ARTHRITIS & RHEUMATISMVol. 62, No. 6, June 2010, pp 1824–1828DOI 10.1002/art.27416© 2010, American College of Rheumatology

Risk Factors for Development of Uveitis Differ BetweenGirls and Boys With Juvenile Idiopathic Arthritis

R. K. Saurenmann,1 A. V. Levin,2 B. M. Feldman,3 R. M. Laxer,4

R. Schneider,4 and E. D. Silverman4

Objective. Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis(JIA) and is associated with considerable morbidity.The aim of this study was to examine the risk factorsassociated with uveitis in JIA.

Methods. We conducted a chart review of 1,047patients with JIA from a single tertiary care pediatricrheumatology center for factors associated with thedevelopment of uveitis. Special emphasis was put on thefollowing known risk factors: oligoarthritis, antinuclearantibody (ANA) status, sex, and age at the time of onsetof JIA.

Results. The risk of uveitis developing was agedependent in girls but not in boys. Among girls, the riskwas maximal (47%) in those who were ANA positive andwere ages 1–2 years at the time of the onset of JIA; thisrisk decreased to <10% in those in whom the age atonset was >7 years. Only girls had an age-dependentand ANA-associated increased risk of uveitis. The timeinterval from the diagnosis of JIA to the diagnosis of

uveitis was statistically significantly longer in patientsin whom the onset of JIA occurred at a younger age (P �0.04). This effect was even more pronounced in ANA-positive patients (P � 0.004). The JIA subtype did notinfluence a patient’s risk of the development of uveitis.

Conclusion. An age-associated risk of uveitis wasobserved only in girls who were younger than 7 years ofage at the time of the onset of JIA. The duration of timebetween the diagnosis of JIA and the onset of uveitis waslonger in patients in whom JIA was diagnosed at ayounger age, especially in those who were ANA positive.We suggest that our findings have implications foruveitis screening in patients with JIA.

Uveitis is the most common extraarticular mani-festation of juvenile idiopathic arthritis (JIA). It is aserious complication, often is asymptomatic at the timeof onset, and is associated with high morbidity, withblindness reported in up to 45% of cases (1). Reportedrisk factors for JIA-related uveitis include antinuclearantibody (ANA) positivity, young age at the time of theonset of JIA, and JIA subtype, especially oligoarticularJIA. Regular ophthalmologic screening examinationswith consideration for combinations of these risk factorsare recommended for all children with a diagnosis of JIA(2,3). Children with ANA-positive oligoarthritis or poly-arthritis with disease onset before age 6 years arereported to have the highest risk of uveitis. It is recom-mended that these children should have routine screen-ing examinations every 3 months for the first 4 years ofthe disease (3). In children in whom the onset ofoligoarthritis or polyarthritis occurs before age 6 yearsbut in whom results of ANA testing are negative, ORthose in whom results of ANA testing are positive but inwhom disease onset occurs after age 6 years, OR thosein whom the first 4 years of disease have elasped, the riskof uveitis is deemed moderate, and the frequency ofscreening examinations is reduced to every 6 months.Children in whom ANA test results are negative AND in

Supported by the Swiss Arthritis Society (RheumaligaSchweiz), Stiftung Sanitas (Switzerland), Brandan’s Eye ResearchFund, and the Foerderer Fund. Dr. Feldman holds the CanadaResearch Chair in Childhood Arthritis at the University of Toronto,and Dr. Silverman holds the Ho Family Chair in Pediatric Auto-immune Diseases at the University of Toronto.

1R. K. Saurenmann, MD: University Children’s Hospital,Zurich, Switzerland; 2A. V. Levin, MD, MHSc, FRCSC: Wills EyeInstitute, Philadelphia, Pennsylvania; 3B. M. Feldman, MD, MSc,FRCPC: The Hospital for Sick Children and University of Toronto,Toronto, Ontario, Canada; 4R. M. Laxer, MD, FRCPC, R. Schneider,MBBCh, FRCPC, E. D. Silverman, MD, FRCPC: University ofToronto, Toronto, Ontario, Canada.

Dr. Saurenmann has received consulting fees, speaking fees,and/or honoraria (less than $10,000 each) from Centocor and Abbott.Dr. Laxer has received consulting fees (less than $10,000) fromGenzyme. Dr. Silverman has received consulting fees, speaking fees,and/or honoraria (less than $10,000 each) from Amgen and Abbott.

