The strong association between JIA and uveitis has been recognised for many years; however, the cause of the intraocular inflammation is not fully understood. Familial cases of JIA-associated uveitis have been reported [20]. However, monogenic or Mendelian patterns of inheritance have not been seen [21], suggesting that both JIA and uveitis are complex genetic traits.

Uveitis in patients with oligoarticular JIA has been associated with the HLA-DR5 haplotype and HLA-DRB*1104 allele; the combination of HLA-DRB1*1104 and HLA-DPB1*0201 is linked with a 7.7-fold increased risk of chronic uveitis [22, 23]. The HLA-DR1 haplotype and HLA-DQA*0101 allele, in contrast, are protective. HLA-B27, which is seen more frequently in enthesitis-related arthritis, confers an increased risk of acute anterior uveitis [24]. The associations with HLA type support the theory that JIA-associated uveitis is an autoimmune disorder. It is thought that an immune response is generated against intraocular antigens including S-arrestin (also known as retinal S-antigen), retinol-binding protein 3 (RBP3) and tyrosinase-related proteins [25].

There appears to be involvement of both B- and T-lymphocytes in pathogenesis of non-infectious uveitis. Immunohistochemistry of eye biopsies from patients with JIA-associated uveitis showed variable levels of CD20⁺ B cells and predominance of CD4⁺ T cells compared with CD8⁺ T cells [26]. CD4⁺ T cells of T-helper type 1 (T_H1) and type 17 (T_H17) subsets produce IFN-γ and IL-17, respectively [27–29]. These pro-inflammatory T cells are counterbalanced by CD4⁺ CD25⁺ FoxP3⁺ T-regulatory (T_REG) cells and inducible T_REG cells. Although there is evidence for a role of T_H1, T_H17 and T_REG cells in uveitis pathogenesis, the exact roles of the T-cell subsets in the course of disease has not been fully defined [26, 30, 31].

The increased risk of uveitis in children with JIA who are ANA-positive raises the question of whether autoantibodies are involved in the pathogenesis [32]. A correlation between ANA and plasma cell infiltration in anterior uveitis has been reported, but the specific intraocular antigens and whether ANAs are actually pathogenic are not clear [26]. Studies have used immunofluorescence of tissue sections from eyes incubated with sera from patients with JIA [33]. There appeared to be an increased frequency of antibodies against the iris and retina but not the ciliary body, in sera from patients compared with sera from healthy control individuals. However, because serum was taken after uveitis was well established, it is not clear whether the anti-ocular antibodies are part of the cause or consequence of disease. In future studies, 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.

In addition to lymphocytes, macrophages are also seen in biopsy samples of eyes with uveitis [26]. Both cell types exert pro-inflammatory effects through secretion of cytokines and chemokines. In one study including children with JIA-associated uveitis, levels of IL-2, IL-6, IL-13, IL-18, IFN-γ, TNF, soluble ICAM-1 (also known as CD54), CCL5 and CXCL10 in the aqueous humour were considerably higher than in controls without uveitis [34].

The diagnosis of JIA and its associated uveitis is clinical. Complete eye examination includes measurement of visual acuity and intraocular pressure together with assessment by slit lamp of the anterior and posterior chambers and retina [46]. The use of a slit lamp allows measurement of anterior chamber flare which results from protein leakage into the anterior chamber following breakdown of the blood–aqueous humour barrier [47]. Flare can also be measured by laser flare photometry which is more quantitative and reproducible. One study showed that increased baseline laser flare was associated with a higher risk of vision loss and ocular complications, including glaucoma [48]. Routine use of laser flare photometry may help identify children at increased risk of complications and poor visual outcome.

The examination of the fundus and macula using direct ophthalmoscopy and a slit lamp should be part of the routine clinical examination of children with uveitis. When available, optical coherence tomography (OCT) can be used to measure the thickness of the macula and fovea. Increased thickness of the macula and loss of its normal concave shape is a feature of cystoid macular oedema (CMO). The incidence of macular involvement in JIA-associated uveitis is high. In a study of 38 patients (62 eyes), 82 % of eyes had maculopathy [49]. Optical coherence tomography is required to detect more subtle macular changes that are not identifiable on biomicroscopy.

The routine measurement of intraocular pressure is a particularly important part of uveitis screening, since intraocular hypertension and glaucoma can develop even after attaining control of active inflammation. A retrospective study of 30 patients with JIA-associated uveitis reported that the first elevation in intraocular pressure occurred during a time of inactive disease in 60 % of eyes and that the mean time between achieving inactive disease status and first detection of elevated intraocular pressure was 4.5 ± 5.3 months [50].

