Ocular Immunology & Inflammation

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Ocular Immunology & Inflammation

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Uveitis in juvenile arthritis A. Tülin Berk; Nilüfer Koçak; Erbil Ünsal Online Publication Date: 01 December 2001 To cite this Article: Berk, A. Tülin, Koçak, Nilüfer and Ünsal, Erbil (2001) 'Uveitis in juvenile arthritis', Ocular Immunology & Inflammation, 9:4, 243 — 251 To link to this article: DOI: 10.1076/ocii.9.4.243.3959 URL: http://dx.doi.org/10.1076/ocii.9.4.243.3959

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Clinical report Uveitis in juvenile arthritis Ocular Immunology and Inflammation 0927-3948/01/US$ 16.00 Ocular Immunology and Inflammation – 2001, Vol. 9, No. 4, pp. 243–251 © Swets & Zeitlinger 2001 Accepted 30 August 2001

A. Tülin Berk1 Nilüfer Koçak1 Erbil Ünsal2 Departments of 1Ophthalmology and 2Pediatrics, School of Medicine, Dokuz Eylül University, Izmir, Turkey

Abstract Purpose: To evaluate the clinical features of and determine the risk factors for uveitis in patients with juvenile arthritis. Methods: The prevalence and clinical characteristics of uveitis were studied retrospectively in 90 children diagnosed with arthritis. Patients with uveitis were compared with those who did not have eye involvement. Results: Uveitis was diagnosed in 11 patients (12.2%). Of these, seven (63.6%) had oligoarticular, two (36.4%) had polyarticular, and one (9.1%) had systemic-onset juvenile rheumatoid arthritis (JRA). One patient (9.1%) was diagnosed with enthesitis-related arthritis (ERA) (9.1%). The prevalence of uveitis was significantly higher in patients with oligoarticular JRA. The mean age at onset of arthritis in the uveitis patients was 4.39 years, which was significantly lower than in the non-uveitis group. There was no gender difference in the risk of developing uveitis.Antinuclear antibodies (ANA) was positive in seven (63.6%) of the 11 uveitis patients, confirming ANA as a significant determinant for uveitis in juvenile arthritis. Rheumatoid factor was not found to be a risk factor. One (9.1%) of the 11 patients developed serious sight-threatening complications during the follow-up period. Conclusion: This study confirmed that oligoarticular onset, ANA positivity, and young age are risk factors for developing uveitis in patients with juvenile arthritis. Gender was not found to be a determining factor. Prompt treatment of uveitis effectively decreased the prevalence of visual impairment. Key words antibodies

Correspondence and reprint requests to: Tulin Berk Huseyin Zeren Cad. Urla Berk Sitesi 143 Urla/Izmir Turkey E-mail: [email protected] Acknowledgement: The authors would like to express their gratitude to Alp Ergör, M.D., for his invaluable help and advice with the statistical work. Presented as a free paper at the VIth International Ocular Inflammation . Symposium, I stanbul, Turkey, 18–23 June 2000.

Arthritis; juvenile arthritis; uveitis; antinuclear

Introduction Childhood uveitis is a serious disease that may lead to sight-threatening complications. Six percent of all uveitis patients are children.1,2 Juvenile rheumatoid arthritis (JRA)-associated uveitis is the most common cause of childhood uveitis with a prevalence between 2% and 21%.3–6 Young girls with positive antinuclear antibody (ANA) have a particularly high risk of developing uveitis.4,7,8 Uveitis in juvenile arthritis