Address correspondence and reprint requests to R. K. Sau-renmann, MD, University Children’s Hospital, Steinwiesstrasse 75,8032 Zurich, Switzerland. E-mail: traudel.saurenmann@kispi.uzh.ch.

Submitted for publication December 6, 2009; accepted Feb-ruary 12, 2010.

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whom disease onset occurs after age 6 years, OR thosewith systemic arthritis, OR those who have experienced4 years of moderate uveitis risk are considered to have alow risk, and ophthalmologic screening every 12 monthsis recommended. Whether female children are at in-creased risk of uveitis is controversial (4–8). The aim ofthe current study was to reconsider the risk factors foruveitis in a large cohort of patients with JIA.

PATIENTS AND METHODS

We conducted a database search and a chart review ofpatients who were followed up in the Pediatric RheumatologyClinic at The Hospital for Sick Children, Toronto, Canada, atertiary referral center. The details of patient identificationhave been previously published (9,10). The study was approvedby the Institutional Ethics Review Board of The Hospital forSick Children.

The study cohort was stratified into groups by 1-yearintervals according to age at the time of the onset of JIA.Differences in the rate of uveitis and in the time intervalbetween the onset of JIA and the diagnosis of uveitis betweenthe different age groups were then analyzed. The presence ofANAs was determined in the routine diagnostic laboratory atThe Hospital for Sick Children, according to the instructions ofthe manufacturer. A titer of �1:40 was considered positive.

Statistical analyses were performed using the Mi-crosoft Excel program and the JMP IN 5.1 program (SASInstitute). The chi-square test, bivariate analysis of variance,logistic regression analysis including tests for interactions, andKaplan-Meier survival analysis were used to assess for differ-ences between groups.

RESULTS

We identified 1,081 patients with a confirmeddiagnosis of JIA. After a mean followup time of 6.9years, uveitis had developed in 142 of these 1,081patients (13.1%). Because our analysis focused on pos-sible implications on the guidelines for ophthalmologicscreening examinations, 20 patients in whom the onsetof uveitis occurred before the diagnosis of JIA wereeliminated from the cohort. Another 14 patients wereeliminated because their first visits to The Hospital forSick Children were several years after the onset of thearthritis, and it therefore was not possible to determinetheir exact ages at the onset of JIA. The remaining 1,047patients comprised the study cohort.

Sixty-six percent of the patients were female.Uveitis was diagnosed in 122 of the 1,047 patients(11.7%). Among patients who were ages 1–2 years at theonset of JIA, 81% were female; the percentage of femalepatients decreased to 55% among those who were ages 9years and older at the time of the diagnosis of JIA (P �0.0001 for between-group differences, by chi-square

test). Girls had a higher rate of ANA positivity com-pared with boys, in all age groups (P � 0.0001). The rateof ANA positivity was 70% overall (73% in girls and50% in boys) among patients who were ages 1–2 years atthe onset of JIA, and this rate gradually decreased to�35% overall in adolescents (45% in girls and 26% inboys). Oligoarthritis was the most common (53%) JIAsubgroup among patients in whom the onset of JIAoccurred at age 9 years or younger (58% in girls and37% in boys), and enthesitis-related arthritis was themost common (26%) subgroup among patients in whomthe onset of JIA occurred when they were older than 9years (10% in girls and 45% in boys).

The maximal rate of uveitis (28%) was observedin the group of patients ages 1–2 years (Figure 1). This

Figure 1. Rate of uveitis in patients with juvenile idiopathic arthritis(JIA), according to age at the onset of JIA, sex, and antinuclearantibody (ANA) status.

SEX AND UVEITIS RISK IN JIA 1825

rate of uveitis in this age group was increased only ingirls (37% versus 7% in boys; P � 0.002). The differencein the prevalence of uveitis between the 2 sexes in-creased further when the analysis was limited to onlyANA-positive patients (47% in girls and 10% in boys;P � 0.015) and to ANA-positive patients with oligoar-ticular JIA (46% in girls and 0% in boys; P � 0.002).Among ANA-positive girls, the risk of uveitis develop-ment was significantly higher among those in whomarthritis was diagnosed before age 2 years comparedwith the group in whom arthritis was diagnosed at ages2–3 years (P � 0.008 by chi-square test) or any other agegroup (P � 0.0001, by chi-square test).

