Tumour necrosis factor a inhibitors in the treatment of childhood uveitis

Rheumatology 2006;45:982 989 Advance Access publication 3 February 2006 Tumour necrosis factor a inhibitors in the treatment of childhood uveitis R. K. Saurenmann, A. V. Levin 1, J. B. Rose, S. Parker, T. Rabinovitch 3, P. N. Tyrrell, B. M. Feldman, R. M. Laxer 2, R. Schneider and E. D. Silverman doi:10.1093/rheumatology/kel030 Objective. To describe the efficacy of anti-tnf- agents in the treatment of childhood uveitis. Methods. We performed a retrospective chart review of all children with uveitis treated with TNF-a blockers at The Hospital for Sick Children, Toronto. Results. Twenty-one children with uveitis were treated with the anti-tnf-a agents etanercept (11 patients) and infliximab (13 patients), resulting in 24 treatment courses. All patients had persistently active uveitis despite treatment with at least one standard immunosuppressive drug before the start of anti-tnf-a therapy. Six of 21 patients (29%) had idiopathic uveitis. In the other 15 patients, the underlying disease was juvenile idiopathic arthritis in 12 (57%), Behc et disease in two (9%) and sarcoidosis in one (5%). Response to etanercept treatment was good in 27%, moderate in 27% and poor in 45% of patients. Response to infliximab treatment was good in 38%, moderate in 54% and poor in 8% of patients. The difference in the percentage of patients with a moderate or good response was statistically significant (P^0.0481). We also observed a lower rate of complications, such as new-onset or worsening or cataract in the infliximab-treated group. Conclusion. Anti-TNF-a treatment was beneficial in a high percentage of patients with childhood uveitis refractory to standard immunosuppressive treatment. Infliximab resulted in better clinical responses with less ocular complications than etanercept. KEY WORDS: Biological agents, Eye diseases, Juvenile idiopathic arthritis, Outcome assessment. Non-infectious uveitis of childhood is rare, with an annual incidence in Western countries of 4 7/100 000 children/yr [1 3]. Unlike what is seen in adults, juvenile idiopathic arthritis (JIA) is the most common underlying disease in children with uveitis [4 7]. The prognosis of paediatric uveitis is poor as a high percentage will eventually develop complications such as cataracts and. It is estimated that up to 45% of patients will end up with visual impairment [1, 5]. Treatment of uveitis relies mainly on local and systemic corticosteroids to control inflammation, dilating agents to prevent synechia formation, and treatment of, cataract and band keratopathy [8, 9]. To reduce corticosteroid use and prevent side-effects of this treatment, immunosuppressive agents have been used with variable success. Published experience with numerous immunosuppressive drugs used to control uveitis both in adults and in children consists largely of case reports and case series, while prospective studies and randomized controlled trials are rare [10 17]. More recently, biological agents, including tumour necrosis factor- (TNF-)-blocking agents, have been used to treat uveitis including the uveitis associated with JIA [18, 19]. However, there have also been reports of worsening or new-onset uveitis during treatment with anti-tnf- agents [20 22]. The aim of our study was to describe the efficacy of two TNF- inhibitors, etanercept and infliximab, in the treatment of children with uveitis in a retrospective setting. Methods The charts of all 102 patients who were started on an anti-tnf- agent (etanercept or infliximab) in the Division of Rheumatology at The Hospital for Sick Children in Toronto, Canada, between 1 January 1997 and 31 December 2003 were reviewed. Twenty-one patients with active uveitis at onset of anti-tnf- treatment were identified. All patients had persistently active uveitis despite treatment with at least one standard immunosuppressive drug before the start of anti-tnf- therapy. The following data were collected: age at initiation of therapy, date of diagnosis of underlying disease (if applicable), date of diagnosis of uveitis, autoantibody status, start and end date of all medications used, and date of diagnosis of uveitis complications (synechiae, cataract, band keratopathy, macula oedema, legal blindness), start date and end date of anti-tnf- treatment and specific anti-tnf- agent used. At each visit while receiving anti-tnf- treatment, data on the patients height, weight and medication doses were collected. Ophthalmological examination (visual