Etanercept and uveitis in patients with juvenile idiopathic arthritis
H. Schmeling and
G. Horneff
Department of Paediatrics, Martin Luther University, Halle-Wittenberg, Halle, Germany.
Correspondence to: H. Schmeling, Department of Paediatrics, Martin-Luther University, Halle-Wittenberg, D-06097 Halle, Germany. E-mail: heinrike.schmeling{at}medizin.uni-halle.de
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Abstract
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Objectives. Etanercept has been shown to be effective for the treatment of juvenile idiopathic arthritis (JIA). The therapeutic efficacy of etanercept for chronic uveitis, a major complication of JIA, has not been evaluated so far. Therefore, the appearance of chronic anterior uveitis and associated complications in JIA patients treated with etanercept was evaluated.
Methods. Questionnaires were sent to paediatric rheumatologists treating a total of 310 JIA patients with etanercept.
Results. Two hundred and twenty-nine questionnaires (74%) were returned. Before institution of etanercept, 31 patients (13.5%) had a history of uveitis with a total of 102 flares. Twenty-eight patients belonged to the high-risk groups of the oligoarticular and seronegative polyarticular subtypes. Upon commencing etanercept, 32 courses of uveitis occurred in 19 patients and in two further patients (1%) in whom uveitis occurred for the first time. Twenty of them belonged to the high-risk group. Uveitis during etanercept therapy occurred in 12 of 15 patients (80%) with more than one course of uveitis, and in seven of 16 patients (44%) with only one course before etanercept therapy. Complications were noted in 12 patients before and in eight during etanercept treatment. In 87% of the uveitis patients, arthritis demonstrated a significant or complete response.
Conclusion. During treatment with etanercept, there were both relapses and first courses of uveitis. In addition, the frequency and severity of uveitis seemed not to be influenced by etanercept. In particular, patients with relapsing uveitis before institution of etanercept treatment remain at high risk of the development of uveitis flares despite etanercept treatment.
KEY WORDS: Uveitis, Etanercept, Juvenile idiopathic arthritis
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Introduction
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Juvenile idiopathic arthritis (JIA) is the most common systemic and chronic autoimmune disease occurring in childhood, with an incidence of 1020 per 100 000 children below the age of 16 yr. Chronic uveitis occurs in up to 30% of children with chronic arthritis, particularly in those with oligoarticular or seronegative polyarticular JIA, and can result in severe sequelae if not detected early and treated appropriately. Further factors found to predispose to ocular inflammation include an age below 7 yr at onset of arthritis, female gender and ANA test positivity. Uveitis probably never occurs in children with systemic arthritis, and it is very rare in those with RF-positive polyarthritis [1]. Although both joints and uvea can be inflamed in several diseases, the pathogenic relationship between these two seemingly disparate entities has not been established. Of interest, inflammatory cell infiltration of the iris, ciliary body and anterior chamber is observed at a high frequency in the adjuvant model of arthritis in Lewis rats.
Treating chronic uveitis is one of the major challenges for paediatric rheumatologists and ophthalmologists. Although topical corticosteroids are the mainstay of initial therapy, response is insufficient in 36% of patients [2]. With the addition of systemic corticosteroids, uveitis remained uncontrolled in about 30% of children [3]. Immunosuppressants are frequently used in the remainder. Unfortunately, experience to date is limited to smaller case studies [4, 5]. Tumour necrosis factor
(TNF-
), an inflammatory cytokine, has been implicated in the pathogenesis of various forms of uveitis and has been studied extensively in several animal models. Etanercept, a TNF receptor blocker, has proven efficacious for joint inflammation in children with polyarticular JIA [6]. Although this agent may offer benefit to children with ocular inflammation, evidence in support of the approach is meagre.