243


Loss of vision in affected eyes due to iridocyclitis in JRA is reported to be as high as 50%.7,9 Compared with earlier data,10–13 recent reports have documented a decrease in the prevalence and severity of uveitis in JRA. The present study was designed to determine the prevalence and severity of juvenile arthritis-associated uveitis in our population. We also analyzed the clinical patterns, ensuing complications, and effect of treatment on the clinical course of the disease. Materials and methods The medical reports of patients who were referred to the pediatric rheumatology clinic were reviewed retrospectively for diagnosis, evaluation, and treatment of idiopathic juvenile arthritis. Ninety patients meeting the criteria of the Pediatric Studying Committee of the International League of Association for Rheumatology14 comprised the study group. JRA was classified according to the pattern of arthritis in the first six months after onset. Oligoarticular-onset JRA affects one to four joints, while polyarticular-onset JRA affects five or more joints. Systemic-onset JRA often presents with arthritis, intermittent high fevers, and rash. Enthesitis-related arthritis (ERA) is the revised definition of seronegative enthesopathy arthropathy (SEA) syndrome.15,16 It is classified as arthritis and enthesitis, or as arthritis or enthesitis with at least two of the following criteria: 1) sacroiliac joint tenderness and/or inflammatory spinal pain; 2) the presence of HLAB27; or 3) medically confirmed HLA-B27-associated disease in at least one first- or second-degree relative. Each patient in the study underwent a full ophthalmologic examination including slit-lamp biomicroscopy, intraocular pressure measurement, and dilated fundus examination. Visual acuity was measured using the Snellen chart whenever the child was able. Uveitis was considered active if slit-lamp biomicroscopy revealed inflammatory cells or keratic precipitates. The patients were evaluated for evidence of uveitis during periodic ophthalmologic examinations. The frequency of these examinations was based on the type of arthritis, ANA positivity, and age at onset of arthritis. The following data were recorded in review of the charts: age at first visit, age at onset of uveitis, gender, laterality and localization of uveitis, underlying etiology, complications, medical treatment, and follow-up time. Statistical evaluation was performed using the Fisher exact test and the Mann-Whitney U test; p < 0.05 was considered significant. Results Fifty-one (56.7%) of the 90 patients were male and 39 (43.3%) were female. Of the 90 patients, 76 (84.4%) had JRA. Thirtyseven (41.1%) of these children had polyarticular and 27 (30.0%) had oligoarticular JRA at the onset of the disease. Twelve (13.3%) children were diagnosed with systemic JRA. Eleven children (12.2%) had enthesitis-related arthritis (ERA) and three (3.3%) had psoriatic arthritis. The mean duration of follow-up of these patients by the rheumatologist was 31.4 months (range: 6 months-10 years). Uveitis was diagnosed in 11 (12.2%) of the 90 patients with juvenile arthritis. Age at 244

A.T. Berk et al.


Patient no.

1 2 3 4 5 6 7 8 9 10 11

Diagnosis

Sex

Age at arthritis onset

Age at uveitis onset

Uveitis delay

ANA

Number of exacerbations

Ocular complications

Polyarticular JRA Oligoarticular JRA Oligoarticular JRA Oligoarticular JRA Oligoarticular JRA Oligoarticular JRA Enthesitis-related arthritis Polyarticular JRA Oligoarticular JRA Systemic JRA Oligoarticular JRA

F M M F F M M

6 mo 4 yr 3 yr 3 yr 4 yr 5 yr 4 yr

7 yr 4.5 yr 6 yr 8 yr 4.5 yr 6 yr 12 yr

6.5 yr 6 mo 3 yr 5 yr 6 mo 1 yr 8 yr

+ + + + + -

7 3 1 1 2 1 1

Posterior synechia – – – – – –

10 yr 7 yr 13 yr 7 yr

5 yr 6 yr 1 yr 3 yr

+ +

1 1 1 2

– – – Posterior synechia; band keratopathy; cataract

M F M M

5 yr 1 yr 12 yr 4 yr

onset of uveitis was 16 years or younger in all cases. The mean followup time of these patients was four years (range: 6 months-8 years). Seven patients were boys (63.6%) and four (36.4%) were girls. Seven patients (63.6%) had oligoarticular, two (18.2%) had polyarticular, and one (9.1%) had systemic JRA. One patient (9.1%) was diagnosed with ERA. The mean age at arthritis onset was 4.36 ± 2.91 years (range: 6 months-12 years). The mean age at onset of uveitis was 8.0 ± 2.90 years (range: 4–13 years). Average latency between onset of arthritis and uveitis in these patients was 3.59 years (range: 6 months-8 years). Seven (63.6%) of the patients were ANA-positive and all were RF-negative (Table 1). Seventy-nine patients did not develop uveitis during the same followup period: 44 (55.6%) boys and 35 girls (44.4%). Thirty-five patients (44.3%) were diagnosed with polyarticular, 20 (25.34%) with oligoarticular, and 11 (13.9%) with systemic-onset JRA. Ten patients (12.7%) had ERA and three (3.8%) had juvenile psoriatic arthritis. The mean age at onset of arthritis was 7.18 ± 4.09 years (range: 6 months-14 years) in the non-uveitis group. Due to the small number of patients in each group, oligoarticular JRA was compared with all other articular pathologies; the prevalence of uveitis was significantly higher in oligoarticular JRA than in the other types of arthritis (p = 0.015) (Table 2). The mean age at onset of arthritis was significantly lower in the uveitis group than the non-uveitis group (p = 0.03). There was no gender difference in the risk of developing uveitis (p = 0.75). Only eight patients (10.12%) were ANA-positive in the non-uveitis group, while 63.6% of the uveitis patients were ANA-positive. This difference was statistically significant (p = 0.00019). Since rheumatoid factor was negative in all patients, it was not considered to be a risk factor. Uveitis was bilateral in five of 11 patients (45.5%). Nine patients had signs of mild inflammation (cells, flare, keratic precipitates) on initial Uveitis in juvenile arthritis

ta b l e 1. Characteristics of the juvenile arthritis patients who developed uveitis.

