Prospective study of uveitis in children with juvenile idiopathic arthritis over a 3-year period

Abstract Juvenile idiopathic arthritis (JIA) is the most common systemic autoimmune disease in childhood, which can cause non-infectious uveitis. Ocular inflammation is the most severe, sight-threatening extra-articular complication. In this prospective three-year study 81 children with identified autoimmune diseases were observed of whom 56 were with JIA. Uveitis was observed in 21 of the children with JIA. All children were followed up for three years between December 2019 and November 2022 in the Department of Ophthalmology, University Hospital ‘Alexandrovska’ and the Department of Paediatric Rheumatology, University Children Hospital, Sofia, Bulgaria. Uveitis developed in 21 (37.5%) of 51 children diagnosed with JIA. Systemic immunosuppressive medications were more common among children with uveitis (31[38.27%]), compared to children without uveitis (27 [23.1%]). Ocular complications occurred in 15[26.78%] of the children with JIA. The early onset of uveitis after the diagnosis of JIA was a risk factor for developing ocular complications. Detected antinuclear antibodies (ANA) was also a risk factor for developing uveitis in children with JIA. The median age at the time of diagnosis of uveitis was 3.76 years. Our results support the recommendation that the screening for uveitis should start immediately when arthritis is suspected or confirmed and that all children with JIA should be monitored by an ophthalmologist every three to six months. Systemic immunosuppressive treatment in combination with biological therapy is considered early in the course of the disease in children with a high risk of developing ocular complications.


Introduction
Non-infectious uveitis is a common cause of vision impairment and blindness in childhood.It is associated with systemic autoimmune disease.
Juvenile idiopathic arthritis (JIA) is the most prevalent cause of non-infectious uveitis in childhood.The disease develops before the age of 16.Its pathogenesis is not completely clear.Chronic bilateral nongranulomatous anterior uveitis is the most frequently observed extra-articular manifestation.The occurrence varies between different reports of paedriatric or ophthalmology departments (15%-42%) [1].Regular evaluation by ophthalmologist, every three to six months, is crucial to prevent ocular complications such as band keratopathy, cataract, secondary glaucoma, macular edema and blindness.Systemic immunosuppression is recommended, rather than long-term steroid therapy (more than 3 months).In children with chronic non-infectious uveitis, the recommended first-line systemic immunomodulatory medication is methotrexate.
The recommended dose is 0.3-0.6 mg/kg once a week.Complete efficiency is achieved after the first three months [2].The early introduction of biological therapy helps mitigate the risk of visual loss.The efficiency of anti-TNF-α antibody adalimumab is demonstrated in several studies [3,4].Usually adalimumab (40 mg every two weeks) is combined with methotrexate.This combination minimizes the risk of neutralizing antibiomedication antibodies [5].
The onset of uveitis in children with JIA occurs during the first 4 years of the disease, according to a few long-term prospective studies [6].Most of the patients are girls 84%.The most common form of JIA is seronegative oligoarthritis 43 (76.78%)(negative rheumatoid factor RF (-)).Other major risk factors are the presence of antinuclear antibodies (ANAs).The level of ANA is correlated with the risk of developing uveitis and its severity [7].Complications are most common when the onset of uveitis is before arthritis, there is a short interval between the onset of JIA and uveitis, male sex and early age.
Our prospective study describes the clinical outcomes, frequency of uveitis, improved visual acuity in children with autoimmune diseases with a risk of noninfectious uveitis, and the use of biological or nonbiological therapy by those children.

Ethics statement
every parent or legal guardian gave their written informed consent.The ethical Review Board approval (reference number 13/13.06.2022) was obtained from the Research ethics Committee of the Medical University of Sofia (Bulgaria).The present study adhered to the principles of the Declaration of Helsinki.

Subjects and study design
Our prospective study includes 81 children who were followed for three years in the Department of Ophthalmology, University Hospital 'Alexandrovska' and the Department of Paediatric Rheumatology, University Children's Hospital.Autoimmune diseases were confirmed in a specific paediatric department (most often in the Rheumatology Department).Data were collected for demographic characteristics, autoimmune diseases, uveitis, family history, previous diseases, previous viral infections.Venous blood samples were collected during this 3-year period.Blood tests included immunological tests, such as ANA, rheumatoid factor (RF). Three-year ophthalmologic examination consisted of measurement of best-corrected visual acuities with a Snellen chart or a picture chart, slit-lamp examination, optical coherence tomography (Topcon 3D-OCT 2000 FA plus ver.8.42), computer perimetry (Zeiss HFA3 830 Visual Field Analyser ver.1.5.3.714),fluorescein angiography (when possible-Canon Fundus Camera) and B-echography (Compact Touch -quantel Medical V.3.02)where necessary.Data for ocular complications such as glaucoma, secondary cataract and 'band' keratopathy were collected-(Figure 1).glaucoma was defined due to OCT examination, retinal nerve fiber layer tinning (RNFl) and ganglion cell complex (gCC), ocular pressure greater than 21 mmHg, visual field defects, history of glaucoma surgery.History of other ocular surgery was also collected, such as cataract surgery, pars plana vitrectomy (PPV).exclusion factors were: age >18 years and infectious uveitis.

Data analysis
Data are presented as mean and percentage values.
Microsoft excel 2016 was used for data processing and analysis.Statistical analysis was performed using T-test in Microsoft excel 2016.