acuity, slit lamp examination, intraocular pressure, fundus examination with or without pharmacological mydriasis as indicated) was performed periodically on a schedule customized to the needs of the patients but not less frequently than every 3 months (for well-controlled uveitis). From 1997 until 2000, etanercept was the only TNF- blocker available for use in children. After October 2000, the choice of drug as well as dose and dose increase of infliximab was an Division of Rheumatology, 1 Department of Ophthalmology and Vision Sciences, 2 Departments of Paediatrics and Medicine, Hospital for Sick Children, Toronto, Canada and 3 North Toronto Eye specialists, Toronto, Canada. Received 20 September 2005; revised version accepted 6 January 2006. Correspondence to: R. Saurenmann, Zurich University Children s Hospital, Postal Box 8032, Zu rich, Switzerland. E-mail: traudel.saurenmann@kispi.unizh.ch 982 ß The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Anti-TNF treatment for childhood uveitis 983 opinion-based decision of the treating ophthalmologist and rheumatologist in collaboration. It was hospital policy that anti-tnf- therapy was never used as a first-line treatment but would only be started after failure of at least one immunosuppressive drug. Doses routinely used for etanercept treatment were 0.4 0.5 mg/kg administered twice weekly as subcutaneous injections. Infliximab infusions at 3 10 mg/kg were given at weeks 0, 2, 6 and then every 4 8 weeks. Infusions were given in a day therapy unit in hospital. The dose of methotrexate for uveitis treatment was 0.3 0.5 mg/kg either orally or subcutaneously once weekly. On infliximab, the methotrexate dose could be reduced to 0.1 0.3 mg/kg by the same route and frequency. All patients treated with infliximab routinely received prophylactic medication with diphenhydramine (1.25 mg/kg) and acetaminophen (paracetamol; 15 mg/kg) 30 min prior to the start of infliximab infusion. Patients were followed by different ophthalmologists, all with expertise in paediatric uveitis, who used best clinical judgement in reducing medications. We used reduction of concomitant medication to assess the response to treatment as an objective measure because of the possibility of interpreter variability in the assessment of anterior chamber cell count. Decisions to discontinue or reduce systemic immunosuppressive agents were at the discretion of the treating physicians based on clinical assessment for both etanercept and infliximab patients. Immunosuppressive drugs were only discontinued if the uveitis had improved or was quiescent and therefore discontinuation of immunosuppressive agent without flare of uveitis was used as indicative of response to anti-tnf therapy. The study was approved by the Research Ethics Board of The Hospital for Sick Children. Written informed consent and authorization for release of information was obtained from patients who were followed by ophthalmologists outside The Hospital for Sick Children. Outcome definitions Treatment response. A good response was defined as a decrease of 50% in both corticosteroid use and immunosuppressive agent (if on immunosuppressive drug at study entry). A moderate response was a decrease of 50% in either corticosteroid or immunosuppressive agent but not both. A poor response was a decrease of <50% in both corticosteroid and immunosuppressive agent. A decrease in corticosteroid dose was defined as either a decrease in the number of drops per eye or a decreased oral prednisone dose. Visual acuity. Snellen linear letters or appropriate-for-age equivalent were used. Normal acuity was defined as best corrected visual acuity 20/40 or better; impaired acuity was best corrected visual acuity between 20/50 and 20/100; blind was defined as best corrected visual acuity 20/200 or worse. TABLE 1. Patient characteristics These groups were chosen in accordance with the values commonly used for granting a driver s licence (20/40) and for legal blindness (20/200). Worsening visual acuity was defined as a change from one of these categories to a category with less best corrected visual acuity. Improving visual acuity was defined as a change to a better category. Glaucoma. Worsening was defined as the need for an increased number of different anti- medications to control intra-ocular pressure, or the need for surgery. Improved was defined as the ability to reduce the number of different medications without surgery. Statistics Fisher s exact test was used to assess differences in response between