Chapter 174 – Uveitis Related to HLA-B27 and Juvenile Arthritis
JUSTINE R. SMITH
JAMES T. ROSENBAUM
Uveitis Related to HLA-B27
Uveitis Related to Juvenile Arthritis
• Ocular inflammation associated with HLA-B27.
• Recurrent unilateral acute (sudden onset) anterior uveitis.
• Photophobia and ocular redness.
• Ciliary injection.
• Often florid anterior chamber reaction that may include formation of hypopyon and/or anterior chamber fibrin clot.
• Posterior synechiae.
• Ocular inflammation associated with juvenile idiopathic arthritis.
• Bilateral chronic (insidious onset) anterior uveitis.
• Usually asymptomatic unless complications have occurred.
• Complications may include band keratopathy, cataract, inflammatory glaucoma.
• Antinuclear antibodies.
Uveitis may occur in association with a variety of systemic inflammatory diseases. However, by far the most common association is between inflammation of the uvea and inflammation of the joints. In adults, the so-called seronegative spondyloarthropathies, which occur in the context of HLA-B27 and include ankylosing spondylitis and reactive arthritis, may be associated with an acute (sudden onset) anterior uveitis. Patients with psoriatic arthritis and inflammatory bowel disease, some of whom may be HLA-B27 positive, may also develop uveitis. In children, each of these types of arthritis occurs and may be associated with uveitis. However, it is more typical for a child to develop a chronic anterior uveitis in association with juvenile idiopathic arthritis (JIA). The patterns of the different uveitis diagnoses that coexist with these rheumatologic diseases are often typical and, in some cases, may be the key to a previously unsuspected systemic diagnosis.
UVEITIS RELATED TO HLA-B27
In humans, the molecules encoded by the major histocompatibility complex (MHC) are generally referred to as human leukocyte antigens (HLAs). Three classes of HLA are inherited separately and perform different functions that are critical for a normal immune response. HLA-B27 belongs to the group known as the class I molecules. Located on the surface of most nucleated cells, the class I molecules present antigens such as viral peptide fragments to T cells. In this capacity, this molecule facilitates the destruction of cells that are infected with virus. The presence of HLA-B27 predisposes to several diseases, including a specific form of anterior uveitis, often termed acute anterior uveitis, which is of sudden onset and short duration but recurrent. Other HLA-B27–associated diseases include the seronegative spondyloarthropathies, ankylosing spondylitis and reactive arthritis.
HLA-B27 is present in 6 to 8% of the Caucasian population in the United States. It is much more common in certain ethnic groups, such as Finns and specific native North American tribes. Conversely, it is relatively uncommon in some populations, such as Japanese, and is virtually absent among others, including the indigenous Australians. There are at least 20 subtypes of HLA-B27, differing from one another by one or multiple amino acid substitutions and named HLA-B*2701, HLA-B*2702, and so on. HLA-B*2705 has been further subdivided on the basis of a silent nucleotide substitution. It has been proposed that different subtypes of HLA-B27 may imply different disease susceptibility and that this may vary with the ethnic population. HLA-B*27052 is the most common subtype and is definitely associated with disease.
Acute (sudden onset) anterior uveitis is the most common form of uveitis, with a lifetime cumulative incidence estimated at 4 per 1000 in the general population. Approximately 50% of all individuals who have acute anterior uveitis are HLA-B27 positive.  In most instances, the uveitis occurs sporadically. However, familial cases of acute anterior uveitis have been described and, in general, affect patients who are HLA-B27 positive. Some patients with HLA-B27–associated uveitis may suffer from a spondyloarthropathy in addition. Psoriasis and inflammatory bowel disease may also be associated with HLA-B27–associated uveitis, although other patterns of uveitis often occur in these groups of patients.