In a logistic regression analysis, the rate of uveitisin girls, regardless of JIA subgroup, was inversely corre-lated with age at the onset of JIA (likelihood ratio [LR]57.8, P � 0.0001) and ANA positivity (LR 12.6, P �0.0004). In boys, there was only a trend for an associa-tion between the rate of uveitis and ANA status (LR 3.8,P � 0.051), and no correlation was observed between thedevelopment of uveitis and age at onset of JIA (LR 0.62,P � 0.43) (Figure 2A). There was a marginally statisti-cally significantly increased age-associated risk of uveitisdevelopment in ANA-negative girls (P � 0.04, by chi-square test) (Figure 2A). Among patients in whom JIA

was diagnosed after age 7 years, the rate of uveitis inANA-positive girls was the same as that in ANA-negative girls and in boys (�10%). There was no sta-tistically significant difference in the risk of uveitisdevelopment in ANA-positive girls with oligoarthritisas compared with ANA-positive girls with non-oligoarticular JIA (P � 0.06, by chi-square test) (Figure2B). ANA-negative girls with oligoarthritis had a sta-tistically significantly higher risk of uveitis develop-ing compared with ANA-negative girls with non-oligoarticular JIA (P � 0.005, by chi-square test). Inboys, a diagnosis of oligoarthritis was not associated withan increased uveitis risk as compared with non-oligoarticular JIA, regardless of ANA status.

An ordinal logistic regression analysis was per-formed with the factors that were demonstrated to bestatistically significant in univariate analysis: age at di-agnosis, ANA status, sex, and JIA subtype, includinginteraction analysis. Age at diagnosis (LR 16.7, P �0.0001), ANA positivity (LR 13.1, P � 0.0003), femalesex (LR 8.0, P � 0,004), and the combination of femalesex and young age at diagnosis (LR 6.7, P � 0.009) weresignificantly associated with the development of uveitis.The combination of ANA positivity and young age at

Figure 2. Risk of uveitis development in patients with juvenile idiopathic arthritis (JIA), according to age at diagnosis of JIA, sex, antinuclearantibody (ANA) status (A), and JIA subtype (B).

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diagnosis (LR 3.3, P � 0.07) showed a marginallysignificant association, whereas oligoarticular JIA did not.

We next performed the same analysis for boysand girls separately. Among girls, risk factors for thedevelopment of uveitis were as follows: the combinationof ANA positivity and young age at diagnosis (LR 5.6,P � 0.01) and young age at diagnosis (LR 3.97, P �0.04); ANA status and oligoarticular JIA were not riskfactors. Among boys, the only marginally significant riskfactor was ANA status (LR 3.8, P � 0.05), whereas ageat diagnosis and oligoarticular JIA were not risk factors.

Among patients in whom JIA was diagnosed atage 6 years or younger, ANA positivity (LR 16.3, P �0.0001), age at diagnosis (LR 7.2, P � 0.007), and femalesex (LR 6.8, P � 0.008) but not oligoarticular JIA (LR0.3, P � 0.59) were significantly associated with thedevelopment of uveitis. For patients who were olderthan age 6 years at the time of the diagnosis of JIA, onlyage at diagnosis (LR 4.7, P � 0.03) was associated withthe development of uveitis, whereas ANA status (LR0.39, P � 0.53), sex (LR 1.28, P � 0.26), and oligoar-ticular JIA (LR 0.22, P � 0.64) were not.

The median time interval between the diagnosisof JIA and the diagnosis of uveitis was 1.4 years (range0–9.9 years, mean 2.23 years).There was an age-dependent statistically significant difference in the timeinterval from the diagnosis of JIA to the diagnosis ofuveitis (P � 0.04 for between-group differences, bychi-square test), with a longer time period until thediagnosis of uveitis among children in whom the onset ofJIA occurred at a younger age. This influence of age onthe time to development of uveitis was present only in

ANA-positive patients (P � 0.004 versus P � 0.15 inANA-negative patients). The time interval between thediagnosis of JIA and the diagnosis of uveitis was longestamong patients in whom JIA was diagnosed at ages 0–1years and 1–2 years, with a mean of 3.2 and 2.9 years,respectively (range 0–9.9 years for both age groups) anddecreased to a mean between 1 year and 2 years (range0–7.3 years) in patients who were older than age 5 yearsat the onset of JIA (Figure 3).

