Degree project, 30 ECTS January 13 2021
Prevalence, Risk Factors, Characteristics and
Complications of Uveitis in a Swedish Cohort of
Children with Juvenile Idiopathic Arthritis
Version 2Author: Eva Jatkola, MB School of Medical Sciences Örebro University Örebro Sweden Supervisor: Pia Lundgren, MD, PhD Department of Ophthalmology Örebro University Hospital Örebro Sweden Word count
Abstract
Introduction
Children with juvenile idiopathic arthritis (JIA) are at risk of developing sight threatening JIA associated uveitis (JIA-U). Swedish children with JIA are included in an ophthalmological screening program, based on European studies, to ensure early detection and treatment of JIA-U.
Aim
The aim of this study was to describe the prevalence, risk factors, clinical characteristics and associated ocular complications of JIA-U and pharmacological therapy in a cohort of Swedish children with JIA.
Methods
The study was conducted as a retrospective review of medical records of children with JIA treated at Örebro University Hospital, Sweden in 2010-2019, with a minimum of one year of ophthalmological follow-up.
Results
Medical records of 200 children with JIA were reviewed, of which 96 children were included in the study. Uveitis was detected in 21/92 (22.8%) children. Boys developed uveitis proportionally more often than girls. JIA-U onset within the first four years after JIA diagnosis occurred in 52.4% and onset occurred later in boys than in girls (p = 0.019). Oligoarthritis was the only significant risk factor for uveitis development (OR 3.111, 95% CI 1.029-9.409, p = 0.044). Uveitis associated complications occurred in 7/21 (33.3%) children.
Conclusion
In this regional cohort study, we found a higher prevalence of JIA-U, a higher proportion of boys developing uveitis and a lower portion of children developing uveitis within the four years of high frequency screening compared to recent Swedish respectively European studies. Our findings indicated the need of future Swedish studies to revise and optimize the current Swedish guidelines for ophthalmological JIA-U screening.
Abbreviations
ANA – antinuclear antibodies
anti-TNFα – anti-tumor necrosis factor alpha CI – confidence interval
DMARDs – disease-modifying antirheumatic drugs HLA-B27 – human leukocyte antigen B27
ILAR – International League of Associations for Rheumatology IOP – intraocular pressure
JIA – Juvenile idiopathic arthritis
JIA-U – Juvenile idiopathic arthritis associated uveitis MTX – Methotrexate
NSAIDs – non-steroid anti-inflammatory drugs OR – odds ratio
p-value – probability value RF – rheumatoid factor
RF(-) – rheumatoid factor negative RF(+) – rheumatoid factor positive
SUN – Standardization of Uveitis Nomenclature VA – visual acuity
1. Introduction
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disorder in children. It is a heterogeneous group of diseases and includes all inflammatory articular disorders with onset before the age of 16 years and a persistence of more than 6 weeks [1]. According to the Swedish Children Rheumatology Register, there are 1200-1700 children with JIA in Sweden [2].
JIA is divided into 7 subgroups. Classification criteria by the International League of Associations for Rheumatology (ILAR), divide JIA into systemic arthritis, oligoarthritis (£4 affected joints), rheumatoid factor (RF) negative (RF(-)) polyarthritis (³4 affected joints), RF positive (RF(+)) polyarthritis, psoriatic arthritis, enthesitis related arthritis and undefined arthritis [3]. The serologic markers RF, human leukocyte antigen B27 (HLA-B27) and antinuclear antibodies (ANA), predict the severity of JIA and the complication risk [4].
The most frequent extra-articular manifestation of JIA is uveitis; a sight threatening inflammation of the uvea, comprising the iris, choroid and ciliary body of the eye [5]. The reported prevalence of JIA-associated uveitis (JIA-U) differs considerably between 10.7-30.8% in different recent studies [6–11].
In order to early identify and treat the commonly asymptomatic JIA-U, all children with JIA are included in an ophthalmological screening programme. There is a shortage of epidemiologic data on JIA-U in Sweden and the current Swedish guidelines for screening are based on European guidelines by The British Society of Paediatric and Adolescent Rheumatology and The Royal College of Ophthalmology, rather than on studies on Swedish JIA children [9,12]. The screening frequency is based on presence of risk factors such as; JIA subgroup, ANA positivity and young age at JIA diagnosis (Table 1) [12].