The pathogenesis of the HLA-B27–associated diseases, including uveitis, remains incompletely understood. A history of infection with gram-negative bacteria, including Salmonella, Shigella, Campylobacter, and Yersinia microorganisms, or Chlamydia trachomatis, is recorded significantly frequently in patients who suffer from these diseases. This is readily apparent in a case of reactive arthritis that follows an acute intestinal or genitourinary infection or in a patient with inflammatory bowel disease. However, ileocolonoscopy has also demonstrated subclinical
bowel inflammation in patients with acute anterior uveitis as well as spondyloarthropathy.   Some studies suggest that antibiotics that alter gut flora may favorably affect the course of both the joint inflammation and the ocular disease.     
Work conducted in animal models supports the concept that HLA-B27 and gram-negative bacteria interact to cause these diseases. The expression of HLA-B27 in transgenic rats is associated with a diarrheal illness and joint and skin involvement that mimic spondyloarthritis. Gram-negative flora appear to be a critical part of this disease because it is ameliorated markedly when the rats are reared in a germ-free environment. An anterior uveitis of sudden onset and short duration can be induced in rats by a systemic injection of endotoxin, also known as lipopolysaccharide, which is the major component of the gram-negative bacterial cell wall.
The exact mechanism of the interaction between HLA-B27 and the bacteria is unclear. It is possible that HLA-B27 presents bacterial peptides that first have been processed within the cell. The molecule might also present endogenous peptides that are produced as a consequence of infection. Presentation to a cytotoxic T cell would allow an immune response to proceed. The molecular mimicry theory explains disease occurrence on the basis that there is structural homology between the amino acid structures of HLA-B27 and the implicated microorganisms. Structural homology does exist between amino acid sequences of HLA-B27 and Klebsiella pneumoniae, for example. According to this theory, an immune response initially directed against an invading pathogen might subsequently be directed against HLA-B27. It has been suggested that misfolding of the HLA-B27 molecule during assembly may be the key to disease pathogenesis,
Figure 174-1 Slit-lamp photograph of left eye of a patient with acute anterior uveitis related to HLA-B27. Limbal injection, a hypopyon, fibrin at the pupil, and posterior synechiae are present. (Photograph provided by NA Rao, MD, Doheny Eye Institute, Los Angeles.)
possibly by stimulating intracellular signaling pathways that influence cellular immune functioning. Aqueous fluid obtained at the time of anterior chamber paracentesis demonstrates the presence of a heterogeneous cell infiltrate in patients with acute anterior uveitis, including substantial numbers of T cells, granulocytes, and macrophages.
CLINICAL FEATURES AND LABORATORY INVESTIGATIONS
The uveitis that typifies HLA-B27 disease is a unilateral, recurrent, acute, anterior uveitis involving the iris and/or the pars plicata ( Fig. 174-1 ). The inflammation is of sudden onset and usually resolves completely within 2 to 3 months after the onset, but has a strong tendency to recur. Although an attack is almost always unilateral, both eyes may be involved on separate occasions. Other forms of uveitis, such as Behçet’s syndrome or Vogt-Koyanagi-Harada syndrome, also tend to be recurrent, but episodes usually subside incompletely such that residual inflammation persists. The complete resolution between attacks is especially suggestive of the HLA-B27 spectrum of disease. In general, the visual prognosis for HLA-B27–associated disease is excellent. So, although the inflammation associated with this illness is often intense, the resolution is usually complete, often with little or no impairment between attacks. Cataract formation has been reported to affect up to 30% of patients. Glaucoma occurs less commonly. In the event that complications do occur, it is not uncommon for these to be multiple in the affected individual.
