Uveitis in Juvenile Idiopathic Arthritis

History: The Association of Arthritis and Uveitis

Ohm first described chronic uveitis and band keratopathy in 1910 in a child with arthritis. The association of ocular disease and juvenile arthritis was confirmed by several authors. In Sury’s large series of children with chronic arthritis, chronic uveitis was found in 15% of the total, and two-thirds of those patients with uveitis had band keratopathy. The majority of his patients had an insidious onset of uveitis with little or no early disturbance of vision; diagnosis was often delayed until slit-lamp examination was performed. The occurrence of “chronic, asymptomatic, nongranulomatous anterior uveitis” became recognized as an important complication of what was called juvenile rheumatoid arthritis , particularly the limited joint disease referred to as pauciarthritis , equivalent to oligoarthritis, a subset of JIA in the International League of Associations for Rheumatology (ILAR) classification, as well as RF-negative polyarthritis and psoriatic arthritis.

Epidemiology

The uveitis associated with JIA accounts for 15% to 67% of cases of uveitis in children reported in large series from tertiary care ophthalmology centers in Europe, North America, and Israel. The documented frequency of chronic uveitis in children with chronic arthritis has varied considerably from 2% in Costa Rica to 11.6% in the United States, 13% in Canada, and 16% in the Nordic countries. ^, It appears to be particularly uncommon in Asian and African populations but has been reported worldwide. A worldwide observational cohort study confirmed disparities in prevalence of JIA-associated uveitis being highest in northern Europe (19.1%) and southern Europe (18.8%) and lowest in Latin America (6.4%), Africa and the Middle East (5.9%), and Southeast Asia (5.0%).

A longitudinal prospective cohort study of 435 children with JIA in Nordic countries identified uveitis in 20.5%. The frequency of uveitis was related to JIA subtype: 35.7% in juvenile psoriatic arthritis, 22.5% in RF-negative polyarticular, 20.5% in extended oligoarticular, 19.1% in persistent oligoarticular, 19.0% in undifferentiated, and 8.3% in ERA. This series reported a very high rate of uveitis among patients with juvenile psoriatic arthritis, but the cohort included only 14 patients with this condition. No patients with systemic (n = 18) or RF-positive JIA (n = 3) developed uveitis, consistent with earlier studies that reported low incidence in these subtypes ^, ( Table 22.3 )

The large Canadian ReACCH-Out (Research in Arthritis in Canadian Children Emphasizing Outcomes) cohort study has reported on the incidence of uveitis in the years after diagnosis of JIA. Of 1183 patients enrolled between 2005 and 2010 with a median follow-up 35.2 months, 87 (7.4%) developed uveitis. The 5-year cumulative incidence calculated by Kaplan-Meier analysis and including patients with uveitis prior to JIA diagnosis was 13.9%. The incidence of new-onset uveitis was 2.8% per year and decreased during the first 5 years but remained at 2.1% in the fifth year. Although decreasing each year, the risk is never entirely absent ^, ( Fig. 22.2 ). This highlights the importance of regular screening for uveitis for at least several years, as discussed in more detail in the Clinical Manifestations section. Uveitis may precede the onset of arthritis in 3% to 7% of children with JIA. In almost half of all patients with uveitis, it occurs just before arthritis is diagnosed, at the time of diagnosis, or shortly thereafter. ^{, ,} In the Nordic study discussed earlier, uveitis developed at a median interval of 0.8 years (range: 4.7 to 9.4 years) after the onset of arthritis. Another study, from Atlanta, Georgia, in the United States, found that 24% of 52 children were diagnosed with uveitis prior to arthritis, 22% within the first year after onset of arthritis and 86% cumulatively within 4 years. A Finnish study of children with JIA and uveitis documented the appearance of uveitis within the first 3 months after onset of arthritis in 49%; 90% developed uveitis within the first 4 years after onset of arthritis. There is some evidence that, although the prevalence of JIA may be increasing, there may be a decreasing frequency of uveitis in children with JIA. A prospective, observational, cross-sectional study from Germany found a small but significant decrease in uveitis prevalence from 2002 to 2013 (13.0% to 11.6%, odds ratio [OR] 0.98, P = 0.015). The authors suggest this may be associated with increased use of synthetic and biological disease-modifying antirheumatic drugs (DMARDs) during this period. Uveitis is bilateral in 70% to 80% of children. ^, Patients with unilateral disease are unlikely to develop bilateral involvement after the first year of disease; however, there are exceptions, and unilateral uveitis may persist for many years in a few children before the other eye is involved.

