Paediatric non-infectious uveitis in Cape Town, South Africa: a retrospective review of disease characteristics and outcomes on immunomodulating treatment

Here we aim to describe the disease characteristics and outcomes on immunomodulatory treatment, of children with non-infectious uveitis managed at a tertiary paediatric referral centre in Cape Town, South Africa.

A retrospective case file review of all children ≤16 years managed for non-infectious uveitis by the paediatric ophthalmology and rheumatology units in Cape Town from 1 January 2010 to 31 December 2017 was conducted.

The tertiary paediatric rheumatology and ophthalmology referral units at Groote Schuur and Red Cross Children’s Hospitals in Cape Town are the main tertiary referral centres for the Western Cape as well as other provinces in South Africa. The Western Cape population numbers around 6.2 million and children <15years constitute 26% [47]. For the purposes of this study, self-reported ancestry is considered, as associations with potentially higher risk and poorer outcomes have been described [28, 29].

Children with non-infectious uveitis managed by the tertiary referral paediatric ophthalmology and rheumatology units were included. Children with JIA were included if uveitis was found on screening during the study period. Screening for JIAU was performed at diagnosis and at 3 monthly intervals as per the Standard Uveitis Nomenclature (SUN) working group recommendations [34, 48]. Children were identified from a review of paediatric rheumatology (PR) and ophthalmology case files and confirmed on the hospital electronic booking system. Data of patients identified with non-infectious uveitis included age, sex, self-reported ancestry, date of first presentation, anatomical location of uveitis, visual acuity, (VA) and complications. For uniformity, VA was converted from the recorded annotation to the log of the minimal angle of resolution (LogMAR) [49]. Data of children with JIA additionally included JIA subtype, time to uveitis diagnosis and arthritis disease activity on treatment.

JIA was defined as per International League of Associations for Rheumatology criteria [50]. Idiopathic uveitis was diagnosed after exclusion of infective and other immune mediated diseases by clinical assessment and laboratory tests. These included but were not limited to toxocara and toxoplasma serology, HIV Elisa or polymerase chain reaction (PCR), ANA, anti-double stranded DNA, anti-streptolysin O (ASO) and, anti-deoxyribonuclease B (Anti-DNAse B) titres, serum angiotensin converting enzyme, Treponema Pallidum Haemagglutination test and/or Venereal Disease Research Laboratory test and urine dipstix. Ebstein barr virus, cytomegalovirus and Lyme disease (not endemic in the Western Cape region of South Africa) serology, were not routinely requested but may have been performed in individual cases. Sarcoidosis was diagnosed based on clinical presentation, histology +/− raised serum angiotensin levels and Behcet’s disease by clinical diagnosis as per the paediatric BD criteria 2015 [51].

Treatment modalities were grouped as standard initial treatment which included corticosteroids (topical and/or systemic) and methotrexate 10–20 mg/m² (maximum dose 20 mg orally or 25 mg subcutaneously). Additional disease modifying anti-rheumatic drug therapy included azathioprine (1–3 mg/kg) and mycophenolate mofetil (250–500 mg/m² bd). Biologic therapy included TNFi Infliximab 6–10 mg/kg iv infusion monthly (after loading) and Adalimumab 20–40 mg subcutaneously every second week.

The primary outcome was considered as clinically inactive disease on treatment. Ophthalmology assessments were performed at weekly to 3-monthly intervals depending on severity of disease. Uveitis activity at 12 months and at the last clinical visit was evaluated. Anterior chamber disease, vitreous haze and posterior disease were assessed utilising the SUN criteria [34]: The response to treatment was defined as a two-step decrease in inflammation or decrease to Grade 0, active disease as ≥ Grade 1 (6–15 cells/slit lamp field and faint anterior chamber flare), inactive disease as Grade 0 (< 1 cell/slit lamp field and no anterior chamber flare) and worsening of disease activity as a two-step increase in level of inflammation or an increase from 3+ to 4+ for anterior chamber disease. Vitreous haze was further evaluated by the Nussenblatt 1985 criteria [52] and posterior disease activity by resolution or non-resolution of retinal vasculitis and/or disc swelling.

For this study, remission was defined as ≥3 months of inactive disease on treatment.

The secondary outcome was considered as improvement in visual acuity.

Children managed for < 3 months or were lost to follow-up, as well as children with proven infectious uveitis were excluded from the study.

Statistical analysis was performed using STATA13 software.

Children with JIAU were most commonly female (female to male ratio of 1:0.75), had a median age of 55 months (IQR 34–86 months), and were predominantly of mixed ancestry (71.4%). All children had chronic anterior uveitis (100%).

Further analysis in relation to the overall JIA cohort managed during the study period was undertaken (Table 3). A total of 229 patients were assessed for JIA of which 12 were excluded according to ILAR criteria. The remaining 217 were evaluated, with a consequent JIAU clinic prevalence of 6.5%. Three children had uveitis for 12, 9 and 4 months prior to the diagnosis of JIA. The majority developed uveitis within a year of diagnosis (Fig. 3). Comparisons for sex (p = 0.68) and ancestry (p = 0.58) were not statistically significant. Children older than 144 months were not diagnosed (p = 0.01) with uveitis. Young age ≤ 84 months (p = 0.01), oligo-JIA subtype (p = 0.01) and positive ANA (p < 0.001) were significant factors. Univariate analysis showed odds ratios (OR) for possible risk factors associated with uveitis as oligo-articular subtype (OR 4.45 CI 1.35–14.7) and positive ANA (OR 33.3, CI 6.83–162.09). Seven (50%) children had complications. Reduced VA at presentation was due to cataracts in 5 children. There was no statistical difference in complications between those diagnosed with uveitis before arthritis and those with uveitis on screening at diagnosis and subsequently (p = 0.28). At time-point 12 months from diagnosis, 9 (64.3%) children on standard initial treatment and one on TNFi had inactive disease. By the end of the study period, 8 (57.1%) were in remission on standard initial treatment, 2 (14.3%) on additional DMARDs and the previously refractory 4 (28.6%) on TNFi treatment. Of children treated with TNFi, 3 were originally commenced on infliximab and 2 were switched to adalimumab due to lack of efficacy. Of these, one was diagnosed with uveitis 12 months before arthritis. The one child on infliximab and all children in the adalimumab group achieved remission. Three children had cataract surgery.