Typically, the onset of the uveitis is heralded by a short prodrome of vague discomfort followed, within 24 to 48 hours, by intense ocular redness with photophobia and lacrimation, pain, and reduced vision. Visual acuity is variably reduced. There is an intense injection of the limbal vasculature. The anterior chamber may contain 3 to 4 plus aqueous cell and a heavy flare. In severe cases a hypopyon may be present or a fibrin clot may form. Hypopyon is rare, but in North America, HLA-B27–associated disease is easily the most common cause of hypopyon in the setting of a noninfectious cause of uveitis. Posterior synechiae are common. Fine, nongranulomatous keratic precipitates collect on the inferior corneal endothelium. Cells in the anterior vitreous are common in cases that involve the ciliary body, but a marked vitritis is not the rule. According to the largest series, cystoid macular edema occurs in approximately 10% of patients. Optic nerve head hyperemia is another possible manifestation. Intraocular pressure tends to fall in the affected eye. Atypical forms of uveitis have been reported in association with HLA-B27, with prominent involvement of the posterior segment of the eye, including vitritis, retinal vasculitis, and pars plana exudates. Given the common occurrence of HLA-B27 in the general population, this observation may sometimes represent coincidence.
TABLE 174-1 — SUMMARY OF THE CLINICAL FEATURES OF ANKYLOSING SPONDYLITIS, REACTIVE ARTHRITIS, INFLAMMATORY BOWEL DISEASE, AND PSORIATIC ARTHRITIS
Reactive Arthritis (Reiter’s Syndrome)
Inflammatory Bowel Disease
In some studies, 80–90% of individuals who have HLA-B27–associated iritis also have systemic disease, either ankylosing spondylitis or reactive arthritis.  Conversely, between 20 and 40% of patients who have reactive arthritis or ankylosing spondylitis develop an anterior uveitis during the course of the joint disease. Although not routinely determined in diagnosing these diseases, rheumatoid factor is negative in these patients, hence the descriptive term seronegative spondyloarthropathy. The spondyloarthropathies, ankylosing spondylitis, and reactive arthritis (previously termed Reiter’s syndrome), are similar diseases with many overlapping clinical features, as listed in Table 174-1 . In general, reactive arthritis is distinguished from ankylosing spondylitis by the involvement of mucosal surfaces, such as conjunctiva, urethra, mouth, or skin.
The most common form of joint involvement associated with HLA-B27–associated iritis is mild, chronic low back pain. Unlike mechanical low back pain, as associated with intervertebral disc disease, inflammatory low back pain tends to start insidiously, to be associated with morning stiffness, and to respond very well to nonsteroidal anti-inflammatory medications, such as ibuprofen or indomethacin. About two thirds of patients who have HLA-B27–associated iritis present to the ophthalmologist without a diagnosis of inflammatory joint disease. Many, of course, are cognizant of chronic low back pain, but the diagnosis of spondyloarthritis has been overlooked.
Ankylosing spondylitis is more common in men. Symptoms typically begin during the teenage years or twenties. Sacroiliitis is the rule, although other sites, particularly other axial joints, may also be involved in the inflammatory process ( Fig. 174-2 ). Reactive arthritis refers to a peripheral arthritis that may follow infection of the genitourinary or genital tract. The disease is most common in young adult males. In the classical presentation, which is rare, a patient suffers from a bilateral conjunctivitis that occurs after or at the time of the infection, but prior to the onset of the arthritis. The arthritis has an acute onset and is typically asymmetrical and oligoarticular. Lower limb joints are most commonly involved. Enthesitis or inflammation at bone attachments of tendons and ligaments is common, especially involving the calcaneus and causing heel pain. Lower back pain also occurs. Characteristic skin lesions include keratoderma blennorrhagicum, a variant of psoriasis that occurs on the palms and soles, circinate balanitis, and mouth ulceration. Aortitis is an uncommon, but serious, association.
Figure 174-2 Patient with advanced ankylosing spondylitis involving the axial skeleton, demonstrating a characteristic posture with forward stoop of the neck. The black lines illustrate the occiput-to-wall measurement, obtained when a patient with back to the wall attempts to touch the wall with his occiput. An unaffected individual performing this test is able to touch the occiput to the wall.