the groups. Results For the patients characteristics, see Table 1. All 21 patients had severe disease refractory to at least one standard immunosuppressive agent. In 18/21 patients, severe refractory uveitis was the indication for treatment with TNF- blockers. In the remaining 3/21 patients, TNF- blockers were started because of severe refractory joint disease. All three had persistently active uveitis requiring local steroid drops despite systemic immunosuppressive treatment, and all three had an excellent response of their joint disease to anti-tnf- therapy. Of the 21 patients, 12 had JIA (57%), six had idiopathic uveitis (29%), two had Behc et disease (9%) and one had sarcoidosis (5%) (Table 2). At study entry, 39/42 eyes had active uveitis with normal visual acuity in 23 (59%), impaired visual acuity in four (10%) and legal blindness in 12 (31%). In three patients (14%), legal blindness was bilateral. Ten of the 21 patients (48%), with 19 affected eyes, had normal best corrected visual acuity in both eyes. In 5/12 eyes, the legal blindness was due to cataract, in 4/12 it was due to cystoid macular oedema, in 2/12 it was due to retinal detachment and in one patient the exact reason for blindness caused by the refractory panuveitis was not clearly determinable. In 22 of the 39 eyes with uveitis (56% of eyes, 14 patients), cataract was diagnosed before study entry. In two of the 22 eyes with cataract (one patient), visual acuity was normal despite the cataract. Thirteen eyes (eight patients) had cataract surgery prior to anti-tnf- treatment and in six eyes (five patients) surgery was performed during anti- TNF- treatment. One patient had cataract surgery in one eye performed before and in the other eye during anti-tnf treatment. One patient had one eye cataract extraction performed only after discontinuing unsuccessful etanercept treatment. Indication for anti-tnf therapy Characteristic Uveitis (n ¼ 18) Joints (n ¼ 3) All (n ¼ 21) female patients (percentage) 13 (72%) 3 (100%) 16 (76%) patients with positive ANA (percentage) 13 (72%) 2 (67%) 15 (71%) Mean age at diagnosis of primary disease, yr (range) 6.5 (1.2 15.2) 1.8 (1.6 2.0) 5.9 (1.2 15.2) Mean duration of uveitis before study, yr (range) 4.5 (1.0 11.0) 5.6 (1.4 10.8) 4.6 (1.0 11.0) Mean total number of immunosuppressive drugs before study (range) 2.2 (1 6) 2 (1 3) 2.2 (1 6) Mean number of immunosuppressive drugs used at study entry (range) 1.5 (1 4) 1.3 (0 3) 1.5 (0 4) Mean dose of oral prednisone used at study entry, mg/kg (range) 0.25 (0 1.2) 0.16 (0 0.33) 0.24 (0 1.2) Mean dose of oral prednisone used at end of study, mg/kg (range) 0.04 (0 0.25) 0 0.035 (0 0.25) Mean time to reach moderate or good response, months (range) 3.4 (1 11) 8.2 (1.5 19) 4.2 (1 19) Mean observation time on anti-tnf therapy, yr (range) 1.7 (0.5 3.5) 2.0 (1.8 2.5) 1.75 (0.5 3.5)

984 R. K. Saurenmann et al. Fourteen patients (22/39 eyes, 56%) had at the time of initiation of anti-tnf- treatment, eight of whom (12 eyes) had previous surgery (Table 3). Thirteen of the 21 patients were treated with infliximab (10 as initial therapy and three following etanercept) and 11 with etanercept (all as initial treatment), resulting in 24 treatment courses. In 18/24 treatment courses, additional immunosuppressive drugs (other than local and/or systemic corticosteroids) were continued at study entry (13 methotrexate, three hydroxychloroquine, three azathioprine, one sulphasalazine, one chlorambucil, one intravenous immunoglobulins). In four of the 18 patients, a combination of two or three immunosuppressive drugs was used in addition to the TNF- inhibitor. During the study period, six patients were able to completely discontinue eight additional immunosuppressive agents (two methotrexate, two azathioprine, one chlorambucil, one sulphasalazine, one hydroxychloroquine, one intravenous immunoglobulins). However, two patients required addition of methotrexate after initiation of TNF- inhibitor treatment to control their uveitis. In both, immunosuppressive therapy with methotrexate or sulphasalazine, respectively, had been discontinued at initiation of etanercept treatment. Another patient on etanercept experienced a flare of uveitis after discontinuation of methotrexate during the study and had to restart methotrexate. Methotrexate was used as a concomitant immunosuppressive drug during 7/11 (64%) treatment courses with etanercept and 10/13 (77%) treatment courses with infliximab (P ¼ 0.66). Outcome Primary outcome variable: uveitis response to