Etiology and Pathogenesis

The pathogenesis of chronic uveitis and the basis of its association with JIA are not fully understood. It is evident that both B and T lymphocytes are participants in the process, and that the innate immune system plays a role. It is thought that an immune response is triggered against intraocular antigens including S-arrestin (also known as retinal S-antigen ), retinol-binding protein 3 (RBP3), and tyrosinase-related proteins.

Immunohistochemistry of eye biopsies from patients with JIA-associated uveitis showed a predominance of CD4 ⁺ T cells compared with CD8 ⁺ T cells and variable levels of CD20 ⁺ B cells. CD4 ⁺ T cells of T helper type 1 (Th1) and Th17 subsets produce interferon (IFN)-γ and interleukin (IL)-17, respectively. ^, The proinflammatory effects of these cells are counterbalanced by CD4 ⁺ , CD25 ⁺ , FOXP3 ⁺ , regulatory T cells (Tregs), and inducible Treg cells. Although there is evidence for a role of Th1, Th17, and Treg cells in uveitis pathogenesis, the exact roles of the T-cell subsets in the course of disease have not been fully defined. ^{, ,} Analysis of peripheral blood samples has shown an increased Th1/Th2 ratio and increased Th17 numbers in patients with JIA-associated uveitis compared with healthy controls.

Evidence of the role of B lymphocytes in JIA-associated uveitis has been supported by transcriptomic and proteomic analysis of iris tissue and aqueous humor. Compared with patients with primary open-angle glaucoma, those with JIA-associated uveitis had significantly upregulated expression of B-lymphocyte–related genes including CD19 and CD20. At the protein level, there was higher expression of immunoglobulin components and the B-lymphocyte–associated protein MZB1. BAFF, APRIL, and IL-6 were also higher in the aqueous humor of JIA-associated uveitis patients. The same group also showed significantly higher levels of serum amyloid A (SAA), IL-8, transforming growth factor beta (TGFβ)-1, TGFβ-3, and tumor necrosis factor (TNF)-α in aqueous humor of patients with JIA-associated uveitis without glaucoma compared with a control group with senile cataracts.

Ooi et al. have reviewed the evidence that IL-1β, IL-2, IL-6, IFN-γ, and TNF-α are present in ocular fluids and tissues of adults with ankylosing spondylitis, and that higher levels of these cytokines are associated with more severe uveitis. Levels of TNF-α were especially elevated in the aqueous of patients with ankylosing spondylitis–associated uveitis. In another study that included children with JIA-associated uveitis, levels of IL-2, IL-6, IL-13, IL-18, IFN-γ, TNF-α, soluble ICAM-1 (also known as CD54 ), CCL5, and CXCL10 in the aqueous humor were considerably higher than in controls without uveitis. The clinical responsiveness of uveitis to the administration of some, but not all, anti–TNF-α agents provides strong support for the premise that TNF-α is at least in part responsible for the inflammation.

Keino et al. demonstrated that the oral administration of an inhibitor of IL-12/IL-23 prevented autoimmune uveoretinitis in animals by reducing the generation of IL-17–producing cells. Other animal studies have shown that anti-Th17 can block the development of uveitis in uveitis-susceptible mice, but that administration of the cytokine itself into uveitis-susceptible rats has a mitigating effect on disease development. Anti–IL-17 treatment of human uveitis (principally posterior disease) was not effective in three randomized controlled trials. However, a subsequent trial using a greater dosage of neutralizing antibody indicated that anti–IL-17 could reduce the inflammation characteristic of uveitis. Despite the implication of IL-17 in uveitis, some models involve either Th1 or Th2 cells exclusively. Animal models may not be entirely relevant to understanding human disease, however. In addition, in the most widely studied T-cell–dependent mouse model of uveitis, experimental autoimmune uveitis (EAU) is predominantly a chorioretinitis whose pathogenesis might differ significantly from anterior uveitis.