Testing for HLA-B27 is useful in patients with acute anterior uveitis. Not only does it help in suggesting the diagnosis of systemic disease, but it also provides prognostic information. One review of eight studies compared HLA-B27–associated anterior uveitis with HLA-B27–negative anterior uveitis. This study showed that when occurring in the context of HLA-B27, anterior uveitis was relatively more severe, more likely to resolve within 3 months, but also more likely to recur. It was more likely to be unilateral and more likely to be associated with spondyloarthropathy. However, the final visual prognosis was no different between HLA-B27–positive uveitis and HLA-B27–negative disease. A large study from a single group has suggested otherwise, reporting a greater number of complications and a higher incidence of legally blind eyes among patients with HLA-B27–associated anterior uveitis versus HLA-B27–negative patients with anterior uveitis.
In patients with inflammatory lower back pain, a radiograph of the sacroiliac joints may be considered ( Fig. 174-3 ). In the early stages of spondyloarthropathy, the lumbosacral x-ray film demonstrates bilateral sacroiliac juxta-articular bony sclerosis, blurring of the joint margins, and/or erosive changes that may give the margins an irregular, serrated appearance. Erosions may also give the impression of widening of the sacroiliac joint. Later, inflammation leads to ossification. There is loss of joint space and finally ankylosis.
The uveitis associated with HLA-B27 generally responds to treatment with topical corticosteroids, instilled frequently. The most useful preparation is prednisolone acetate 1%, which penetrates the cornea to achieve high levels within the anterior chamber. Other topical corticosteroids have less tendency to raise the intraocular pressure but are also less potent anti-inflammatory treatments. One randomized controlled clinical trial comparing topical indomethacin with topical dexamethasone indicated that both treatments were effective but that the nonsteroidal anti-inflammatory preparation took significantly longer to work. Generally, eyedrops are instilled as frequently as every hour initially and then tapered as the inflammation begins to decrease in intensity. Most patients require about 6 weeks of treatment. Patients who have recurrent episodes may be instructed to begin treatment at the onset of the prodrome, to abort the attack early and reduce the duration of treatment. Mydriatic-cycloplegic preparations such as topical homatropine or cyclopentolate are useful during an acute attack to prevent formation of posterior synechiae. If posterior synechiae are present, it may be necessary
Figure 174-3 Radiograph of the sacroiliac joints from a patient with ankylosing spondylitis showing bilateral juxta-articular sclerosis with irregularity of the joint margins.
to use more aggressive treatments, such as a mydriatic cocktail that might include atropine or a subconjunctival injection of Mydricaine (epinephrine, atropine, and procaine). In the early stages, frequent follow-up visits are suggested. For exceptional cases that fail to respond to topical therapy, treatment with a periocular injection of corticosteroid, such as triamcinolone acetonide, or a short (1- to 2-week) course of oral corticosteroid, such as prednisone, may be required to abort the attack. Cataract in a patient with HLA-B27–associated uveitis can be successfully managed with surgical extraction and intraocular lens implantation.
Prevention of recurrent episodes is a frequent dilemma for the clinician. Although long-term topical corticosteroid use would probably be effective in this regard, the benefit is far outweighed by the risks of corticosteroid-induced cataract and glaucoma as well as susceptibility to infections. The evidence supporting the role of gut infection in the HLA-B27 diseases has led some groups to consider the possibility of using antibiotic prophylaxis to prevent attacks. A 12-month double-blind randomized, placebo-controlled trial conducted in Australia, including patients with reactive arthritis and/or recurrent acute anterior uveitis, failed to demonstrate any difference in outcome between ciprofloxacin-treated and control-treated groups.  On the other hand, a number of European studies have suggested a useful role for sulfasalazine as prophylaxis for recurrent anterior uveitis.    