Table 1. Swedish national guidelines for ophthalmological
screening of children with Juvenile idiopathic arthritis (JIA). • ANA positive and < 7
years at JIA diagnosis
Every third month for four years and then every sixth month until the age of 14. • ANA negative
• ANA positive and ³ 7
years at JIA diagnosis
Every third month for two years and then every sixth month to the age of 14. • Systemic JIA Once a year for four years. Abbreviations: ANA; Antinuclear antibody. JIA; Juvenile idiopathic arthritis.
Uveitis is, according to the Standardization of Uveitis Nomenclature (SUN), divided into anterior (involving the anterior chamber), intermediate, posterior and pan uveitis depending on the primary site of inflammation. The course of uveitis can be acute, chronic of recurrent [13,14]. Asymptomatic chronic anterior uveitis, characterized by insidious onset and binocular engagement, is the most common presentation of JIA-U. JIA-U may also present as symptomatic acute anterior uveitis characterized by sudden onset of monocular uveitis with a limited duration [1,4,15,16]. The most frequently seen clinical signs of uveitis are flare, cells and/or precipitates in the anterior chamber. Uveitis commonly follows soon after arthritis onset but can also occur simultaneously with or before the arthritis [17]. If not detected and treated in time, JIA-U can lead to devastating ocular complications and severe visual impairment. The most frequent complications include cataract and ocular hypertension/glaucoma in addition to band keratopathy, posterior synechiae, epiretinal membrane, macular oedema and optic disc oedema [9,10,18,19].
JIA subgroup, ANA positivity, age at onset of JIA, HLA-B27 positivity and gender are identified risk factors for developing JIA-U [8,18,20,21]. Chronic anterior uveitis is more common in ANA positive girls with oligoarticular or RF(-) polyarticular JIA and young age at onset of arthritis. Whereas acute anterior uveitis is more common in HLA-B27 positive boys with enthesitis related arthritis [5,15,16,20]. Short duration between JIA diagnosis and onset of uveitis, onset of uveitis before arthritis, male gender and presence of complications at first examination are reported risk factors for developing severe JIA-U and ocular complications
In the last decade, there has been significant advances in the field of JIA- and JIA-U therapy. Instead of prolonged treatment with traditional non-steroid anti-inflammatory drugs (NSAIDs) and corticosteroids, earlier introduction of steroid-sparing systemic immunosuppression; disease-modifying antirheumatic drugs (DMARDs) and biologic drugs, is recommended [23]. The DMARD Methothrexate (MTX) is now the first-line treatment in most JIA children [24]. Among biologics, anti-tumor necrosis alpha (anti-TNFα) agents, such as Adalimumab and Etanercept have shown great efficacy in controlling JIA [25,26].
In JIA-U therapy topical steroids (Dexamethasone) is still regarded as first-line treatment; a treatment that has to be carefully monitored due to the risk of ocular side effects like cataract, ocular hypertension and secondary glaucoma [27,28]. Systemic second-line treatment with DMARDs or biologic drugs should be used immediately for JIA-U in high risk patients [29]. MTX is recommended as the first second-line treatment for JIA-U, followed by Adalimumab that recently was approved as the first biologic drug in JIA-U therapy [30]. In contrast, Etanercept has been proven not to be effective in preventing and controlling JIA-U and is no longer recommended in JIA-U therapy [31].
1.1 Aim
This study aims to describe the prevalence of JIA-U and associated ocular complications in JIA children included in the ophthalmological JIA-U screening programme in Region Örebro County, Sweden 2010-2019. Risk factors, ocular complications, clinical characteristics and pharmacological therapy will be described.
2. Material and Methods
2.1 Patient identificationThis study was a retrospective review of medical records of 200 children with JIA, diagnosed according to ILAR criteria, treated at Örebro University Hospital, Sweden 2010-2019. Patient inclusion is described in Figure 1. Ophthalmological screening was performed in line with national guidelines [32].
Figure 1. Patient inclusion in the study.
Abbreviations: ICD-10-SE; Swedish edition of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems. JIA; Juvenile idiopathic arthritis.