Results
Our prospective study includes 81 children with autoimmune diseases that are associated with non-infectious ocular inflammation.All patients were fully examined by the ophthalmologist.Forty of them have uveitis (49.38%).The most common autoimmune systemic condition was JIA-56 (69.13%).Uveitis was diagnosed in 21(37.5%) of the children with JIA; 84% of the children with JIA-U were girls.The average age at the time of diagnosis of uveitis was 3.76 years (it varies from 3 to 11 years).The average age of diagnosis of JIA was 4.26 years.In 57.89% of the children, uveitis affected both eyes.In 2 (10.5%) of the children with JIA, uveitis was diagnosed before the onset of arthritis.Uveitis was most common in children with positive ANA (70%), female gender (84%).and age less than 4 years (Figure 2).ANA was a significant predictor factor of developing uveitis, as in other european studies [8].ANA positive values were higher in children with JIA-U than in those  without non-infectious uveitis (p < 0.006).The rheumatoid factor (RF) was positive only in one child in our study with juvenile polyarthritis.

Characteristics of non-infectious uveitis in children with JIA
Iridocyclitis was observed in 17 (80.95%) of the children with uveitis.One patient (4.76%) had parsplanitis, 3 (14.88%) of the children had panuveitis.Of the patients with non-infectious uveitis 68.42% have ocular complications: cataract in 8 (38.09%), secondary glaucoma in 3 (14.28%)[9,10], 'band' keratopathy in 10 (47.61%).Improving BCVA (best corrected visual acuity) was observed in 5 of the patients.All of them were threatened with biological agents.Biologic disease-modifying antirheumatic drugs were also administered to 12 (57.14%) of the patients without uveitis.We observed an improvement in BCVA in 9 (23.68%)out of 38 eyes with ocular inflammation, associated with arthritis.In our study one child was blind with the more severely affected eye, and none of the children was blind with both eyes.There was one case of vision impairment (because of severe panuveitis) and four children improved BCVA (Figure 3).The most frequently reported viral infection associated with worsening of the course of JIA was varicella zoster as in other european countries [11].long-term poor visual outcomes were associated with a short interval between the onset of JIA and uveitis (p < 0.01), high positive ANA (p < 0.006), female gender (p = 0.013), age less than 4 years (p < 0.01, according to T-test).Macular edema as an ocular complication was observed in 4 (7.14%) of the children (Figure 4) [12].
In the group of children with uveitis, (2 [9%]) were treated with topical steroids, 3 (14.28%)with systemic corticosteroids -(methylprednisolone), 3 (14.28%)with methotrexate (MTX) and systemic corticosteroids-3 (14.28%), with MTX and biological therapy and 4 (19.04%) with a biological agent.Methotrexate is an antimetabolite that inhibits DNA replication and RNA transcription in B and T lymphocytes (for review see [13]).The monoclonal antibody adalimumab is given every other week subcutaneously − 40 mg [14].TNFα drives Th1 cells to response.It is synthesized by monocytes, neutrophils, mast cells and macrophages [15].The efficiency in JIA and JIA -associated uveitis was proven in several studies: SyCAMORe and  APTITUDe [13,16].Tocilizumab is antibody against Il-6.It reduces macular edema in patients with uveitis [17].etanercept interferes with TNF and acts as TNF inhibitor.Three of the children underwent an ocular operation: two needed phacoemulsification and one operation with Ahmed glaucoma valve.

Discussion
early treatment with a combination of methotrexate and anti-TNF agent decreases the risk of uveitis and ocular complications in children with non-infectious uveitis.The most common biological medicament was the monoclonal antibody adalimumab, which is an anti-TNFα monoclonal antibody.The effect of etanercept on ocular inflammation has not been well defined like that of adalimumab and tocilizumab [18].Anti-TNF-α antibodies are the most effective treatment in children with JIA associated with uveitis [19].In our prospective study, the median time to onset of uveitis was 2 years after JIA was diagnosed.All patients were diagnosed during the first 7 years after the onset of arthritis.We suggest that every child with JIA and ANA positive results should be examined by an ophthalmologist every three months during the first 7 years of the disease.It would be beneficial to avoid viral infections such as VSV, eBV and CMV.In this 3-year period, 15 (26.79%) of the examined children developed ocular complications.This rate is similar to other countries in europe [20][21][22].
Ocular complications are more often seen in cases of a short interval between the onset of JIA and uveitis.In 4 (7.14%) of the patients with JIA BCVA improved in this 3-year period.early diagnosis and adequate treatment (early biological therapy or surgical treatment, when it is needed) lower the risk of sight-threatening ocular complications, for example cataract, secondary glaucoma, 'band' keratopathy, and macular edema.Screening children with JIA every 3 to 6 months is crucial to prevent blindness and low vision in the younger population [23].It is also important to minimize the risk of viral infections during the first seven years of systemic disease by vaccination (when possible) [24].

Conclusions
Based on our observations, we ecommend that the screening for uveitis should start immediately after arthritis is suspected or confirmed.All children with JIA should be monitored by an ophthalmologist every three to six months.Systemic immunosuppressive treatment in combination with biological therapy is considered early in the course of the disease in children with a high risk of developing ocular complications.The positive results in the treatment of children with JIA-U are due to good collaboration between the pediatric rheumatologist and the ophthalmologist.Non-infectious uveitis in children with JIA must be detected early, which is possible by slit lamp examination every three months.

Figure 1 .
Figure 1.Rate of ocular complication in children with Jia-u in percentages.

Figure 2 .
Figure 2. age of onset of Jia and uveitis in children with Jia-u.

Figure 3 .
Figure 3. BcVa outcome in our group of children with Jia-u after systemic therapy.

Figure 4 .
Figure 4. uveitic macular edema in a child with Jia. the green line shows the section of the fundus that corresponds to the image in the right part of the figure.the image was taken using topcon 3D-oct 2000 Fa plus ver.8.42.