INFLAMMATORY BOWEL DISEASE AND PSORIATIC ARTHRITIS
Inflammatory bowel disease and psoriatic arthritis are diseases that may also occur in association with HLA-B27, although the association is less strong than for ankylosing spondylitis or reactive arthritis. Of patients who have either ulcerative colitis or Crohn’s disease, approximately 5% develop uveitis at some point during their lifetime. Crohn’s disease is far more likely than ulcerative colitis to be associated with uveitis, at least in a referral setting. These patients are also at risk for other inflammatory eye diseases, in particular episcleritis and scleritis. Psoriatic arthritis is a condition that affects approximately 5% of persons with psoriasis. It may take various forms, including asymmetric oligoarthritis or monoarthritis, symmetric polyarthritis, and axial arthritis. Ankylosing spondylitis, reactive arthritis, inflammatory bowel disease, and psoriatic arthritis share many features, which include diarrhea, joint involvement and sacroiliitis, skin lesions, and, of course, uveitis. Despite this clinical overlap, which is presented in Table 174-1 , the eye manifestations of the latter two conditions are frequently distinct from the ocular presentation of the former two conditions.
Some of the differences between uveitis in association with inflammatory bowel disease and psoriatic arthropathy, and uveitis in association with spondyloarthropathy are highlighted in Table 174-2 . Uveitis in association with inflammatory bowel disease or psoriasis is frequently bilateral, often involves prolonged or continuous inflammation, may start insidiously, and commonly has a posterior component.  However, in some patients with psoriatic arthritis or inflammatory bowel disease, uveitis is identical to that typically observed in patients with ankylosing spondylitis. It is hypothesized that male sex, axial arthritis, and the presence of HLA-B27 are factors that predispose to an acute (sudden onset) anterior uveitis. Interestingly, the rate of complications does not appear to differ substantially between these two forms of uveitis. Uveitis does tend to coexist with other extracolonic manifestations of inflammatory bowel disease, such as joint and skin disease, but the correlation with bowel activity is not particularly strong. In more than half of cases, a diagnosis of uveitis precedes the diagnosis of inflammatory bowel disease. As is true for spondyloarthritis, the uveitis may be a clue to the diagnosis of inflammatory bowel disease. Patients who have iritis of unknown cause should be questioned carefully about bowel habits. In psoriatic arthritis, the diagnosis typically follows the joint diagnosis.
One other form of HLA-B27–associated spondyloarthropathy is known as undifferentiated spondyloarthropathy, implying that the patient does not fit a specific disease category but has one or more features consistent with the diagnosis. Although uveitis may occur in association with undifferentiated spondyloarthropathy, this group of patients has not been systematically studied to define the uveitis phenotype.
UVEITIS RELATED TO JUVENILE ARTHRITIS
Various forms of childhood arthritis may occur in association with uveitis. The group of inflammatory joint diseases implied by the umbrella term juvenile idiopathic arthritis are by far the most common arthritides encountered in pediatric patients with uveitis. Further, these diseases are the most common of all the systemic conditions associated with childhood uveitis, affecting up to approximately 40% of children who present with uveitis and up to approximately 80% of children who present with anterior uveitis. In one large study from a tertiary eye care center, JIA-associated uveitis accounted for almost 6% of the total uveitis population. In other children, uveitis may be associated with various forms of inflammatory joint disease that also occur in adults, including the HLA-B27–associated seronegative arthropathies, inflammatory bowel disease, sarcoidosis, Behçet’s disease, and infectious entities such as Lyme disease. In addition,
TABLE 174-2 — SUMMARY OF UVEITIS OCCURRING IN ASSOCIATION WITH ANKYLOSING SPONDYLITIS, REACTIVE ARTHRITIS, INFLAMMATORY BOWEL DISEASE, AND PSORIATIC ARTHRITIS
Average Age at Onset of Uveitis (years)
Gender Ratio (male:female)
HLA-B27 Positivity (%)
Lifetime Incidence of Uveitis (%)
Clinical Pattern of Uveitis
Ankylosing spondylitis and reactive arthritis
Unilateral, anterior, sudden onset, episodic
Inflammatory bowel disease
Frequently bilateral, posterior, insidious onset, continuous*
Frequently bilateral, posterior, insidious onset, continuous**
Adapted from Paiva ES, Macaluso DC, Edwards A, Rosenbaum JT. Characterisation of uveitis in patients with psoriatic arthritis. Ann Rheum Dis. 2000;59:67–70.