2.2 Data collection
Clinical data was registered in a protocol developed for an upcoming nationwide population-based study. Data of interest included sex, date for onset of JIA (defined as the date when the ICD-10-SE diagnostic code for JIA first was used), JIA subgroup (defined according to ILAR-criteria by the treating paediatrician), diagnostic markers; ANA, RF and HLA-B27, systemic JIA therapy over the whole study period and data on visual acuity (VA) at first and last ophthalmological examination. ANA was considered positive if ³200 and RF if >5,0 IU/mL.
For children with uveitis, date at onset, characteristics of uveitis such as subgroup and if unilateral or bilateral, symptoms and clinical signs at onset and uveitis therapy was registered. Data on uveitis associated unilateral/bilateral ocular complications including synechiae, cataract, band keratopathy, vitritis, macular oedema, optic disc oedema, ocular hypertension requiring treatment, secondary glaucoma, surgical intervention and visual impairment was obtained. Ocular hypertension was defined as intraocular pressure (IOP) >21 mmHg and secondary glaucoma was assessed by the treating ophthalmologist. Visual impairment was defined as VA <6/18 (Snellen scale) as defined by the World Health Organisation [33].
For 6 patients that lacked data on exact dates for onset of JIA or uveitis, 1st of June of the year concerned was chosen when the year was known (four children) and the 15th day of the month when the year and the month was known (two children).
JIA children treated at the Paediatric
clinic at Örebro University Hospital
2010-2019, n = 200 •identified with
ICD-10-SE diagnostic codes; M080, M081, M082, M083, M084, M088, M089, M090 and M091. Baseline: ≥ 1 year of ophthalmological screening & age <
14 at study start, n = 96 Complete follow-up regarding uveitis development, n = 92
2.3 Statistical analysis
Statistical analyses were performed using the SPSS version 27.0 software (IBM Corp. Released 2020. Armonk, NY, USA). Descriptive statistics (frequencies, percentages, medians, ranges) were used to summarize the data. Comparison between groups was performed with Chi-2 Test or Fischer’s Exact test and Mann-Whitney U-Test as appropriate for categorical respectively continuous variables. Risk factors were assessed with binary logistic regression analysis, presented with Odds ratios (ORs) and 95% confidence intervals (95% CIs), probability value (p-value) <0.05. The fit of the models was checked with the Hosmer-Lemeshow goodness-of-fit Test.
2.4 Ethical consideration
The study was ethically approved by The Swedish Ethical Review Authority, D.nr 2020-02584, and conducted according to the declaration of Helsinki. All data was pseudonymised after initial data collection. No informed written consent was obtained.
3. Results
3.1 Characteristics of the total cohort
Of the 200 JIA children reviewed, 96 were eligible and included in the cohort. Of these children 59/96 (61.5%) were girls. Oligoarthritis was the most prevalent JIA subgroup, present in 54/96 (56.3%) children and more prevalent in boys 22/37 (59.5%) than girls 32/59 (54.2%). Median age at JIA diagnosis was 6.3 years (range 1.1-16.6) (Table 2). Four children included at baseline were lost to follow-up due to move to another county.
3.2 Uveitis in the cohort
Uveitis was detected in 21/92 (22.8%) children and the majority were girls 12/21 (57.1%). However, boys 9/37 (24.3%) developed uveitis proportionally more frequently than girls 12/59 (20.3%). Oligoarthritis was the most prevalent JIA subgroup in the JIA-U group 16/21 (76.2%) (Table 2). Median age at uveitis onset was 8.0 years (range 2.0-17.1), significantly later in boys than girls, at a median of 10.8 (5.0-17.1) versus 6.9 (2.0-11.9) years (p = 0.019) (Figure 2 and Table 3). Two out of 21 (9.5%) children had onset of uveitis 9.5 months respectively 8.9 years before JIA diagnosis. Median time between JIA diagnosis and uveitis onset in the remaining 19/21 (90.5%) children was 3.1 (range 0-9.3) years. Eleven out of 21 (52.4%) children had
onset within the first four years after JIA diagnosis and 3/21 (14.3%) had onset after the age of 14.