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Patients and treatment
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The occurrence of chronic uveitis, as diagnosed by an ophthalmologist, and the numbers of flares and ocular complications were recorded using a standardized anonymized questionnaire sent to contributors at 38 paediatric rheumatology departments in Germany. Written informed consent was obtained from all patients and parents from whom data were collected. Uveitis was diagnosed by slit-lamp biomicroscopy in local ophthalmology departments. Since this was a retrospective study, it was not possible to grade the severity of uveitis. Giannini's criteria were used to define joint disease improvement [7].
The ethics committee of the Martin-Luther University of Halle-Wittenberg approved the clinical study.
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Results
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The questionnaire was returned from 229 JIA patients (74%). There were 25 centres reporting all their patients, 11 centres which did not answer, and only two centres where not all JIA patients treated with etanercept were reported. Forty-three (19%) of patients belonged to the systemic onset subset, 65 (29%) to the seronegative polyarticular onset subset, 27 (12%) to the seropositive polyarticular onset subset, eight (3%) to the persistent oligoarticular disease subset, 38 (16%) to the extended oligoarticular disease subset, 27 (12%) to the enthesitis and arthritis subset, and nine (4%) to the psoriasis and arthritis subset; 12 (5%) had unclassified arthritis. ANA and HLAB27 were present in 39 and 28%, respectively, of the entire patient group.
Thirty-three patients (22 girls and 11 boys) had uveitis (Table 1). At the time of writing, the mean age (±S.D.) was 13.5±3.8 yr (range 621 yr). The mean age at disease onset was 4.8±4.1 yr (range 115 yr). The mean disease duration at the start of etanercept therapy was 6.9±3.2 yr (range 112 yr). The reason for initiating etanercept therapy in all patients was active, non-remittent articular disease refractory to multiple treatment regimens. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg twice weekly, as recommended. Thirty patients received concomitant DMARD therapy [methotrexate (n = 23), cyclosporin A (n = 6), azathioprine (n = 6), sulphasalazine (n = 2)]. Sixty-seven per cent of the patients received oral corticosteroids and 94% non-steroidal anti-inflammatory drugs.
Thirty-one patients had a history of uveitis before institution of etanercept. Uveitis was diagnosed in two patients before arthritis occurred and at the same time in three patients. In three patients, the age at the first course of uveitis was unknown. Thirteen of 25 patients who first were diagnosed as having JIA developed uveitis during the first 2 yr of the disease and the remainder thereafter. A total of 102 flares of uveitis in 229 patient years were noted before treatment. Twenty-two patients (71%) belonged to the oligoarticular onset subtype and seven patients (23%) to the seronegative polyarticular onset subtype, who were at high risk of chronic uveitis. ANA and HLAB27 were present in 20 (60%) and 10 (30%) of the patients (Table 1). Only one of the HLAB27-positive patients with oligoarticular onset (n = 8) had had enthesitis and was classified as having enthesitis-related arthritis. In the remainder, there was no family history of HLAB27-related disease. However, one patient (patient 23) had been adopted.
After commencing treatment, 29 relapses of uveitis occurred in 19 of 31 patients during a period of 54 patient years. In a further two patients, uveitis occurred for the first time upon treatment with etanercept. Five flares occurred during the first 3 months of etanercept therapy, 1 during months 46, 6 between months 7 and 12, and seven thereafter. All but one of the patients with enthesitis-related arthritis of these 21 patients exhibited the oligoarticular or seronegative polyarticular onset subtype. Uveitis during etanercept therapy occurred in 12 of 15 patients, who had multiple relapses prior to etanercept therapy. In 12 patients, uveitis did not recur during etanercept treatment. In the total group of 33 patients, there were 0.45 courses of uveitis per patient year before and 0.57 courses during etanercept therapy. The frequency of uveitis flares seemed to be slightly higher during etanercept therapy than during the pretreatment period but the difference did not reach significance (Fig. 1).

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FIG. 1. The number of uveitis flares before and during etanercept therapy in 33 patients. Before institution of etanercept, 102 flares of uveitis occurred during a total of 229 patient years, with a mean frequency of 0.45 events/yr (median 0.3). During etanercept, 32 flares occurred in 21 of 33 patients in a total of 56 patient years. In 12 patients, uveitis did not flare. The mean frequency increased to 0.57 events/yr (median 0.4).