* Some patients with psoriatic arthritis or inflammatory bowel disease have uveitis that follows the pattern seen with ankylosing spondylitis and reactive arthritis. Axial arthritis, male sex, and the presence of HLA-B27 might be factors that predispose to the unilateral, anterior, sudden onset, episodic pattern.
a rare inherited syndrome known as familial juvenile systemic granulomatosis, which includes uveal and joint inflammation, typically presents in childhood.
JUVENILE IDIOPATHIC ARTHRITIS
The term juvenile idiopathic arthritis refers to a collection of different diseases that share three common features—the presence of arthritis, an onset prior to the 16th birthday, and no identifiable cause for the joint inflammation. By definition, the arthritis must have been present for a minimum of 6 weeks. At different times in the past, this group of diseases has been described as Still’s disease, juvenile chronic arthritis, and juvenile rheumatoid arthritis. The current nomenclature was suggested by the Task Force for Classification Criteria of the Pediatric Standing Committee of the International League of Associations for Rheumatology, which defined seven subsets of JIA. This classification is presented in Box 174-1 . Interestingly, psoriatic arthritis is included within this classification, whereas other HLA-B27–associated arthropathies, ankylosing spondylitis and reactive arthritis, are excluded. As
Classification Criteria for Juvenile Idiopathic Arthritis
CATEGORIES OF JUVENILE IDIOPATHIC ARTHRITIS
Polyarthritis (rheumatoid factor negative)
Polyarthritis (rheumatoid factor positive)
Fits no other category
Fits more than one category
Adapted from Petty RE and the Task Force for Classification Criteria. Revision for the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol. 1998;25:1991–4.
Figure 174-4 Patient with juvenile idiopathic arthritis who has bilateral elbow flexion contractures that prevent straightening of the arms.
many as 20% of patients with JIA develop uveitis, usually after, but within 7 years of, the onset of the arthritis.
Clinical Features and Laboratory Findings
Although ocular inflammation may occur in association with any form of JIA, it is most commonly associated with oligoarthritis. This arthritis involves no more than four joints, frequently the large joints such as the knee, and often resolves completely ( Fig. 174-4 ). It may even be absent clinically. Of the patients who present with oligoarthritis, approximately 25% are affected by uveitis. Female gender is a well-documented risk factor for the development of ocular inflammation.  Most patients who have JIA and uveitis test positively for circulating antinuclear antibodies and negatively for rheumatoid factor. The presence of the antinuclear antibody in a patient with JIA is considered another risk factor for the development of uveitis.
The uveitis associated with JIA is usually bilateral, anterior, and chronic with an insidious onset ( Fig. 174-5 ). The eye disease behaves independently of the joint disease. Whereas joint inflammation often resolves in childhood, ocular inflammation may persist into adulthood. Characteristically, there is no pain or redness. In most cases, this asymptomatic ocular involvement is detected during a routine screening examination. Visual acuity may be variably affected. Slit-lamp examination reveals an absence of limbal injection. There are often inferiorly located small to medium-sized keratic precipitates. Aqueous cell counts are generally low, in the order of trace to 2 plus cell, and generally associated with a chronic flare. Exacerbations with 4 plus aqueous cell may be observed, but hypopyon formation is rare. Posterior synechiae are frequently present, and, in some cases, a pupillary fibrin membrane may occur. Posterior eye inflammation is unusual.
Band keratopathy, cataract, and glaucoma are frequent complications of JIA, one large series reporting the incidences as 41%, 42%, and 19% of patients, respectively. These complications are the usual cause of reduced visual acuity. The rate of blindness in patients with JIA would appear to be decreasing, from about one third of patients in the 1950s and 1960s to 6% in a survey in 2001, the largest undertaken to date. This recent study indicates that the single most significant risk factor associated with the development of complications is the severity of the uveitis at onset of the disease. 