Table 2. Baseline characteristics in the total cohort, Juvenile Idiopathic arthritis (JIA) children
without uveitis and children with JIA associated uveitis.
Total cohort, n = 96 JIA children without uveitis, n = 71 JIA children with uveitis, n = 21 p-value Male gender, n (%) 37 (28.5) 27 (38.0) 9 (42.9) 0.690
Age at JIA diagnosis, median
(range) 6.3 (1.1-16.6) 6.3 (1.1-16.6) 6.0 (1.2-12.1) 0.599 JIA subgroup, n (%) Systemic 7 (7.3) 6 (8.5) 0 0.330 Oligoarthritis 54 (56.3) 36 (50.7) 16 (76.2) 0.038 RF(-) Polyarthritis 14 (14.6) 13 (18.3) 0 0.035 RF(+) Polyarthritis 1 (1.0) 0 1 (4.8) 0.228 Psoriatic 3 (3.1) 2 (2.8) 1 (4.8) 0.545 Enthesitis related 6 (6.3) 5 (7.0) 1 (4.8) 1.000 Undefined 11 (11.5) 9 (12.7) 2 (9.5) 1.000 ANA positivity, n (%) a 54/92 (58.7) 39/68 (57.4) 13/20 (65.0) 0.541 HLA-B27 positivity, n (%) b 7/10 (70.0) 4/5 (80.0) 2/4 (50.0)
a Data missing in 4/96 children.
b Data missing in 86/96 children. No statistical evaluation performed.
Abbreviations: ANA; Antinuclear antibodies. HLA-B27; Human leukocyte antigen B27. JIA; Juvenile idiopathic arthritis. RF(-); Rheumatoid factor negative. RF(+); Rheumatoid factor positive.
Table 3. Clinical characteristics of juvenile idiopathic arthritis associated uveitis (JIA-U) at onset in all
children with JIA-U and in boys and girls with JIA-U.
Children with JIA-U, n = 21 Boys with JIA-U, n = 9 Girls with JIA-U, n = 12 p-value
Age at uveitis onset, median (range) 8.0 (2.0-17.1) 10.8 (5.0-17.1) 6.9 (2.0-11.9) 0.019 Symptomatic onset, n (%) a 9/19 (47.4) 6/8 (75.0) 3/11 (27.3) 0.070
Asymptomatic onset, n (%) a 10/19 (52.6%) 2/8 (25.0) 8/11 (72.7) 0.070
Unilateral uveitis, n (%) a 9/19 (47.4) 6/8 (75.0) 3/11 (27.3) 0.070
Bilateral uveitis, n (%) a 10/19 (52.6) 2/8 (25.0) 8/11 (72.7) 0.070
Chronic course during study period,
n (%)
13/21 (63.2) 4/9 (44.4) 9/12 (75.0) 0.203
a Data on symptomatic/asymptomatic and unilateral/bilateral uveitis missing in 2/21 children; one boy and one girl.
Abbreviations: JIA; Juvenile Idiopathic Arthritis. JIA-U; Juvenile idiopathic arthritis associated uveitis.
3.3 Clinical characteristics of Uveitis
Clinical characteristics of uveitis at onset is presented in Table 3. Data was missing in 2/21 (9.5%) children. Initial symptoms, such as red eyes, photophobia, pain, blurred vision,
Figure 2. Age distribution at onset of uveitis in relation to
gender in the 21 children that developed uveitis during the study period.
lacrimation and miosis, occurred in 9/19 (47.4%) children. Symptoms were more frequently present in boys 6/8 (75.0%) compared to girls 3/11 (27.3%). Symptomatic children were found to have a significantly later onset of uveitis than asymptomatic children, at median 9.8 (range 2.0-17.1) versus 5.9 (range 2.6-11.9) years (p = 0.050). All three children with onset of uveitis after the age of 14 were symptomatic.
3.4 Risk factors for Uveitis
Only oligoarthritis was significantly more prevalent in children that developed JIA-U (p = 0.038) (Table 2). When comparing risk factors for girls and boys separately, oligoarthritis was significantly more prevalent only in girls developing uveitis (p = 0.020). Simple logistic regression analysis identified oligoarthritis as a potential predictor for developing uveitis (OR 3.111, 95% CI 1.029-9.409, p = 0.044).