Sarcoidosis (6.9%) was diagnosed in 2 females. Both had bilateral uveitis and no complications at presentation. They had inactive disease by 12 months, achieved remission on standard initial therapy and had preserved vision.

The 120 month old male of mixed ancestry with BD, presented with unilateral chronic anterior uveitis, had no complications and responded to standard therapy within 3 months.

Comparison with two studies from developed countries (Table 4), the large multicentre Canadian Research in Arthritis in Canadian Children emphasizing Outcomes (ReaCCH-out) study cohort and a single centre Atlanta study [27, 61], showed similarities in median age of JIA presentation, relative frequencies of poly-articular RF negative JIA subtype and ANA positivity. However, an older age at JIAU presentation and a lower frequency of oligo-articular JIA is seen in our cohort. The prevalence of JIAU here (6.5%) is also lower than reported in those studies (8.5% and 18%), as well as other developed country descriptions of up to 20% [62]. Paediatric rheumatology is a relatively new sub-speciality in South Africa, with a formal training program only established within the last 10 years. Under-recognition and lack of referral may play a role in the low frequency of JIA cases reported here. This seems to be in keeping with the few published studies from SSA [14, 20, 21, 63].

The chronic anterior uveitis, presenting at a younger mean age, significantly in the ≤ 84-month age group (p = 0.001), also fits more developed country descriptions [62]. The majority of children with JIAU were ANA positive (78.6%). However, this is in contrast to previous studies from South Africa, where children with uveitis had polyarthritis and were ANA negative [14, 19]. Whether ancestry has an influence on these differences is uncertain. Further prospective studies to elucidate the role of sex, ancestry, JIA subtype and positive ANA, is needed.

A high percentage (21.4%), compared to the 3–7% generally described [48], developed uveitis before arthritis was diagnosed. Eleven were detected on screening and half presented with complications, 71.4% of which were cataracts. This raises further concerns of diagnostic delays in our setting. Notably, treatment was escalated to manage uveitis as arthritis was in remission.

In our study, idiopathic uveitis (36.3%) had a relatively lower frequency, reflecting the small number of referred patients likely for reasons as previously discussed. As in other descriptions, refractory disease with chronic anterior and panuveitis, complications and the need for surgery is noted. Similar severity and poorer outcome were reported in black South African children in historical studies [64‐66], prior to the availability of TNFi. Here, children with refractory disease showed significant improvement in disease activity and VA on TNFi treatment.

Sarcoidosis is rare in children and may affect the uveal tract. Both children in our study responded well to systemic corticosteroid treatment and methotrexate. Escalation to TNFi was not needed here, as has been reported in other studies [67‐71].

Paediatric BD is rarely reported from SSA although adult case series highlight severe skin and ocular manifestations [72, 73]. In contrast to paediatric case series from North Africa [24, 73], our patient had few recurrences, no complications and near normal vision at the last clinical assessment. HLAB51 was not done here.

Other immune mediated diseases including Vogt Koyanagi Harada syndrome, tubulointerstitial nephritis associated uveitis, uveitis with SLE and other autoinflammatory disorders were not represented in this study.

Overall, remission on standard initial uveitis treatment (58.6%) endorses its use as first line therapy in our resource limited setting. Azathioprine and MMF were used less frequently due to gastrointestinal adverse effects and perceived lower efficacy. Neither cyclosporine nor intraocular corticosteroid injections were used in our cohort, as low evidence and side effect profile in young children were considered to outweigh the benefit [37, 46, 74, 75]. TNFi were only used in refractory cases due to availability and cost and showed good efficacy. Infliximab has been shown to be safe and efficacious in children with refractory disease [76, 77]. Here, infliximab was successfully used in 2 patients, while one switched to adalimumab due to lack of efficacy and another due to an adverse reaction to the infliximab infusion. Adalimumab was used in conjunction with methotrexate in all our patients with good effect. The small sample size limits inferences that can be made from this study but previous studies [26, 39, 40, 78] have shown good outcomes. The use of DMARDs and biologic therapy, allowed successful discontinuation of topical corticosteroid therapy in the majority of children. Further research into the efficacy of these agents in our setting is needed.

Five children with visually significant uveitic cataracts underwent lensectomies, together with pars plana vitrectomies (PPV), as is standard practice at our institution. This was due to the presence of associated vitritis or cyclitic membranes, which could only be removed by PPV.

Not all children with immune-mediated uveitis may have been referred, thus community prevalence is not reflected. Children with JIA are routinely assessed for uveitis screening and may be over-represented in this sample.

This retrospective case file review was dependent on the availability and accuracy of the medical records reviewed.

The small sample size limits inferences that can be made from these results.