245

table 2. Type of arthritis in the study population.


Subtype

Male : Female

With uveitis No.

Oligoarticular JRA Polyarticular JRA Systemic JRA Psoriatic arthritis ERA arthritis

16 : 11 16 : 21 8:4 1:2 10 : 1

Total

51 : 39

7 2 1

Without uveitis

Entire group

%

No.

%

No.

%

63.6 18.2 9.1

20 35 11 3 10

25.3 44.3 13.9 3.8 12.7

27 37 12 3 11

30.0 41.1 13.3 3.4 12.2

– 1 11

9.1

79

90

examination, and only one of them was visually symptomatic (red eye). The keratic precipitates were characteristically small to medium in size and were located mainly in the inferior half of the corneal endothelium. Two patients had advanced uveitis with large keratic precipitates and posterior synechiae at their first visit. One of these patients also had lens opacification and band keratopathy, and was the only patient in the study to develop serious sight-threatening complications during the follow-up period. Four patients had multiple exacerbations of their uveitis. None of the patients developed glaucoma during follow-up. One patient developed mild bilateral posterior subcapsular cataracts as a side effect of long-term treatment with systemic corticosteroids. Every child who developed uveitis initially was treated with topical cycloplegic drops (cyclopentolate or atropine) and topical corticosteroids. In the uveitis group, systemic nonsteroid anti-inflammatory drugs (NSAIDs) were used in all patients for the control of arthritis. Additional systemic immunosuppressive therapy was administered in four of 11 (36.0%) patients: methotrexate in three patients and azathioprine in one patient. In the non-uveitis group, 53 patients received only NSAID therapy, 23 patients received a combination of NSAIDs and immunosuppressive therapy, and three patients were treated with immunosuppressive therapy with systemic steroids. There was no statistical difference between the two groups in terms of treatment regime (p = 0.59). Discussion A wide spectrum of diseases may present with anterior uveitis in childhood.1,4,9,17 The association between intraocular inflammation and rheumatic disease must always be considered in children who may suffer long-term morbidity with undiagnosed uveitis and arthritis. The prevalence of uveitis was found to be 12.2% in our study population. Ten of the 11 uveitis patients were diagnosed with juvenile rheumatoid arthritis (JRA). Earlier studies have reported the prevalence of uveitis in patients with JRA to range from 2% to 21%.3–6 This wide range may be due to the variations in the follow-up period. Boone et al.12 and Akduman et al.10 reported the prevalence of uveitis among their populations to be 9% and 12%, respectively. Other studies have underscored the importance of a longer follow-up period, because the development of uveitis may occur several years after the onset of 246

A.T. Berk et al.


Authors/year

Prevalence of girls (%)

ANA (+) (%)

Mode of onset (%) Systemic

Kimura et al.,18 1967 Schaller et al.,22 1974 Chylack et al.,3 1975 Kanski,19 1977 Ohno et al.,8 1977 Wolf et al.,7 1987 Kanski,20 1989 Dana et al.,21 1997 Akduman et al.,10 1997 Boone et al.,12 1998 Berk, 2001

Polyarticular

Oligoarticular

Others

6

14

78

2

– 1 – 3 14 9

12 9 19 38 23 18

88 90 81 53 63 64

– –

92 88 83 76 82 74 86 74 100 36

71 83 75 90

64

arthritis.4,7 Recent reports have shown a decrease in the prevalence of uveitis. Comparing patients with oligoarticular JRA seen in 1975 to a matched population in 1989, Sherry and colleagues11 found a decrease in the prevalence of uveitis from 45% to 13%. In that study, the two groups had identical follow-up periods. The decrease in disease severity and prevalence may be related to an earlier surveillance for ocular disease and more effective treatment. Our results are consistent with the known risk factors for developing uveitis: young age, oligoarticular onset, and ANA positivity. JRA is more common in girls than boys by a 3 : 2 ratio, and several studies have reported that girls are more likely to have anterior uveitis than boys (Table 3).3,7,10,12,18–21 It has also been shown that girls without an associated arthritis or other systemic disease are more likely to have chronic anterior uveitis than boys.1,8 It is unclear why girls appear to have an increased susceptibility to uveitis, and our study does not support this general finding. The prevalence of uveitis did not differ statistically between boys and girls in our population, with boys composing 63.3% of the uveitis group and 55.6% of the non-uveitis group. Data from other centers are necessary to determine if our finding is unique to our region. The most common type of JRA in other series was oligoarthritis (50–90%), while polyarticular and systemic arthritis each made up about 20% of the cases.4 In the present study, 41.1% of the arthritis patients had a polyarticular and 30.0% an oligoarticular presentation. However, the patients with the oligoarticular form of the disease comprised 63.6% of the patients with uveitis. Our results are in accordance with similar studies; a great association exists between the mode of onset of JRA and the subsequent risk of uveitis. Patients with polyarticular or systemic onset are generally less likely to develop iridocyclitis (Table 3).3,7,10,12,20,21 The relatively high incidence of polyarthritis might partially explain the low prevalence of uveitis in our study population. The reported prevalence of ANA in patients with uveitis and JRA ranges between 71% and 90% (Table 3).7,8,20–22 The actual role of ANA Uveitis in juvenile arthritis

