chapter 4 ). For granulomatous anterior uveitis we will also require a purified protein derivative test, a chest X-ray, and a serum and urine calcium test and a serum angiotensin-converting enzyme level to rule out asymptomatic tuberculosis or sarcoidosis.
Treatment
The breakthrough in the treatment of ocular inflammation came with the discovery of corticosteroids. In 1949, Hench and colleagues reported the beneficial effect of 17-hydroxy-11-dehydrocorticosterone and pituitary adrenocorticotropic hormone in patients with rheumatoid arthritis. During the following year, two papers were published in the Journal of the American Medical Association showing effects on ocular inflammatory disease. , This was a vast improvement from previous therapy. Earlier in the 20th century, patients with ocular inflammation were treated by inducing hyperpyrexia. Early on, patients were placed in steam baths in which their temperature was raised to 40–41°C for 4–6 hours. In some patients the inflammation improved, but many developed severe complications. Later, patients were injected with milk protein or typhoid toxin to induce fever. Despite complications with their use, corticosteroids were a welcome advance in our treatment of inflammation.
Patients with idiopathic anterior uveitis tend to have nongranulomatous inflammation that responds well to topical corticosteroid therapy. Acetate preparations of topical corticosteroids tend to penetrate the cornea better than other preparations especially if the epithelium is intact, and we tend to use prednisolone acetate 1%. To prevent the development of posterior synechiae and to moderate symptoms of pain and photophobia caused by inflammation of the ciliary muscle, mydriasis and cycloplegia are indicated. Scopolamine 0.25% given twice daily is usually sufficient. For resistant disease, periocular injections of corticosteroids may be useful. Systemic corticosteroids are rarely needed to treat anterior uveitis. However, patients with anterior uveitis may develop posterior segment disease. These patients frequently require more aggressive antiinflammatory therapy including periocular or systemic corticosteroids or other immunosuppressive therapy.
HLA-B27–associated anterior uveitis
HLA-B27-associated anterior uveitis appears to be a distinct clinical disorder. This form of the disease has frequent associations with systemic diseases, including ankylosing spondylitis, Reiter’s syndrome, inflammatory bowel disease, Whipple’s disease, and psoriatic arthritis. Nevertheless, as stated earlier, many patients with the HLA-B27 haplotype and anterior uveitis have no associated systemic illness.
Epidemiology
Some studies suggest that as many as 50% of patients with acute anterior uveitis are HLA-B27 positive, and half of these have spondyloarthropathies. In a systematic review of 126 articles describing 29 877 patients with spondyloarthropathy, Zeboulon and colleagues reported a uveitis prevalence of 32.7%. This prevalence increased with the duration of disease.
Demographics and clinical findings
Patients with HLA-B27-associated anterior uveitis are more often male and tend to develop uveitis at a younger age than those who are HLA-B27 negative. However, some studies indicate that the long-term visual prognosis is similar for both groups.
In a retrospective cohort study of 177 HLA-B27 patients with uveitis, the average age at onset of acute anterior uveitis was 36 years with no difference between males and females. HLA-B27-associated systemic disease developed earlier in males and bilateral uveitis developed more frequently in females.
Should HLA typing be performed in all patients with anterior uveitis? We obtain HLA typing for patients with their first episode of acute anterior uveitis, especially if they have back pain or other systemic symptoms or signs. In addition, if patients develop severe chronic anterior uveitis, we will obtain HLA typing for the patient because the finding of the HLA-B27 haplotype often obviates the need for an extensive laboratory evaluation to rule out infectious or other treatable causes of the disease.
Etiology
The finding of the HLA-B27 haplotype is also of interest as a clue to the possible pathogenesis of the disease. Of particular interest is the potential role of Gram-negative bacteria and their interaction with major histocompatibility complex (MHC) class I antigens in triggering the anterior uveitis. , More recently, Helicobacter pylori has also been associated with anterior uveitis. Unfortunately, this possible link between microbial antigens, HLA-B27, and anterior uveitis has not lead to improved therapy for the disorder because antimicrobial agents have not been proved to affect the course of disease. This may be due to a lack of efficacy or the dearth of trials investigating this therapeutic approach. A possible explanation for the lack of efficacy of antimicrobial agents is that the infection induces inflammation through toll-like receptors (TLR) and the process becomes separate from the active infection.