3.5 Uveitis associated complications
Uveitis associated complications occurred in 7/21 (33.3%) children, noted at first examination after uveitis onset in 3/21 (14.3%) (Figure 3). The most prevalent complication was treatment requiring ocular hypertension detected in 6/21 (28.6%) children, all treated with topical steroids for uveitis at onset (Figure 3). Two children with ocular hypertension developed secondary glaucoma, of which one needed glaucoma surgery. Unilateral visual impairment was noted in both (2/21, 9.5%) children with secondary glaucoma.
The children with JIA-U and at least one complication were more often male and ANA-positive and had a shorter time between JIA diagnosis and uveitis onset than JIA-U children without complications. The differences were not significant. Data not presented.
eyes
3.6 Therapy
The majority of children received various systemic JIA therapies during the study period (Table 4). MTX was the most frequently used systemic second line treatment in all groups. Treatment with other DMARDs such as Sulfasalazine, Chloroquine Phosphate and Hydroxychloroquine occurred in 8/92 (8.7%) patients. Biological drugs were initiated in 47/92 (51.1%) children of which all eventually received an anti-TNFα agent (Table 4). The anti-TNFα agents Adalimumab and Etanercept where the most frequently used biological drugs. Adalimumab was significantly more common in the JIA-U group (p = 0.010).
At uveitis onset 10/19 (52.6%) children had no second line treatment, 4/19 (21.1%) children had MTX with or without additional NSAID, 2/19 (10.5%) children had biological therapy only and 3/19 (15.8%) children had biological therapy in combination with MTX. All five children with biological treatment at onset of uveitis were treated with Etanercept. Second line treatment was initiated due to uveitis in 6/21 (28.6%) children during the study period. MTX and Infliximab in one child and Adalimumab in five children.
0 2 4 6 8 10 Visual impairment Secondary glaucoma Macular oedema Cataract Vitritis Band keratopathy Posterior synechiae Ocular hypertension At least one ocular complication
Eyes with JIA-U, n = 30 Children with JIA-U, n = 21
Figure 3. Uveitis associated ocular complications in number of eyes
with juvenile idiopathic arthritis associated uveitis (JIA-U) and number of children with JIA-U.
4. Discussion and conclusions
The current Swedish ophthalmological screening guidelines, to early identify uveitis and prevent sight threatening complications in children with JIA, are based on European studies. Swedish studies, describing the prevalence and characteristics of JIA-U and associated ocular complications, are warranted for optimal care of Swedish children with JIA. This study constitutes the first regional cohort, Region Örebro County, in a Swedish nationwide population-based study on JIA-U.
The prevalence of uveitis in our total cohort of JIA children was 22.8%, of which the majority had oligoarthritis (76.2%). Boys developed uveitis proportionally more often than girls. Onset within the first four years after JIA diagnosis occurred in 52.4%. Uveitis associated
Table 4. Systemic treatment over the whole the study period in the total cohort, in JIA children without
uveitis and in children with JIA-uveitis. Systemic treatment Total cohort, n = 92 JIA children without uveitis, n = 71 JIA uveitis, n = 21 p-value Systemic steroids, n (%) 56 (60.9) 40 (56.3) 16 (76.2) 0.102
Systemic second line treatment, n (%) 74 (80.4) 54 (76.1) 20 (95.2) 0.063
DMARDs, n (%)
Methothrexate 73 (79.3) 53 (74.6) 20 (95.2) 0.062
Biological drugs, n (%)
Any anti-TNFα agent a 47 (51.1) 33 (46.5) 14 (66.7) 0.104
Adalimumab 31 (33.7) 19 (26.8) 12 (57.1) 0.010
Etanercept 28 (30.4) 22 (31.0) 6 (28.6) 0.833
IL-inhibitor b 5 (5.4) 5 (7.0) 0 0.585
Inhibitor of T-cell
costimulation c 1 (1.1) 1 (1.4) 0 1.000
a Adalimumab, Etanercept, Golimumab or Infliximab b Sekukinumab or Tocilizumab
c Abatacept
Abbreviations: anti-TNFα; Anti tumor necrosis factor alpha. DMARDs; Disease modifying anti rheumatic drugs. IL; Interleukine. JIA; Juvenile idiopathic arthritis.
complications occurred in 33.3% and visual impairment due to complications in two children (9.5%). Methothrexate was the most frequently used systemic second line treatment followed by Adalimumab.