Management of Uveitis
The uveitis associated with JIA is often a considerable therapeutic challenge because of its chronic nature and the unique problems
Figure 174-5 Slit-lamp photograph of the right eye of a patient with chronic anterior uveitis related to juvenile idiopathic arthritis. As is typical of this condition, the eye appears uninflamed. Band keratopathy is present.
presented in the treatment of uveitis in childhood. The aim is to eradicate intraocular inflammation, although some practitioners are stricter with this goal than others. Topical corticosteroid, in the form of prednisolone acetate 1%, is generally effective in controlling the disease. Given the risks of cataract and glaucoma associated with both the therapy and the disease, frequent review is necessary to tailor the frequency of instillation of the eyedrops to the degree of inflammation. A mydriatic is frequently prescribed to avoid the formation of posterior synechiae. For the relatively small number of patients who fail to respond to topical therapy, options include periocular corticosteroid injections, orally administered corticosteroid, and/or systemic immunosuppressive agents. The frequent requirement for general anesthesia to administer a periocular injection to a child makes this form of treatment less appealing than it is for adult patients.
Oral corticosteroid therapy is associated with a multitude of side effects in a patient of any age. However, in children, retardation of growth is an additional concern. For this reason, oral corticosteroid is not favored except in the short term to control a severe exacerbation. Instead, one or a combination of other systemic immunosuppressive therapies is generally used, including the antimetabolites, methotrexate and azathioprine, and the T-cell inhibitor, cyclosporine. Risk of secondary malignancy and variable therapeutic success explain why alkylating agents, such as cyclophosphamide and chlorambucil, are rarely employed in children. The most frequently used drug is methotrexate, which is also effective for the joint disease. Advantages include once-a-week administration, low expense, and high tolerability. Some clinicians advocate the use of nonsteroidal anti-inflammatory agents if local corticosteroid therapy is unsuccessful before opting for a systemic immunosuppressive agent. One small prospective study has reported success in treating 10 patients with JIA-associated uveitis using the new inhibitor of tumor necrosis factor, etanercept. However, a second, retrospective study has been less optimistic, and the results of ongoing larger prospective studies are awaited.
Course and Outcome
Band keratopathy may require treatment when it involves the visual axis and reduces visual acuity. Chelation therapy using ethylenediaminetetraacetic acid is the simplest option. More recently, the excimer laser has been used successfully to remove the calcium by phototherapeutic keratectomy. One large series included a small number of patients with band keratopathy related to JIA-associated uveitis.  However, no information about the age at the time of treatment or about the specific outcome for the patients with JIA was included in the report.
Appropriate management of cataract in the context of JIA-associated uveitis is highly controversial. Amblyopia in a patient who is younger than 10 years must be considered. Yet, cataract surgery in a patient with uveitis or a pediatric patient is never routine, and the combination of both situations, a child with JIA-associated uveitis, is particularly challenging. Observing the principle of a quiet eye for a minimum of 3 months prior to the surgery is recommended. Some surgeons perform anterior segment surgery, whereas others include pars plana vitrectomy. Positive results have been published by a number of centers, although the success of intraocular lens implantation has been variable, and it remains unclear whether this should be performed following the extraction of the lens. One study has reported a best corrected vision of 20/20 to 20/50 in 8 of 10 eyes. Another study published in the same year reported visual acuity of 20/200 or worse in 4 of 5 eyes operated on during childhood. The need for aphakic correction needs to be considered and weighed against the substantial risk of membrane formation and posterior capsule opacification. Age of the patient and the presence or absence of amblyopia appear to be important factors in predicting the success of the procedure.
TABLE 174-3 — FREQUENCY OF OPHTHALMOLOGIC VISITS FOR CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS AND WITHOUT KNOWN IRIDOCYCLITIS*
Age at Onset of Arthritis
Juvenile Idiopathic Arthritis Subtype at Onset
Pauciarticular (ANA positive)
Pauciarticular (ANA negative)
Polyarticular (ANA positive)
Polyarticular (ANA negative)
Adapted from American Academy of Pediatrics Section on Rheumatology and Section on Ophthalmology. Guidelines for ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 1993;92:295–6.