As noted previously, ANA positivity is a risk factor for JIA-associated uveitis, which raises the question of whether autoantibodies are involved in the pathogenesis. Although a correlation between ANA and plasma cell infiltration in anterior uveitis has been reported, it is not clear whether ANAs are actually pathogenic and the specifically recognized antigens are not known. Potential targets of autoantibodies have been studied using immunofluorescence of tissue sections from eyes incubated with sera from patients with JIA. When using patient sera compared with controls, there appeared to be an increased frequency of antibodies against the iris and retina, but not the ciliary body. However, because blood samples were taken after uveitis was well established, it is not clear whether the antiocular antibodies are part of the cause or a consequence of disease. In the future, serial serum samples taken from JIA patients before and after onset of uveitis could enable the potential prognostic significance of antibody binding to be investigated.

The basis of the association between inflammatory joint disease and inflammatory ocular disease is unexplained, but it is likely that a shared genetic predisposition plays a part.

Genetic Background

Genetic susceptibility to uveitis in JIA is complex. A few case reports have documented the occurrence of oligoarthritis and chronic anterior uveitis in siblings. However, monogenic or Mendelian patterns of inheritance of JIA-associated uveitis have not been seen.

A number of sometimes contradictory studies have reported an array of HLA alleles associated with chronic anterior uveitis in JIA. The strongest and most consistent associations appear to be with genes in the class II region. Studies from the United States ^, have documented a strong association with DRB1∗1104 (formerly called DR5 ), and associations with DQA1∗0501 and DQB1∗0301, which are in linkage disequilibrium with DRB1∗1104. The combination of HLA-DRB1∗1104 and HLA-DPB1∗0201 is associated with a 7.7-fold increased risk of chronic uveitis. The association of uveitis in JIA with DRB1∗11 noted in American children was confirmed in one Italian study but not in another. An association with DRB1∗13 has been reported in British and Greek children. An increased prevalence of HLA-DR9 (DRB1∗09) (OR 2.33) was also noted in one study. In a European cohort of patients with JIA, the presence of a serine residue at position 11 of HLA-DRB1 was associated with an increased risk of uveitis (OR 2.60) specifically in girls. Acute anterior uveitis is associated with the class I gene HLA-B27 . ^,

Genetic polymorphisms of non-HLA genes have been less well studied. TNF gene polymorphisms (−238 and −308 GA) have been linked with HLA-B27–associated uveitis. In patients with acute anterior uveitis, an association was found with another single nucleotide polymorphism (SNP) (857T) in the TNF gene. The TNF locus is located in the HLA/major histocompatibility complex (MHC), and large studies are needed to determine whether TNF associations reflect linkage disequilibrium with class I or class II loci.

Clinical Manifestations

Insidious Onset, Chronic Uveitis

Chronic anterior uveitis, which is characteristic of oligoarticular JIA (persistent or extended) and most children with psoriatic or RF-negative polyarticular JIA (see Table 22.3 ), is usually completely asymptomatic with an insidious onset. Later in the disease course, and if untreated, some children have symptoms attributable to the uveitis such as pain, redness, headache, photophobia, and change in vision, although these are more typical features of acute anterior uveitis ( Table 22.4 ).

TABLE 22.4

Ocular Signs and Symptoms in Children with Chronic Uveitis and Arthritis

Data summarized from published studies.

Characteristic	Percent Affected (Range)
Bilateral uveitis	25–89
Symptoms
Ocular pain and or redness	0–25
Change in vision	0–30
Photophobia	0–8
Headache	0–6
None	51–97