Other immunologic studies have been performed in an attempt to determine the pathogenesis of anterior uveitis. Increased levels of complement and immunoglobulin (Ig) G compatible with breakdown of the blood–aqueous barrier can be detected in the aqueous of patients with anterior uveitis. There is also evidence of complement activation in the aqueous of patients with anterior uveitis, measured by the presence of C3a, C4a, and C5a. Evidence of increased serum fibrin degradation products has suggested a pathogenic role of the clotting pathways. Increased expression of cell adhesion molecules has been associated with the development of intraocular inflammation. Increased expression of intercellular adhesion molecule-1 (ICAM-1) in the irides of patients with uveitis has been reported, and expression of cell adhesion molecules in the anterior uvea has been shown to precede the infiltration of inflammatory cells in animal models of acute anterior uveitis. , Finally, polymorphisms within the tumor necrosis factor (TNF)-α promoter region have been identified, and individuals with these single-nuleotide polymoprhisms (SNPs) show a higher susceptibility towards developing uveitis.
HLA-B27–associated anterior uveitis with systemic disease
Ankylosing spondylitis
Ankylosing spondylitis is a chronic, inflammatory arthritis that primarily affects the spine and sacroiliac joints. The disease was previously known as Bechterew’s disease and Marie Strumpell disease, and is now discussed as a spondlyoarthropathy. Without treatment, the disease can progress and result in fusion and rigidity of the spine known as bamboo spine.
Ocular involvement occurs in 25% of patients with ankylosing spondylitis. In 80% of patients both eyes are involved, but they are rarely inflamed simultaneously. Although the ocular findings associated with ankylosing spondylitis include both iritis and conjunctivitis, the iritis is the more significant manifestation. The disease course is quite variable. Recurrence of the ocular inflammation may occur as frequently as every 2–3 weeks. Some patients have fewer than one exacerbation per year. Interestingly, recurrence may be seasonal, although this variation appears to be more frequent in patients with idiopathic anterior uveitis.
The anterior uveitis associated with ankylosing spondylitis usually has a presentation similar to that of idiopathic disease, occurring as a unilateral acute iritis with pain, photophobia, and redness ( Fig. 19-1A ). Patients often complain of the onset of an attack 1–2 days before anterior chamber cell and flare are evident on slit-lamp biomicroscopy. The use of laser photometry may help determine when initial breakdown of the blood–aqueous barrier occurs in relation to the development of symptoms and clinical signs of inflammation. Vision may decrease transiently during an acute episode as a result of anterior chamber inflammation, or less often because of associated cystoid macular edema. A fibrin clot may form in the anterior chamber ( Fig. 19-1B ). Posterior synechiae commonly develop unless attacks are treated promptly with corticosteroids and cycloplegic agents ( Fig. 19-2 ).
Ankylosing spondylitis has been reported to affect men 2.5–3 times more frequently than women. Women may have a milder disease that may present with more peripheral joint manifestations. It is a common disorder that affects 0.1% of white adults. Because HLA-B27 antigen is dominantly inherited and expressed, 50% of offspring will carry the gene, but the disease will be manifest in only 10% of them. Approximately 96% of patients with ankylosing spondylitis have the HLA-B27 antigen, compared to 6–14% of a control white population without ankylosing spondylitis. HLA-B27 is found in 0–4% of African-Americans. Thus the relative risk for ankylosing spondylitis in patients with the HLA-B27 antigen is as high as 100. Nevertheless, only 1.3% of all HLA-B27-positive patients will have the disease.