treatment. The 21 patients (39 involved eyes) accounted for 24 treatment courses for 44 involved eyes (Table 2). Overall, 38% of patients treated with infliximab had a good response, 54% a moderate response and 8% a poor response. By comparison, 27% of patients treated with etanercept had a good response, 27% a moderate response and 45% a poor response (Fig. 1). The three patients who failed etanercept and were then treated with infliximab all had a moderate response to infliximab (mean dose of 5.0 mg/kg with a range of 4.8 5.7 mg/kg). Overall, 18/24 (75%) treatment courses resulted in a moderate or good response. For duration of treatment, see Table 1. The mean duration of anti-tnf- treatment needed to achieve the criterion for a moderate response was 4.2 months (range 1 19 months) for all patients, with 3.4 months for infliximab-treated patients and 5.4 months for etanercept-treated patients. For response rates according to the underlying disease, see Table 2. When the response of patients to therapy was divided into only two categories TABLE 2. Response to treatment according to underlying disease Anti-TNF- agent rather than the initial three [poor vs moderate or good response (moderate/good)], there was a statistically significant difference in the percentage of patients with a moderate/good response to infliximab compared with the percentage of patients with a moderate/good response to etanercept (92 vs 55%; P ¼ 0.0481). Four of the eight patients with a good response (three on infliximab and one on etanercept) and 5/10 patients with a moderate response (three on infliximab and two on etanercept) were able to discontinue systemic corticosteroid treatment. However, only two patients were able to completely discontinue all corticosteroid treatment (topical and systemic): one patient with polyarticular JIA and one patient with severe uveitis and psoriatic arthritis, who had complete remission of psoriasis, arthritis and uveitis. Both patients were maintained on low-dose methotrexate and infliximab. The mean dose of infliximab in the patients who responded was 5.4 mg/kg (range 2.9 10.7 mg/kg). The infusions were given at 4-week intervals in eight patients (62%) and at 8-week intervals in three patients (23%). In two patients (15%), the initial interval of 4 weeks was gradually increased to 6 weeks after improvement of disease. The etanercept dose routinely used was between 0.4 0.5 mg/kg and the dose was increased to 0.8 mg/kg in only one patient (this patient, with severe uveitis, had shown some response to the standard dose of etanercept and had additional improvement when the dose was increased). Three patients experienced a flare of their uveitis after the interval between infliximab infusions was increased from 8 to 12, from 8 to 9 and from 4 to 6 weeks, respectively. This relapse was controlled again in all of them upon return to the previous infusion interval. Secondary outcome variables. Eleven patients (16 eyes) had decreased visual acuity at study entry. Best corrected visual acuity improved in 5/11 patients (7/16 eyes, 43%). Four patients (5/16 eyes, 31%) improved as a result of cataract surgery. In two eyes (two patients, both on infliximab), improvement of visual acuity from 20/400 to 20/70 and from 20/400 to 20/20, respectively, was unrelated to cataract surgery. The difference in improvement of visual acuity between etanercept- and infliximab-treated patients was not statistically significant (P ¼ 0.15). At study entry, best corrected visual acuity was better than legal blindness in 27 eyes (18 patients). Vision decreased in 2/18 patients (2/27 eyes, 7%) from 20/100 to 20/200 and from 20/60 to 20/200 respectively, both on etanercept (13% of etanercept treated eyes) due to uncontrolled inflammation, and remained unchanged in 16 patients (25 eyes) during the study (difference between etanercept and infliximab treated group, P ¼ 0.48). For changes in visual acuity during the study, see Fig. 2. Response Underlying disease Etanercept Infliximab Good Moderate Poor eyes involved JIA subtype Persistent oligoarticular (n ¼ 3) 1 3 0 3 1 6 Extended oligoarticular (n ¼ 2) 1 2 0 1 2 3 Polyarticular, RF-negative (n ¼ 4) 3 1 2 2 0 8 Psoriatic (n ¼ 2) 1 1 1 0 1 3 Enthesitis-related arthritis (n ¼ 1) 0 1 1 0 0 1 Idiopathic uveitis Anterior (n ¼ 3) 1 2 2 1 0 6 Intermediate (n ¼ 1) 1 0 0 0 1 2 Panuveitis (n ¼ 2) 1 1 0 2 0 4 Behc et s (n ¼ 2) 2 1 1 1 1 4 Sarcoidosis (n ¼ 1) 0 1 1 0 0 2 Total (21 patients with 24 treatment courses) 11 13 8 10 6 39 RF, rheumatoid factor.