The reported prevalence of JIA-U ranges between 10.7-30.8% with some of the highest prevalence’s in Nordic countries compared to southern Europe [6–11]. The JIA-U prevalence in the current study is in accordance with the cumulative incidence of 22.1% recently reported in a population-based Nordic study [22]. Compared to earlier Swedish studies, the JIA-U prevalence is considerably higher in our study. Papadopoulou et. Al. reported a JIA-U prevalence of 11% in western Sweden and Skarin et. Al. reported a prevalence of 15.7% in southern Sweden [6,34]. It cannot be ruled out that geographical variations might exist within Sweden. Furthermore, the study period in the study by Skarin et. Al. (1973-1982) was noticeably earlier than our study period [34]. The now more well-developed ophthalmological screening programme leading to detection of more asymptomatic cases of uveitis could partly explain the higher prevalence in our study compared to Skarin et. Al.
The current study is in accordance with earlier larger studies describing oligoarthritis as the most prevalent JIA subgroup in children with JIA-U [8,9,22]. Expectedly no child with systemic JIA in our cohort developed uveitis. Oppositely to earlier findings, suggesting RF(-) polyarthritis as the second most prevalent subgroup in JIA-U and RF(+) polyarthritis and systemic arthritis as the least prevalent ones, none of the 13 children with RF(-) polyarthritis developed uveitis whereas the only child with RF(+) polyarthritis did [8,9,22].
The median age at uveitis onset in the present study was 8.0 years, which is considerably higher than in various earlier studies [6,8,9,17,22]. The distribution of asymptomatic (52.6%) and symptomatic (47.4%) uveitis was equal compared to results in some earlier studies with a greater predominance of asymptomatic uveitis [8,9,22]. Our finding of boys having a significantly later uveitis onset and being symptomatic more frequently than girls, is in accordance with findings in some earlier studies [8,35]. Two earlier studies have reported uveitis onset at median 5.0 and 6.2 years but had a markedly lower prevalence’s of male gender in children with uveitis (21.9% respectively 20.4%) [6,8]. Consequently, the comparatively high prevalence of male gender (42.9%) in the JIA-U group in the present study most likely explains both the high median age at uveitis onset and the higher proportion of symptomatic uveitis. Why boys were more frequently affected by JIA-U in our cohort needs to be further
evaluated. All three children with onset of uveitis after their 14th birthday presented with symptoms. This result supports the current guidelines recommending screening until the age of 14, since screening is necessary in particular for detection of asymptomatic cases.
Reportedly uveitis precedes arthritis in 3-12.7% of children [8,36]. In the present cohort two (9.5%) children had onset of uveitis before arthritis, as early as 8.9 years before JIA diagnosis, in accordance with a case report by Parentin et. Al. [37]. The median time from JIA diagnosis to uveitis onset in the remaining children was 3.1 years and only 52.4% had uveitis onset within the first four years after JIA diagnosis, considered as a high-risk period for uveitis development. Earlier studies have reported uveitis onset in median 3.6 months to 1.6 years after JIA diagnosis and within four years after JIA onset in 80-90% [9,22,38]. The cause of difference compared to earlier studies is unknown. Our results may suggest an indication for continued high frequency ophthalmological screening even after four years from JIA diagnosis.
Oligoarthritic JIA, ANA-positivity and young age at arthritis onset are considered to be independent risk factors for JIA-U while results about gender as a risk factor have been inconsistent [9,18,39]. In the present study oligoarthritic JIA was the only risk factor identified as a potential predictor of uveitis, however when stratified for gender, only significant for girls. Oppositely to multiple earlier European studies describing female gender as a risk factor for uveitis, uveitis was in the present study proportionally more prevalent in males than in females, with 24.3% of the boys respectively 20.3% of the girls developing uveitis [6,8–10,34]. However, similarly to the present study, a few earlier Nordic studies have found that uveitis was proportionally as prevalent or more prevalent in boys than in girls [22,38,39]. The earlier reported higher cumulative incidence of JIA-U in girls is thought to be caused by the predominance of ANA positivity and oligoarthritic JIA with an early onset in girls [5,8]. In our total cohort ANA positivity and early onset was accordingly more common in girls (data not shown) while oligoarthritis contrariwise was more prevalent in boys (59.5%) than girls (54.2%). It is known from earlier studies that the interplay between the known risk factors for JIA-U is complex.