6 – 9

ta b l e 3. Literature review of the prevalence of girls, the presence of ANA, and the mode of onset in patients with uveitis and JRA.

247


positivity in the pathogenesis of uveitis in JRA is unclear, but its association with uveitis is well documented. In our study, ANA positivity was significantly higher in uveitis patients (64%) than in non-uveitis patients (10%). Most reports have substantiated the infrequent occurrence of uveitis prior to the onset of arthritis.7,10,20 Iridocyclitis may be detected at the time of the initial diagnosis of arthritis, but it most often presents over the following five to seven years. In our study, arthritis preceded uveitis in all patients. Only one patient had advanced iridocyclitis when uveitis was first diagnosed. The mean age at uveitis onset was 8.0 ± 2.9 years, and none of the patients developed uveitis before the age of four years. The average latency between the onset of arthritis and that of uveitis was 3.59 years, ranging from six months to eight years. The mean age at onset of arthritis was significantly lower in the uveitis group than in the non-uveitis group. In Kanski’s study,20 arthritis preceded the diagnosis of uveitis in 94% of cases, and of these, 90% developed uveitis within seven years. The average age at the time of uveitis diagnosis was six years (range: 1–35 years). Kanski stated that the risk of developing uveitis was small after seven years with arthritis. In contrast, Chaylack et al.3 reported that 30% of their patients developed uveitis after the age of 16. In Akduman and associates’ study,10 three of seven patients developed iridocyclitis a decade after the onset of arthritis. In light of these findings, the peak onset of arthritis in this group is age two to five years with the subsequent development of iridocyclitis within the next five to seven years. Children with JRA, however, remain at risk of developing iridocyclitis even longer, making close monitoring for asymptomatic uveitis necessary. Most published reports emphasize the asymptomatic nature of the ocular inflammation.5 Its presence is usually initially detected during routine slit-lamp biomicroscopy. In previous studies, 12–25% of the patients with uveitis presented with symptoms of severe pain, redness, and photophobia. In our study, only one of 11 (9.1%) patients was symptomatic with red eye. In contrast, 44% of the patients with uveitis in Chylack’s series3 had signs or symptoms such as red eye, ocular pain, decreased visual acuity, or photophobia. Most cases of iridocyclitis are bilateral; children with unilateral iridocyclitis may progress to bilateral iridocyclitis after the initial 12 months of eye disease. The incidence of bilateral involvement varies between 67% and 89%.5,7,21 Our prevalence of 45.5% bilaterality is less than that of the previously reported series. Previous reports have shown a great deal of variability in the prevalence and severity of ocular complications related to uveitis in JRA. This variability may reflect different referral patterns rather than any real change in prevalence. The duration of follow-up is an important variable, because visual impairment usually develops over a long period of time. In a long-term study of patients with JRA in which uveitis was diagnosed before the development of complications, Kanski5 divided patients into three groups: the first group (25% of patients) had mild inflammation and responded rapidly to topical treatment. The second group (25%) had severe, prolonged inflammation 248

A.T. Berk et al.


and was unresponsive to topical medication. The visual prognosis in this group was fair. The third group (50%) had moderate uveitis that required long-term treatment for the control of inflammation. Uveitis diagnosed simultaneously with JRA has been associated with a higher risk of visual impairment. Wolf et al.7 stated that initial ocular examination not only correlated with long-term visual outcome, but also with ocular complications. Those patients with a normal examination or signs of mild uveitis at initial ocular examination had less visual loss and fewer complications than the ones who had advanced uveitis (posterior synechiae) at the initial examination. They also found a great association between systemic corticosteroid use and cataract and glaucoma formation. Regarding the JRA patients with advanced uveitis at the time of initial examination,Tugal-Tutkun et al.9 demonstrated an overall prevalence of cataract (71%), glaucoma (30%), and band keratopathy (66%). These findings were comparable to those by Wolf et al.,7 who showed incidences of 81%, 45%, and 77%, respectively. These high rates of complications reported from tertiary referral centers reflect the severity of the ocular disease in patients referred with chronic arthritis. Tugal-Tutkun et al.9 reported poor vision (