Anti-TNF treatment for childhood uveitis 985 TABLE 3. Cataract and before and after start of anti-tnf- treatment Before start of treatment with TNF inhibitor After start of treatment with TNF inhibitor medications used surgeries cataract extractions eyes with new cataracts eyes with new medications used surgeries cataract extractions eyes with cataracts eyes with Underlying disease JIA (21 eyes) 8 7 3 4 13 4 3 2 0 11 Idiopathic uveitis (12 eyes) 8 9 5 10 7 0 2 2 1 11 Behcet s disease/sarcoidosis (6 eyes) 6 6 4 12 12 0 0 2 13 2 Total (39 eyes) 22 22 12 26 32 4 5 6 14 24 Time to complication, yr (range) 1.1 (0.3 2.0) 1.22 (0.3 2.9) 0.77 (0.1 1.7) 0.59 (0.1 1.6) In 14/21 patients (22/39 eyes), cataracts were diagnosed before anti-tnf- treatment. New cataracts were diagnosed in 4/7 of the remaining patients (5/17 eyes, 29%) during the study. Two patients (three eyes) were on etanercept and two patients (two eyes) were on infliximab. However, these newly diagnosed cataracts did not affect visual acuity and did not lead to cataract surgery during the study period. Pre-existing improved in 4/22 eyes (18%) of 4/14 patients during the study: three on infliximab and one on etanercept (difference between etanercept- and infliximab-treated groups, P ¼ 0.61). In three of these eyes, all medications were stopped without the requirement for surgery (one etanercept, two infliximab). One patient on infliximab required surgery in one eye; in the other eye improved without surgery. New-onset during anti-tnf- treatment was diagnosed in two patients (4/17 eyes, 24%), both on etanercept, despite a moderate response of the uveitis to this treatment. Pre-existing worsened in 7/22 eyes (32%) of five patients: two treated with etanercept, two treated with infliximab and one treated with both etanercept and infliximab consecutively, of which five eyes (four patients) required surgery (Fig. 3). Overall, we observed new-onset or worsening in 7/20 (35%) eyes in the etanercept-treated group and 4/24 (17%) eyes in the infliximab-treated group (difference between etanercept and infliximab treated group, P ¼ 0.29) Five patients (six eyes) had cataract surgery during the course of the study. In four of the five patients, the extraction of a cataract which was present before initiation of anti-tnf- treatment was only possible because the previously heavy inflammation was well controlled. In four patients (five eyes), surgery (total, 14 procedures) was performed during the study period. One patient had both cataract surgery (two eyes) and surgery (seven surgeries) after initiation of anti-tnf- treatment. Adverse reactions One of the 21 patients (5%) had an infection (cellulitis of the forearm) requiring hospitalization and intravenous antibiotic treatment. Etanercept was temporarily withheld. No other adverse reactions were seen in any of the remaining 20 patients, including infusion reactions, infections requiring hospitalization or any new-onset autoimmune disease. We did not measure the financial or psychosocial impact of the all day visits to the hospital for infliximab infusion vs the home injections of etanercept. Discussion Non-infectious uveitis in childhood can be either idiopathic or associated with a systemic autoimmune disease. Although many patients respond to topical therapy, recalcitrant uveitis leads to significant ocular morbidity despite topical and systemic therapy with immunosuppressive agents and corticosteroids. In this study, we have shown that the majority of patients (86%) with active, recalcitrant uveitis had a favourable response to treatment with TNF- inhibitors after failing other immunosuppressive agents. The response to anti-tnf- therapy was independent of the underlying cause of the uveitis. Although the majority of patients responded to therapy, we found a statistically significant difference in the response rate between etanercept- and infliximab-treated patients, favouring infliximab. There was a trend for fewer complications and higher rate of improvement of both and visual acuity in the infliximab-treated group compared with the etanercept-treated group. Interestingly, we also found that three patients responded to infliximab following failure of etanercept. The one patient with a poor response to infliximab did not have a trial on etanercept.