The prevalence of JIA-U associated ocular complications in the current study was 33.3% and complications were noted at the first ocular examination in 14.3%. Previous studies have reported complication rates between 21.0-56.0% and complications at first examination in up
higher since a few children with uveitis onset late in the study period had a relatively short follow-up regarding complications. The most frequently occurring complication in the present study was ocular hypertension (28.6%). The prevalence of 28.6% is in accordance with the 28.0% prevalence reported in a previous Swedish study [6]. Cataract and posterior synechiae have commonly been reported as the most frequently occurring complications in earlier studies, of which only one included ocular hypertension in analysis [6,9,10,22,41].
In the present study MTX was the most frequently used second-line treatment over the whole study period in both the total cohort (79.3%) and the JIA-U group (95.2%). Adalimumab was significantly more commonly used in the JIA-U group, which could be an indicator of a more severe JIA course requiring more potent therapy. Moreover, treatment with Adalimumab was initiated due to uveitis in five children. All children treated with a biological drug at time of uveitis onset received Etanercept. This result supports an earlier study proving that Etanercept is not effective in preventing JIA-U [31].
The small proportion of loss to follow-up (4.2%) is a strength of this study. Use of standardized ILAR classification criteria and SUN criteria in the present study increases the comparability to other studies. The risk for selection bias is small, since study participants were enrolled from the total population of JIA children treated at the Paediatric rheumatology department during 2010-2019. Weaknesses in this study include the retrospective nature, in some children a short follow-up time, small sample sizes of JIA subgroups and the small total cohort size leading to high variability and lowering the generalizability of our results to the total population of JIA children.
In conclusion, we found a higher prevalence of JIA-U and a higher proportion of boys developing uveitis compared to some recent Swedish respectively European studies. Our findings may suggest a variance in JIA-U prevalence between genders and between geographical areas within Sweden. Furthermore, we found a comparatively low proportion of children developing uveitis within the first four years after JIA diagnosis, which is the recommended high frequency screening time, according to current Swedish guidelines based on European studies. Our findings indicate a need of future Swedish studies to revise and optimize the current Swedish guidelines for ophthalmological JIA-U screening. However, a re-evaluation of our results in the larger upcoming Swedish national population-based study is needed before generalised conclusions can be drawn.
5. Acknowledgement
I would like to express my very great appreciation to my supervisor Dr Pia Lundgren for her patient and professional guidance and valuable support throughout the study. I also wish to thank Dr Gunnar Skeppner for data requisition and valuable advice.
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Cover letter (250 ord)
Örebro, Sweden, 2020-12-18 Dear Professor Kaarinranta,
Please find enclosed our manuscript entitled ”Prevalence, Risk Factors, Characteristics and Complications of Uveitis in a Swedish Cohort of Children with Juvenile Idiopathic Arthritis”, which we would like to submit for publication in Acta Ophthalmologica.
The current Swedish guidelines for ophthalmological uveitis screening of children with juvenile idiopathic arthritis (JIA) are based on European guidelines rather than studies on Swedish JIA children. Swedish studies are warranted for optimal care of Swedish children with JIA.
The study was conducted as a retrospective review of medical records of 200 children with JIA treated at Örebro University Hospital, Sweden in 2010-2019. 96 children with a minimum of one year of ophthalmological follow-up were included. We found a 22.2% prevalence of uveitis, which is higher than in earlier Swedish studies. Furthermore, we found a higher proportion of boys developing uveitis and a lower portion of children developing uveitis within the four years of high frequency screening compared to recent Swedish respectively European studies.
We believe that our findings would be of interest to the readership of Acta Ophthalmologica since they indicate a need of future Swedish studies to revise and optimize the current Swedish guidelines for ophthalmological JIA-U screening.