Regular screening for uveitis by slit-lamp biomicroscopy in patients with JIA is essential to detect clinically silent but potentially vision-threatening disease. Younger children in particular may be unable to report reliably any visual changes, so the need for formal assessment of vision and the education of families of the importance of this is vital. The early detection of chronic uveitis requires slit-lamp biomicroscopy, which should be performed in every child at the time diagnosis iof JIA is suspected rather than waiting for confirmation of the diagnosis at a pediatric rheumatology specialist center. Ophthalmological examination should be repeated at prescribed intervals during the first few years of the disease. Screening guidelines have been published from several countries including the United Kingdom, Germany, and the United States. The recommended frequency of ophthalmological examinations is influenced by the level of risk of uveitis ( Table 22.5 ). U.S. guidelines recommend that slit-lamp examinations be performed every 3 months for the first 4 years in children in the high-risk group (early age at onset, oligoarthritis or polyarthritis, and ANA positivity) and every 6 months thereafter for a period of 7 years at a minimum. In children with ANA-negative disease, slit-lamp examinations should be done initially at 6-month intervals. Children with psoriatic arthritis are also at considerable risk for the development of uveitis and should be followed at the same frequencies as children with oligoarticular or polyarticular JIA. In children with systemic-onset JIA, examinations once a year are probably sufficient. Subsequent to the publication of these guidelines, there have been suggestions for their modification. ^, Heiligenhaus et al. proposed guidelines that conformed to the ILAR classification of JIA ( Table 22.6 ).

TABLE 22.5

American Academy of Pediatrics Guidelines for the Ophthalmological Screening of Children with JIA

Adapted from Cassidy J, et al., American Academy of Pediatrics Section on Rheumatology and Section on Ophthalmology. Ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 2006;117(5):1843-1845.

JIA Onset Type	ANA	Screening Schedule
		Onset ≤6 Years ∗	Onset >6 Years †
Oligoarthritis	Positive	Every 3 months ‡	Every 6 months
Oligoarthritis	Negative	Every 6 months	Every 12 months
Polyarthritis	Positive	Every 3 months ‡	Every 6 months
Polyarthritis	Negative	Every 6 months	Every 12 months
Systemic	Negative or positive	Every 12 months	Every 12 months
High risk: Screen every 3 months Moderate risk: Screen every 6 months Low risk: Screen every 12 months

ANA, Antinuclear antibody; JIA, juvenile idiopathic arthritis.

∗ All patients are considered to be at low risk 7 years after onset of arthritis; they should have yearly ophthalmological examinations indefinitely.

† All patients are considered to be at low risk 4 years after onset of arthritis; they should have yearly ophthalmological examinations indefinitely.

‡ All high-risk patients are considered to be at medium risk 4 years after onset of arthritis.

TABLE 22.6

Recommendations for Screening Based on the ILAR Classification of JIA

Adapted from Heiligenhaus A, Niewerth M, Ganser G, et al. German Uveitis in Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology (Oxford). 2007;46(6):1015–1019.

JIA Subgroup	ANA	Age At Onset of JIA	Duration of JIA	Screening
Oligoarthritis	+	<7 years	<5 years	3 months
RF-negative polyarthritis
Psoriatic arthritis
Undifferentiated arthritis
	+	<7 years	>4 years	6 months
	+	<7 years	>7 years	12 months
	+	>6 years	<3 years	6 months
	+	>6 years	>2 years	12 months
	—	<7 years	<5 years	6 months
	—	<7 years	>4 years	12 months
	—	>6 years	NA	12 months
Enthesitis-related arthritis		NA	NA	12 months
RF-positive polyarthritis		NA	NA	12 months
Systemic arthritis		NA	NA	12 months
Patients in any category with uveitis		NA	NA	According to uveitis course

ANA, Antinuclear antibody; ILAR, International League of Associations for Rheumatology; JIA, juvenile idiopathic arthritis; NA, not applicable; RF, rheumatoid factor.

The 2019 American College of Rheumatology (ACR)/Arthritis Foundation guideline recommends that, for children and adolescents with JIA and controlled uveitis who are tapering or discontinuing topical glucocorticoids, ophthalmic monitoring should take place within 1 month after each change in topical treatment. The British Society for Paediatric and Adolescent Rheumatology and the Royal College of Ophthalmologists in the United Kingdom recommend two monthly screenings for 6 months after stopping systemic immunosuppression. European consensus guidelines suggest that all patients with JIA-associated uveitis who stop systemic treatment should have three times monthly ophthalmology monitoring for at least 3 years off all forms of treatment. Any child who has had uveitis should be considered to be at high risk, even if it has remitted, and continued surveillance is essential.