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Complications were noted in 12 patients before and in eight patients during etanercept therapy (Table 2). There was no patient with blindness due to rapid uveitis progression during etanercept therapy. Treatment with etanercept was discontinued in five patients, as decided by their responsible physician. Reasons were uveitis in two patients, oesophagitis in one patient and ongoing articular disease in two patients. A cataract was noted in a total of 11 patients, six of whom were treated with corticosteroids in the long term.
Eighty-seven per cent of the patients with uveitis flares demonstrated a significant or complete response of articular symptoms according to the ACR criteria for juvenile rheumatoid arthritis (JRA), with a decrease of at least 30% in at least three of six response criteria and more than 30% worsening of no more than one of the six criteria [7]. The degree of response was not different from that of patients whose data were collected in the German JIA etanercept registry who were not suffering from chronic uveitis. Thirty patients reached a maximal response level of 30%, 28 patients reached a 50% level and 23 patients a 70% response level. Treatment was not efficient in only two patients.
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Discussion
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Chronic uveitis frequently occurs in JIA patients with an uncertain long-term prognosis. Remission was seen in 43% of 150 patients followed for an average of 4 yr, but complications occurred in 21% [8]. In a study of 49 JIA patients with uveitis in 1994, loss of vision was seen in 15% and blindness occurred in 10% [9]. But perhaps with newer medication and early recognition these numbers are lower nowadays.
Etanercept has been shown to be effective for the treatment of articular symptoms [6, 10]. The therapeutic efficacy of etanercept for chronic uveitis has been evaluated in case series only. In 10 of 16 inflamed eyes of 10 patients, there was some reduction of inflammation, including remission in four eyes [11]. No significant efficacy above placebo was shown in a randomized, double-blind, placebo-controlled trial using etanercept for treatment of chronic or recurrent uveitis [12].
In a further study, only six of 16 patients with ocular inflammation (38%) who were treated with etanercept or infliximab experienced improvement of their eye disease, while their joint disease responded excellently [13]. Five patients (31%) developed inflammatory eye disease for the first time upon treatment, three of 14 eyes achieved remission, five remained unchanged and one eye worsened.
In our patients, relapses of uveitis occurred in 19 of 31 patients (61%) upon commencing treatment with etanercept. Especially patients with relapsing uveitis before institution of etanercept treatment were at high risk of the development of uveitis flares on etanercept treatment (80%). In addition, two patients suffered from uveitis for the first time while being treated with etanercept. There was no difference in the uveitis flare rate per year before compared with during etanercept. Although ophthalmologists had diagnosed uveitis, it was recorded retrospectively. This limitation of the study did not allow evaluation of the severity of uveitis flares. The occurrence of complications before and upon commencing etanercept, however, seemed to be equal (Table 1).
Interestingly, and in keeping with the current literature, there was a relatively high rate of clinical benefit for joint disease among those patients with co-existing inflammatory arthritis having this treatment [10]. The finding of differential efficacy of TNF inhibition in treating inflammatory eye disease and associated rheumatic disease suggests differences in the pathogenic mechanism of ocular inflammation compared with related joint inflammation.
Further, there are indications that, at least in some subjects, there is the potential that certain immunomodulatory therapies could induce or aggravate the expression of uveitis. The use of TNF-
-inhibiting agents has been associated with the first appearance of uveitis in both experimental animals and human subjects, suggesting that inhibition of TNF-
might contribute to the induction or exacerbating uveitis in certain circumstances [1417].
The only way to determine the efficacy of etanercept in the uveitis of JIA would be to have either a double-blind, placebo-controlled study in two groups of patients matched for age and disease duration/severity, or a matched cohort of patients with similar age, sex, disease duration and medication who did not receive etanercept.
For patients with well-controlled articular disease, the minimum recommendation should be ophthalmology screening.