Visual acuity is a key part of the assessment of a child with uveitis both at the time of diagnosis and at follow-up. Age-appropriate tests should be used to measure best corrected visual acuity, recorded monocularly and binocularly, and the results should be converted to the logMAR (logarithm of the minimum angle of resolution) score. Visual acuity is a measure of both disease activity and damage, which results not only from long-term uncontrolled active uveitis but also from complications of treatment.

Laboratory investigations are not particularly helpful in the diagnosis or management of JIA-associated uveitis. In a child with JIA, ANA positivity is associated with increased risk of developing uveitis. However, ANA positivity alone cannot predict which children with JIA will develop uveitis. In one study using ELISA to detect ANA, there was not a clear association with uveitis, demonstrating that this test should not be used to determine the frequency of eye examinations [51]. In contrast, indirect immunofluorescence-based ANA assays may offer better predictive value in uveitis particularly when high titres are found. In a cohort of 100 children with JIA, 16 developed uveitis, of whom 14 were positive for ANA (titre ≥1:80 on immunofluorescence assay) and 13 were positive for antihistone antibodies (titre ≥8 U/ml). The authors of this study suggested that the combination of antihistone antibodies ≥8 U/ml, immunofluorescence-detected ANA ≥1:320 and a young age at onset of JIA might identify a subgroup of patients at increased risk of developing chronic uveitis [51].

A further predictor of an increased risk of uveitis seems to be an elevated erythrocyte sedimentation rate (ESR) at the time of diagnosis with JIA. In a retrospective chart review of patients with oligoarticular JIA who were recruited at the time of diagnosis [52], data on demographics were collected, inflammatory markers were measured and genotyping for allelic variants in genes-encoding TNF, IL-1β, IL-6, IL-10 and IL-1Ra was performed. ESR was significantly higher in the group who developed uveitis versus those who did not (52 mm/h versus 24 mm/h, respectively; odds ratio [OR] 1.05, 95 % CI 1.01–1.09). ANA status and cytokine gene polymorphisms were not associated with development of uveitis. Multivariate analysis showed that ESR >22 mm/h and patient age <3 years at onset of arthritis were associated with ORs of 5.28 and 3.80, respectively, for the development of uveitis. The researchers suggest that treatment and disease outcomes might be improved by using these parameters to select a population for more intensive screening or to predict which children will develop uveitis.

Treatment of uveitis depends on its underlying cause. If it is secondary to infection, then an appropriate antimicrobial is indicated. Before commencing any anti-inflammatory or immunosuppressive therapies, infection and masquerade syndromes must be excluded.

The treatment for all forms of JIA-associated uveitis follows a broadly similar stepwise therapeutic pathway [53]. The first-line treatment is topical corticosteroids ranging from once daily to hourly depending on the degree of inflammation [53–55]. High-potency steroids such as prednisolone acetate 1 % or dexamethasone phosphate 0.1 % have the greatest efficacy [56].

Treatment is indicated if the anterior chamber cell grade is >0.5+, if there is fibrin in the anterior chamber or keratocytic precipitates with corneal oedema and loss of visual acuity [53]. The aim is to achieve a persistent anterior chamber cell grade of 0. Escalation of immunosuppressive treatment is required when there is absence of improvement in inflammation or presence of poor prognostic factors (poor initial vision, cataract, macular oedema, dense vitreous body opacification, ocular hypotony and glaucoma). Cataract, glaucoma, synechia and band keratopathy alone, in the absence of active uveitis, do not require anti-inflammatory treatment [53].

Although topical steroids alone can be effective, for severe or sight-threatening JIA-associated uveitis, systemic corticosteroids are sometimes necessary to achieve rapid control of inflammation, given either orally (prednisolone 1–2 mg/kg daily) or as intravenous pulses (methylprednisolone 20–30 mg/kg daily for 1–3 days) [55]. Periocular or intraocular steroids are occasionally used to treat severe uveitis. Steroids should be reduced and stopped as early as possible to avoid the side effects associated with cumulative long-term use. Frequent treatment with steroid eye drops is clearly associated with an increased incidence of cataracts [57]. In an observational study, ≤3 drops daily of topical corticosteroids was associated with a significantly lower risk of cataracts than >3 drops daily (RR 0.13, 95 % CI 0.02–0.69; P = 0.02). These are reasons for earlier introduction of systemic steroid-sparing immunosuppression in patients with moderate to severe JIA-associated uveitis [58].

Failure to adequately control inflammation after 3 months of topical treatment, particularly if >3 drops of topical corticosteroid daily are used, is an indication for systemic immunosuppression with a DMARD [53]. A wide range of non-biological immunosuppressive agents are used to treat JIA-associated uveitis (Table 49.3). Controlled clinical trials of these drugs in management of JIA-associated uveitis have not been performed; therefore, the evidence base derives mainly from retrospective case series.