The diagnostic signs of anterior uveitis on slit-lamp examination are the presence of inflammatory cells (“cells”) and increased protein concentration (“flare”) in the aqueous humor of the anterior chamber (AC) of the eye ( Fig. 22.3 ). Deposition of inflammatory cells on the inner surface of the cornea (keratic precipitates) may be detected at presentation or develop later. Terms used to describe uveitis and its complications are listed in Table 22.7 .

TABLE 22.7

Terms Used by Ophthalmologists to Describe Abnormalities in Uveitis

Term	Definition
Anterior uveitis	Ocular inflammation that is predominantly anterior to the lens. Subsets of anterior uveitis include iritis and iridocyclitis; the latter term is preferred if the ciliary body is involved.
Intermediate uveitis	Ocular inflammation in which the predominant manifestation is leukocytes in the vitreous humor.
Panuveitis	Ocular inflammation involving the anterior chamber, the vitreous humor, and the retina and/or choroid.
Mutton-fat precipitates	Large concretions of leukocytes attached to the endothelial surface of the cornea.
Granulomatous uveitis	Uveitis usually characterized by large concretions of cells on the corneal endothelium (granulomatous keratic precipitates) or iris nodules. Although these findings are more common in a granulomatous disease such as sarcoidosis or tuberculosis, the histology of these lesions is not a granuloma.
Nodules	Cellular nodules in a patient with uveitis including Koeppe nodule at the pupillary margin and Busacca nodules in the iris stroma.
Pars planitis	A subset of intermediate uveitis in which the inflammation is predominantly over the pars plana, an anatomical region just posterior to the ciliary body.
Cystoid macular edema	Collection of fluid in the macula, a common cause of vision loss in patients with uveitis.
Vitritis	Inflammation in the vitreous humor.
Cyclitic membrane	Fibrotic tissue that forms posterior to the lens capsule and impedes the visual axis.
Cataract	Opacification of the lens as occurs from aging, chronic oral or topical corticosteroid use, or chronic inflammation.
Glaucoma	Optic nerve injury usually resulting from a chronic elevation of intraocular pressure.
Hypotony	Excessively low intraocular pressure.
Posterior synechiae	Adhesions between the iris and the anterior lens capsule.
Anterior synechiae	Adhesions between the iris and the cornea.
Iris bombé	Circumferential posterior synechiae resulting in impaired flow of aqueous humor and a marked elevation of intraocular pressure.
Keratic precipitates	Concretions of cells that deposit on the corneal endothelium during uveitis.
Band keratopathy	Deposition of calcium in the corneal epithelium as can occur from chronic anterior uveitis in JIA.
Phthisis	The irreversible end stage of chronic inflammation or infection.
Snowbanking	The cellular exudate over the pars plana, a characteristic of pars planitis.

JIA, Juvenile idiopathic arthritis.

Intraocular inflammation is graded according to the SUN criteria, which take into account AC cells, AC flare, vitreous cells, and vitreous haze or debris ( Tables 22.8 and 22.9 ). The criteria also provide definitions of improvement and worsening of the condition ( Table 22.10 ) allowing reproducible assessment and monitoring of uveitis activity. It is important to note that 0.5+ AC cells should not be considered inactive uveitis.

TABLE 22.8

Standardization of Uveitis Nomenclature Grading Scheme for Anterior Chamber Cells

Grade	Cells in Field ∗
0	<1
0.5+	1–5
1+	6–15
2+	16–25
3+	26–50
4+	>50

∗ Field size is 1 mm by 1 mm slit beam

TABLE 22.9

Standardization of Uveitis Nomenclature Grading Scheme for Anterior Chamber Flare

Grade	Description
0	None
1+	Faint
2+	Moderate (iris and lens details clear)
3+	Marked (iris and lens details hazy)
4+	Intense (fibrin or plastic aqueous)

TABLE 22.10

Standardization of Uveitis Nomenclature Activity of Uveitis Terminology

Term	Definition
Inactive	Grade 0 cells ∗
Worsening activity	Two-step increase in level of inflammation (e.g., anterior chamber cells, vitreous haze) or increase from grade 3+ to grade 4+
Improved activity	Two-step decrease in level of inflammation (e.g., anterior chamber cells, vitreous haze) or decrease to grade 0
Remission	Inactive disease for >3 months after discontinuing all treatments for eye disease