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Acknowledgments
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The authors thank the following contributors for answering the questionnaire: T. Biedermann, J. Brunner, I. Fedderson, I. Foeldvari, D. Föll, G. Ganser, H. Girschick, G. Heubner, T. Hospach, S. Kastner, R. Keitzer, M. Kirschstein, R. Küster, H. Michels, D. Möbius, S. Müller, T. Niehues, J. Quietzsch, B. Rogalski, M. Sailer-Höck, O. Schofer, A. Thon, A. Urban, K. Vocke and E. Weissbarth-Riedel.
G.H. is a member of the advisory board of Enbrel in Rheumatology in Germany. H.S. has declared no conflicts of interest.
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References
|
---|
- Petty RE, Smith JR, Rosenbaum JT. Arthritis and uveitis in children. A pediatric rheumatology perspective. [Review]. Am J Ophthalmol 2003;135:87984.[CrossRef][ISI][Medline]
- Chylack LT Jr. The ocular manifestations of juvenile rheumatoid arthritis. Arthritis Rheum 1977;20(2 Suppl.):21723.
- Nguyen QD, Foster CS. Saving the vision of children with juvenile rheumatoid arthritis-associated uveitis. JAMA 1998;280:11334.[Free Full Text]
- Weiss AH, Wallace CA, Sherry DD. Methotrexate for resistant chronic uveitis in children with juvenile rheumatoid arthritis. J Pediatr 1998;133:2668.[ISI][Medline]
- Kilmartin DJ, Forrester JV, Dick AD. Cyclosporin A therapy in refractory non-infectious childhood uveitis. Br J Ophthalmol 1998;82:73742.[Abstract/Free Full Text]
- Lovell DJ, Giannini EH, Reiff A et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000;342:7639.[Abstract/Free Full Text]
- Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:12029.[ISI][Medline]
- Edelsten C, Lee V, Bentley CR, Kanski JJ, Graham EM. An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis associated uveitis and other chronic anterior uveitis in early childhood. Br J Ophthalmol 2002;86:516.[Abstract/Free Full Text]
- Cabral DA, Petty RE, Malleson PN, Ensworth S, McCormick AQ, Shroeder ML. Visual prognosis in children with chronic anterior uveitis and arthritis. J Rheumatol 1994;21:23705.[ISI][Medline]
- Horneff G, Schmeling H, Biedermann T et al. The German Etanercept Registry for Treatment of Juvenile Idiopathic Arthritis (JIA). Ann Rheum Dis 2004;63:163844.[Abstract/Free Full Text]
- Reiff A, Takei S, Sadeghi S et al. Etanercept therapy in children with treatment-resistant uveitis. Arthritis Rheum 2001;44:14115.[CrossRef][ISI][Medline]
- Foster CS, Tufail F, Waheed NK et al. Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. Arch Ophthalmol 2003;121:43740.[Abstract/Free Full Text]
- Smith JR, Levinson RD, Holland GN et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001;45:2527.[CrossRef][Medline]
- Kasner L, Chan CC, Whitcup SM, Gery I. The paradoxical effect of tumor necrosis factor alpha (TNF-alpha) in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 1993;34:29117.[Abstract]
- Reddy AR, Backhouse OC. Does etanercept induce uveitis? Br J Ophthalmol 2003;87:925.[Free Full Text]
- Rosenbaum JT, Han YB, Park JM, Kennedy M, Planck SR. Tumor necrosis factor-alpha is not essential in endotoxin induced eye inflammation: studies in cytokine receptor deficient mice. J Rheumatol 1998;25:240816.[ISI][Medline]
- Smith JR, Hart PH, Standfield SD, Coster DJ, Wing SJ, Williams KA. Apoptosis is a prominent feature of acute anterior uveitis in the Fischer 344 rat. Br J Ophthalmol 2000;84:20511.[Abstract/Free Full Text]
Submitted 9 September 2004;
revised version accepted 18 March 2005.