The study was ethically approved by the Swedish Ethical Review Authority and conducted according to the Declaration of Helsinki. This manuscript is our original work and has not been published elsewhere nor is under consideration by any other journal.
Sincerely
Eva Jatkola, MB
School of Medical Sciences Örebro University
Populärvetenskaplig sammanfattning (249 ord)
J
uvenil idiopatisk artrit (JIA) är den vanligaste ledsjukdomen bland barn. I Sverige finns 1200–1700 barn med JIA. Dessa barn löper ökad risk att drabbas av uveit; en inflammation i ögats druvhinna (uvea). Eftersom uveiten allt som oftast inte orsakar några symptom men kan leda till potentiellt synhotande komplikationer, gårJIA barn på regelbundna
screeningkontroller på ögonkliniken. Svenska riktlinjer för ögonscreening är baserade på europeiska studier.
Det finns ett begränsat antal tidigare studier om JIA associerad uveit i Sverige. Syftet med denna studie var att ta reda på förekomsten av JIA associerad uveit och ögonkomplikationer bland barn som behandlats för JIA vid barnkliniken på Universitetssjukhuset Örebro under 2010– 2019. Samt att beskriva riskfaktorer för att utveckla uveit och ögonkomplikationer och beskriva läkemedelsbehandlingen hos dessa barn. Av 200 barn med JIA inkluderades 96 barn med minst 1 års ögonuppföljning i studien. Studien genomfördes som en retrospektiv granskning av sjukvårdsjournaler.
Av barnen inkluderade i studien fick 22.2% uveit och 33.3% av dessa barn utvecklade även ögonkomplikationer. Andelen barn som fick uveit är betydligt högre än i tidigare studier från andra delar av Sverige. Vi fann även att pojkar fick uveit oftare än flickor, i motsats till vad majoriteten av tidigare studier visat, och att andelen barn som fick uveit tidigt var lägre än i tidigare studier. Våra resultat antyder att det kan föreligga skillnader i förekomsten av JIA uveit både mellan könen och mellan geografiska områden i Sverige. Våra fynd behöver dock styrkas av större framtida svenska studier om JIA uveit.
Bild. Barn med juvenil idiopatisk artrit
undersöks regelbundet med ögonmikroskop.
Child's optometry - little girl hecks eyesight in eye ophthalmological clinic (Adobe Stock).
Etisk reflektion (250 ord)
Vid forskning på barn och ungdomar, alltså personer med nedsatt autonomi tillhörande en utsatt grupp, bör vissa etiska forsknings principer utöver de etiska grundprinciperna beaktas. Det ska finnas en kunskapsvinst som inte kan nås på annat sätt och forskning som kan göras på äldre barn eller ungdomar bör inte göras på små barn. Dessutom ska forskningspersonen utsättas för minimal risk samt ha direkt nytta av deltagandet.
Eftersom Juvenil idiopatisk artrit (JIA) och den associerade uveiten är pediatriska tillstånd måste forskning inom området oundvikligen ske på barn. Barn med debut av JIA i tidig ålder löper större risk att utveckla uveit, varför små barn inte kunde exkluderas ur studien.
Det finns endast ett fåtal svenska epidemiologiska studier på JIA uveit. Nuvarande svenska riktlinjer för ögonscreening av JIA barn är utformade utifrån europeiska studier. Det är oklart om riktlinjerna är optimala för svenska barn med JIA. Denna studie utgör startkohorten för den första nationella populationsbaserade svenska studien om JIA-U. Det är av högsta värde att utreda om det finns någon geografisk variation på JIA uveit i Sverige jämfört med resten av Europa. En potentiell optimering av screening-riktlinjer utifrån studieresultat och vidare forskning skulle direkt gagna deltagande forskningspersoner.
Eftersom studien är utförd som en retrospektiv journalgranskning och känsliga uppgifter av hälsa har samlats in och behandlats av en person som inte är direkt involverad i vården, utsätts forskningspersonen för ett integritetsintrång. Den svenska etikprövningsnämnden har i detta fall avgjort att den möjliga preventiva nyttan väger upp den kränkning av autonomiprincipen som integritetsintrånget utgör.