* High risk (H) patients should have ophthalmologic examinations every 3 to 4 months. Medium-risk (M) patients should have ophthalmologic examinations every 6 months. Low-risk (L) patients should have ophthalmologic examinations every 12 months. ANA indicates the antinuclear antibody test.
† All patients are considered at low risk 7 years after the onset of their arthritis and should have yearly ophthalmologic examinations indefinitely.
‡ All patients are considered at low risk 4 years after the onset of their arthritis and should have yearly ophthalmologic examinations indefinitely.
§ All high-risk patients are considered at medium risk between 4 and 7 years after the onset of their arthritis.
Although medical therapy, including topical antiglaucoma medications and oral carbonic anhydrase inhibitors, may control intraocular pressure, the largest series of patients with JIA-associated uveitis and glaucoma, which included 41 eyes, demonstrated that surgery was required in approximately two thirds of patients. The increase in availability of different types of antiglaucoma medications may allow control to be achieved medically in a larger number of affected individuals. Although earlier studies gave pessimistic results for glaucoma surgery, one more recent report described a success rate (normalized intraocular pressure with the same or less antiglaucoma medications as preoperatively) by life-table analysis of 90% at 52 months of follow-up after implantation of a valve device.
Some patients with JIA come to medical attention because of complications such as band keratopathy, glaucoma, and cataract, sometimes associated with amblyopia. To avoid these complications and consequent visual loss, ophthalmic screening of all patients with JIA is recommended. “High-risk” patients whose disease began before age 7 years and who have pauciarticular or polyarticular disease with antinuclear antibodies should be examined every 3–4 months. Other recommendations for screening, which were developed by the American College of Pediatrics, appear in Table 174-3 .
OTHER FORMS OF JUVENILE ARTHRITIS
In some children, uveitis may occur in the context of an HLA-B27–associated seronegative arthropathy not included within the JIA classification, that is, ankylosing spondylitis or reactive arthritis. In this situation, the uveitis is identical to that occurring in adults, in other words, a recurrent, unilateral, acute (sudden onset), anterior uveitis as described earlier. Older children with sarcoidosis develop a typical adult-type disease, with prominent pulmonary involvement, lymphadenopathy, and constitutional symptoms. However, children younger than 4 years have a characteristic presentation including a skin rash, uveitis, and arthritis. A complete description of sarcoid uveitis is presented in Chapter 175 . Behçet’s disease is one other multisystem inflammatory disease that may result in childhood uveitis and arthritis. Although uveitis appears to occur more commonly in children with Behçet’s disease, the disease appears to run a more benign course in this age group. Further information
Figure 174-6 Outstretched hand of a patient with familial juvenile systemic granulomatosis demonstrating the typical finding of camptodactyly or fixed flexion deformity of the fingers.
Figure 174-7 Peripheral fundus photograph from a patient with familial juvenile systemic granulomatosis showing multiple, small, rounded chorioretinal lesions, many of which are pigmented.
about the uveitis associated with Behçet’s disease may be found in Chapter 176 .
Familial juvenile systemic granulomatosis, also referred to as Blau syndrome or Jabs syndrome, is a rare granulomatous inflammatory syndrome that is inherited in an autosomal dominant fashion. The responsible allele was identified as a mutation of a gene known as CARD15 or NOD2 that is located on chromosome 16. The protein product of the gene is expressed in monocytes, cells having the capacity to differentiate into the phagocytic cells that are found in granulomas. Interestingly, other mutations of the same gene have been shown to predispose to Crohn’s disease. Familial juvenile systemic granulomatosis is characterized by granulomatous uveitis, dermatitis, and an arthritis that most commonly affects the hands and feet ( Fig. 174-6 ). Although initial descriptions indicated that uveitis affected the anterior eye, posterior eye involvement, including vitritis and chorioretinal lesions, has been described more recently ( Fig. 174-7 ).
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