986 R. K. Saurenmann et al. 60 50 Percent of patients 40 30 20 10 0 Etanercept (n=11) Infliximab (n=13) FIG. 1. Response to anti-tnf- therapy in patients with active uveitis. Treatment is shown on the horizontal axis and the percentage of patients who responded on the vertical axis. A good response is shown by the medium grey box, a moderate response by the dark box and poor response by light grey box. Visual acuity 0.5 1 0.1 0.01 At start of anti-tnfa treatment Last value during anti-tnfa treatment FIG. 2. Changes in visual acuity during the study in nine eyes of seven patients. Patients treated with etanercept are shown with triangles and dotted lines and patients treated with infliximab are shown with squares and bold lines. An open triangle or square indicates cataract surgery during study. Snellen chart values for visual acuity are transformed into a single number dividing the numerator by the denominator. A differential response to etanercept and infliximab therapy has been reported in studies of patients with Crohn s disease, but not in patients with inflammatory arthritis [18, 23, 24]. Although all TNF- inhibitors work by binding to and inhibiting the effect of TNF-, they are usually divided into two groups: monoclonal antibodies and soluble receptors. It has been hypothesized that the beneficial effect of infliximab in Crohn s disease is the result of apoptosis of monocytes and/or T lymphocytes [25, 26]. However, the effect of etanercept on colonic T lymphocytes has not been studied. In addition, if infliximab is superior to etanercept in causing apoptosis of monocytes, it is not clear why this should be important in Crohn s disease and not in inflammatory arthritis. TNF- has been demonstrated to play an important role in the development of uveitis [27, 28]. However, it may also have a protective effect in some situations [29]. To date, there have been only two prospective studies of anti-tnf- therapy, both using etanercept, in children with uveitis [19, 30]. The two trials, one controlled and one uncontrolled, showed similar response rates of 57 and 50%, respectively. However, the rate of response to therapy in the controlled trial was not statistically significant different from that in the control group. Despite the different methods we used

Anti-TNF treatment for childhood uveitis 987 40 35 30 Percent of eyes 25 20 15 10 5 0 for assessing improvement, our etanercept response rate (54%) is consistent with the previous studies. In our study, we found that the response to anti-tnf- was independent of the underlying disease as 12 patients had JIA, six had idiopathic uveitis, two had Behc et disease and one had sarcoidosis. These results are similar to the results of the open-label trial in which patients with idiopathic uveitis and uveitis secondary to JIA were studied [19]. All patients in the placebo-controlled trial had JIA [30]. Systemic corticosteroid treatment was discontinued in 9/16 of our patients after the start of TNF- blocker therapy (six on infliximab, three on etanercept). This effect was also described in 5/6 patients in the study of Richards et al. [34], whereas only one patient in Reiff s group [19] and four patients in Smith s study [30] had systemic corticosteroids at study entry and any further systemic corticosteroid requirement of these patients was not described. Treatment with TNF- blockers allowed the discontinuation of concomitant immunosuppressive medication in 6/18 patients in our study, an effect that was also observed in 3/6 patients in Richards study with infliximab. However, in three of our patients etanercept alone was not able to control uveitis. This finding is in accordance with results published by Foster et al. regarding the efficacy of etanercept to maintain uveitis remission achieved with methotrexate [31]. Case reports and small series exist describing infliximab in the treatment of children with uveitis also show a positive effect [32 34]. For adult patients, striking improvement of both inflammation and best corrected visual acuity with infliximab have been reported for the treatment of uveitis related to a variety of underlying diseases, most of them for Behc et disease and for HLA B27-related uveitis [35 37]. No direct comparison of the two most commonly used anti- TNF- agents, etanercept and infliximab, for the treatment of uveitis have been previously performed to our knowledge. We observed changes in visual acuity unrelated to cataract surgery in four patients, with improvement in two eyes on infliximab and worsening in two eyes on etanercept. Previous paediatric studies have reported both improvement and worsening of visual acuity [19, 30]. In a recently published prospective trial of infliximab in refractory uveitis of 23 patients, one of them a child with idiopathic uveitis, Suhler et al. [37] also described Cataract Glaucoma Decreased visual acuity FIG. 3. New complications encountered during anti-tnf- therapy. Individual complications are shown on the horizontal axis and the percentage of eyes with the complication is shown on the vertical axis. Eyes treated with etanercept (n ¼ 20) are shown in the light boxes and the eyes treated with infliximab (n ¼ 24) in the dark boxes. Visual acuity refers to best corrected visual acuity. improvement of visual acuity in 10/44 eyes, whereas worsening visual acuity occurred in both eyes of one patient experiencing a uveitis flare after 8 weeks of treatment with infliximab. In a group of adult patients, resolution of cystoid macular oedema has been described during treatment with infliximab; however, a similar response to treatment with etanercept has not been looked for to our knowledge [38]. Although macular thickness was not measured routinely in our patients, this effect might be a possible explanation for improvement of VA in our infliximab treated patients. In neither of the two prospective studies were new-onset cataracts observed, a complication we observed in 5/17 eyes without prior cataract. However, previous work has shown that development of cataract in patients with paediatric uveitis is strongly correlated with the duration of uveitis [39]. Our patients had a mean duration of uveitis of 4.6 yr at study entry and a mean observation time on TNF- inhibitor treatment of 1.75 yr, whereas both the mean disease duration and follow-up duration were shorter in the previous paediatric studies [19, 30]. The mean duration from the start of anti-tnf- treatment to the diagnosis of new-onset cataract in our patients was 1.2 yr. Therefore, the difference in observation time on anti-tnf- treatment might be one possible explanation for this previously undescribed complication. However, very little is known about the role of TNF- in the development of cataract, and therefore careful long-term monitoring is required to determine the role of anti-tnf- therapy in cataract formation. Glaucoma is a common complication in children with chronic uveitis. Treatment consists of topical anti- agents with oral carbonic anhydrase inhibitors and/or surgery for more severe cases [40]. Goniotomy provides good results in children with sight-threatening related to uveitis, but in most cases topical therapy still has to be continued [41]. An unexpected finding in our study was an improvement of without surgery in four patients. Both drugs were associated with this outcome. However, two patients had new-onset (both on etanercept) despite the improvement of uveitis, and five patients (two each on etanercept and on infliximab and one on both etanercept and infliximab consecutively) had worsening despite a moderate to good response for their uveitis.