∗ Applies to anterior chamber inflammation

Measurement of visual acuity (VA) is an important part of assessment and gives an indication of both disease activity and damage resulting from both chronic inflammation and failure or complications of treatment. Guidelines for measuring outcome in JIA-associated uveitis, which include assessment of VA as a key component, have been developed. This should be best corrected visual acuity (BCVA) using age-appropriate tests recorded monocularly and binocularly and converted to logarithm of the minimal angle of resolution (logMAR). LogMAR is calculated using the following formula: logMAR = –log ₁₀ (VA fraction).

Complications of chronic anterior uveitis are frequent and increase with increasing duration of active disease. Earlier systemic treatment is likely to have resulted in a lower frequency of complications in later series. Posterior synechiae, inflammatory adhesions between the iris and anterior surface of the lens, result in an irregular or poorly reactive pupil ( Table 22.11 ; Fig. 22.4 ). This abnormality may be the first obvious clue to the presence of uveitis on ophthalmoscopic examination, but it is frequently a sign of long-standing or severe disease. Synechiae that are circumferential prevent the free flow of aqueous humor between the posterior and anterior chambers, resulting in bulging of the iris (iris bombé) and increased intraocular pressure.

TABLE 22.11

Frequency of Complications of Chronic Uveitis in Reported Cases

Complication	Reported Range (%)
Synechiae	37–75
Band keratopathy	11–56
Cataract	6–75
Glaucoma	8–25
Hypotony	5–10
Phthisis bulbi	0–14
Cystoid macular edema	3–6

Band keratopathy is caused by deposition of calcium in the corneal epithelium and tends to be a late occurrence ( Fig. 22.5 ). Initially, crescentic gray-to-brown depositions are seen at the corneal limbus. With time, the band progresses centrally at the equator of the eye and impairs light entry through the pupil. Cataracts result either from the inflammatory disease or the use of topical corticosteroids. Changes in intraocular pressure can result in serious complications including blindness: Raised pressure is associated with glaucoma and low pressure (hypotony). ^{, ,} Chronic ocular inflammation or persistent hypotony may rarely result in phthisis bulbi, irreversible end-stage disease characterized by a shrunken, nonfunctional eye. Cystoid macular edema, which affects central vision, is reported in some series ( Fig. 22.6 ). ^,

Rare ocular conditions associated with childhood rheumatic diseases include papillitis, scleritis, episcleritis, and keratoconjunctivitis sicca. Keenan et al. suggest that granulomatous uveitis may be more common than has been thought. Using a definition of granulomatous uveitis as the presence of Busacca or angle nodules, mutton-fat keratic precipitates (KPs), or hyalinized ghost KPs, they observed granulomatous uveitis in 28% of 71 children with JIA. Granulomatous uveitis may be more common in black patients (67% of those patients with granulomatous disease in the series) than white patients (25%). Many of these patients had only ghost KP as evidence of disease; this may account for the higher incidence of granulomatous uveitis than in other studies of juvenile arthritis. It should be noted that “granulomatous” in this context does not indicate the presence of granulomata as seen in tuberculosis or sarcoidosis.

Differential Diagnosis

Anterior uveitis without evidence of joint or systemic involvement probably accounts for most children with anterior uveitis. ^, Such children should be evaluated for the presence of occult inflammatory joint disease (including leg length inequality and muscle wasting) and monitored for the possible development of arthritis or other systemic disease over time.

Uveitis and arthritis occur together with high frequency in a number of diseases other than JIA. Inflammation of the anterior uveal tract may complicate the arthropathy of inflammatory bowel disease and reactive arthritis. Uveitis also occurs in chronic infantile neurological cutaneous and articular syndrome (CINCA)/neonatal-onset multisystem inflammatory disease (NOMID), sarcoidosis, Blau syndrome, Behçet disease, and Kawasaki disease. Uveitis that occurs in these disorders is discussed in the respective chapters. Uveitis rarely occurs in systemic lupus erythematosus, polyarteritis nodosa, or Henoch–Schönlein purpura. Syndromes associated with uveitis are listed in Box 22.1 .