DISCUSSION

Uveitis is the most common and most significantextraarticular manifestation of JIA. Because this com-plication is usually asymptomatic and is associated withsignificant sequelae in a large proportion of affectedchildren, the American Academy of Pediatrics has pro-duced guidelines for routine eye examinations in pa-tients with juvenile arthritis that are, at least in part,based on risk factors (3). In our large cohort of patientswith JIA, we examined how the factors of age at theonset of JIA, sex, and ANA status, individually and incombination, influenced the rate of uveitis. To ourknowledge, this study is the first to demonstrate that therisk of uveitis development is strongly related to thepatient’s age at the time of arthritis onset and ANApositivity, in girls but not in boys.

The association of uveitis and early-onset oligo-articular arthritis was described as early as 1957 (11).Approximately 20 years later, when ANA testing inchildren with arthritis became routine, the association ofANAs and uveitis was described (12). Despite multipleinvestigations, previous studies either were not suffi-ciently powered or did not stratify patients in order todetermine which individual factor led to the recognizedincreased prevalence of uveitis in ANA-positive girlswith early-onset oligoarticular arthritis. In a previousstudy of this cohort (9), we also were unable to demon-strate a sex-related increased risk of uveitis, but the agegroups in that study were larger than those used in thecurrent study. It was only when we stratified patientsinto smaller age groups that the age-associated risk ofuveitis in association with female sex became apparent.This age dependency was also present in ANA-negativegirls, although the combination of the risk factors ANApositivity and young age at disease onset greatly in-creased the risk of uveitis development. In boys, we werenot able to demonstrate any age dependency and ob-served only a marginal influence of ANA status.

A sex difference in the age at onset of JIA, witha much higher prevalence of JIA in girls during the earlyyears of life, has been known for many decades but was

Figure 3. Probability of uveitis developing during followup in allpatients with juvenile idiopathic arthritis (JIA), according to age atdiagnosis of JIA. For ages 0–2 years, n � 162. For ages 2–3 years, n �133. For ages 3–5 years, n � 162. For ages 5–8 years, n � 120. For ages8–16 years, n � 470.

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usually attributed to differences in the prevalence of JIAsubtypes between boys and girls. Our current analysissuggests an age-dependent influence of sex that is inde-pendent of JIA subtype. This important sex difference soearly in life may suggest a need for further researchabout factors influencing the development and matura-tion of the immune system and the inhibition of auto-immunity.

In contrast to the results of other studies (5,6,8),we did not observe a difference in the risk of uveitisdevelopment in ANA-positive patients with differentJIA subtypes. This finding further supports a newlyevolving hypothesis made by Ravelli et al, that patientswith ANA-positive JIA constitute a homogeneous sub-group irrespective of the course of joint disease (13) andsuggests that modifications to the International Leagueof Associations for Rheumatology classification criteriafor a diagnosis of JIA (14) may be needed.

Despite the large size of the cohort, our study waslimited by the relatively small number of boys andANA-negative girls. The risk of uveitis developing inthese patients may be underestimated. Several groups ofinvestigators have already recommended extending oc-ular screening examinations to all ANA-positive patientswith early-onset JIA, independent of the JIA subtype(8,15,16). Our results, therefore, need to be reevaluatedin other large cohorts of patients with JIA beforeguidelines for ophthalmologic screening examinations inchildren with JIA are changed.

The risk of developing JIA-related uveitis re-mained high for a longer period of time in children inwhom JIA was diagnosed at an earlier age. Based on ourfindings, we suggest that the patients who require themost intensive screening are ANA-positive girls in whomJIA was diagnosed before 7 years of age regardless oftheir JIA subtype, and that patients in whom JIA wasdiagnosed before age 5 years should have the period ofregular 3-monthly screening examinations extended un-til 7 years after the diagnosis of JIA. With the exceptionof extremely low-risk systemic JIA and rheumatoidfactor–positive JIA, the JIA subtype should not influ-ence the screening protocols in ANA-positive patients.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors approvedthe final version to be published. Dr. Saurenmann had full access to allof the data in the study and takes responsibility for the integrity of thedata and the accuracy of the data analysis.

Study conception and design. Saurenmann, Levin, Silverman.Acquisition of data. Saurenmann, Levin, Feldman, Laxer, Schneider.Analysis and interpretation of data. Saurenmann, Levin, Feldman,Laxer, Silverman.

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