Sacroiliitis may be asymptomatic early in the course of disease, but can be associated with severe lower back pain and debilitating stiffness and decreased range of motion. X-rays of the sacroiliac joints show blurring of the joints followed by sclerotic changes and eventually obliteration as the disease progresses (see Fig. 19-1C ). A common mistake in the initial evaluation of patients with possible ankylosing spondylitis is to order lumbosacral spine films instead of radiographs of the sacroiliac joints. In severe disease, however, patients develop a fusion of the spine that begins in the lumbar region but can involve all parts of the spine. This leads to back pain and stiffness, and in severe disease may cause pulmonary restriction and a stiff, flexed neck, making positioning for slit-lamp biomicroscopic examination difficult (see Fig. 19-1D ). Interestingly, the associated uveitis does not appear to correlate with the severity of the underlying spondylitis. Aortic insufficiency, cardiomegaly, and conduction defects are also associated with this disease.
Etiology
The reason for the association between HLA-B27 and ankylosing spondylitis remains unknown. As mentioned above, some data suggest that environmental triggers such as infection with Gram-negative bacteria are important for the development of the disease. This information has led to several theories. One hypothesis suggests that HLA-B27 is a receptor for the infectious agent. A second suggests that HLA-B27 may cross-react with foreign antigens and induce tolerance. Others have suggested that HLA-B27 is a marker for an immune response gene that determines susceptibility to an environmental stimulus, or that microbial agents activate toll-like receptors and induce inflammation.
Treatment
It is important to make the diagnosis of ankylosing spondylitis in patients with uveitis because if the disease is recognized and treated early, spinal deformity can be prevented. Treatment usually involves physical therapy and antiinflammatory drugs, including nonsteroidal antiinflammatory drugs (NSAIDs). Sulfasalazine is used in patients who fail to respond to NSAIDs or who have contraindications to NSAID therapy. Cytotoxic therapy such as methotrexate is reserved for severe cases, but can reduce rates of recurrence. More recently, anti-TNF drugs have been used to treat ankylosing spondylitis. NSAIDs may have some role in treating the uveitis associated with this disorder; however, data from large controlled trials are lacking. A meta-analysis of four placebo-controlled studies with anti-TNF agents in ankylosing spondylitis reviewed the effect on anterior uveitis. The frequency of flares of anterior uveitis was significantly less in patients receiving anti-TNF therapy than in patients receiving placebo (6.8 anterior uveitis flares per 100 patient-years vs 15.6 uveitis flares per 100 patient-years).
Reactive arthritis (Reiter’s syndrome)
Reactive arthritis is a systemic disorder characterized by arthritis, conjunctivitis, and urethritis. It was first described in 1818, but is named after Reiter, who described the entity in 1916. Reiter’s syndrome is now more commonly referred to as reactive arthritis, a form of seronegative spondyloarthropathy that includes ankylosing spondylitis, psoriatic arthritis, juvenile chronic arthritis, and the arthropathy associated with inflammatory bowel disease. This change is due in part to the desire to use names that are more clinically descriptive, and because of Reiter’s activities with the Nazis during WWII. Reactive arthritis is the most common cause of inflammatory oligoarthropathy in young males and, like ankylosing spondylitis, is related to both HLA-B27 and a specific infection that may trigger the disease. The disease develops in at least 1% of patients with nonspecific urethritis and occurs in about 2% of patients after dysentery caused by Shigella spp.
Many patients do not manifest the classic triad of arthritis, conjunctivitis, and urethritis. In addition, many of the findings of reactive arthritis are easily missed. For example, urethritis may be mild and missed. Other systemic associations include a scaling skin eruption called keratoderma blennorrhagicum, balanitis, and an aphthous stomatitis. Rheumatologic features of the disease include arthralgias, plantar fasciitis, and tenosynovitis. About 20% of patients with reactive arthritis develop sacroiliitis and ascending spinal disease similar to ankylosing spondylitis. Hyperkeratotic skin lesions occur and may be indistinguishable from psoriasis. A number of classification systems have been proposed for reactive arthritis ( Box 19-1 ), but none are used uniformly in clinical practice.