988 R. K. Saurenmann et al. In Richards study of six patients with JIA-associated uveitis treated with infliximab, improvement of without surgery was observed in 2/6 patients [34]. Reiff and co-workers did not observe changes in intraocular pressure during their prospective open-label study with etanercept [19], and in the masked placebo-controlled study of Smith [30] and co-workers intraocular pressure was not one of the outcome variables. Like cataract, development of is correlated with duration of uveitis and therefore also for this complication the longer overall disease duration of our patients may have played a role [39]. The role of TNF- in the development of is not clear and our results, showing both improvement and worsening of, do not allow any insight into the role of TNF- in the development of. Our study is limited by a small sample size, retrospective data and heterogeneity of the underlying diseases and patients. Furthermore, we did not control for any difference in concomitant use of immunosuppressive agents other than methotrexate between the two groups. Patients treated with infliximab were allowed to increase the dose while patients on etanercept did not have a similar dose escalation. Yet, to our knowledge, this is the largest number of patients with refractory childhood uveitis treated with TNF- inhibitors reported and the only study that has compared the effect of the two TNF- inhibitors currently available for treatment in children. In conclusion, treatment for recalcitrant uveitis with anti- TNF- medications was associated with a favourable response in the majority of cases. Our results suggest that infliximab is superior to etanercept not only by decreasing the number of concomitant medications required to control the uveitis but also due to a lower rate of new-onset and cataract. Both medications had excellent short-term side-effect profiles. We suggest that a large, prospective, multicentre, interdisciplinary (rheumatology and ophthalmology) controlled study be conducted to confirm our findings. Rheumatology Key messages Anti-TNF- treatment was beneficial in a high percentage of patients with severe refractory childhood uveitis. Infliximab resulted in better clinical responses than etanercept. Treatment with infliximab seemed to lead to less ocular complications Acknowledgements This work would not have been possible without the contributions of the involved ophthalmologists throughout Ontario and the contribution of the Rheumatology Volunteers of The Hospital for Sick Children (HSC). We wish to thank Dr L. Spiegel and Dr B. Cameron, Division of Rheumatology, HSC, for their support and contribution, Dr D. Derzko-Dzulynski, Dr A. Budning and Dr Amy for sharing their patients ophthalmology records, and Clinical Coordinator Katarzyna Gogol and Research Assistants Enza Perruzza and Erica Bell from the Department of Ophthalmology and Vision Sciences for their support. Grant support was received from the Swiss Arthritis Society (Schweizerische Rheumaliga), Stiftung Sanitas (Switzerland) and Brandan s Eye Research Fund. R.K.S. has served as a paid consultant for Centocor. The other authors have declared no conflicts of interest. References 1. Edelsten C, Reddy MA, Stanford MR, Graham EM. Visual loss associated with pediatric uveitis in English primary and referral centers. Am J Ophthalmol 2003;135:676 80. 2. Paivonsalo-Hietanen T, Tuominen J, Saari KM. Uveitis in children: population-based study in Finland. Acta Ophthalmol Scand 2000; 78:84 8. 3. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California: the Northern California Epidemiology of Uveitis Study. Ophthalmology 2004;111:491 500. 4. 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