MATERIALS AND METHODS

Study design

The patients all attended the screening programmes of the clinical research centre rheumatology department, Northwick Park Hospital (now transferred to Great Ormond Street Hospital, London) and Wexham Park Hospital, Slough. All patients had chronic painless anterior uveitis. Screening for uveitis in those with suspected JIA was performed according to a standard protocol.³ Some patients with chronic painless anterior uveitis first presented with painful red eyes when severe inflammation was untreated. No patient developed pain or redness with each relapse or episode of increased disease activity.

We included patients who first attended after January 1982 and who had ophthalmic records from the onset of uveitis. Patient factors recorded included sex, race, year seen (pre/post 1990), age at joint disease and uveitis onset, the gap to the first slit lamp examination, antinuclear antibody (ANA) status, past ocular and medical history, length of follow up, regularity of attendance, and any ophthalmic treatment outside our unit. Disease factors recorded included laterality, uveitis severity at onset, the total duration of the uveitis, best corrected visual acuities at onset and at the last visit, and any ocular co-morbidities. JIA type at onset and current disease were reviewed by a rheumatologist to ensure a consistent and contemporary joint diagnosis. Therapeutic measures noted included the duration and the type of treatment, the use of systemic immunosuppression, ocular hypertensive medication, the timing and type of ocular surgery. The JIA diagnosis subtypes were established according to the ILAR Task Force classification.¹⁰ Severe uveitis at onset was defined as the presence of synechiae. The year of presentation was noted as an indicator of consistency of clinical practice and referral patterns over the period of the study. 1990 was the median year of presentation in this group of patients. There were two comprehensive searches of the outpatient database in 1990 and 1998. Patients developing uveitis before 1990 were more likely to have been lost to this method of case retrieval. The British paediatric rheumatology database started in 1986 and cases before this date are likely to be biased towards more severe and prolonged disease.

Patients with chronic anterior uveitis may develop many complications over many years. Some complications such as amblyopia and retinal detachment only occur in association with and subsequent to other complications. Some complications such as posterior synechiae or band keratopathy are not necessarily visually disabling. We chose end points that were both frequent and primary—both cataracts and ocular hypertension are usually the first complications in those that subsequently develop visual loss. The first end points were an intraocular pressure above 21 mm Hg given treatment, the development of visually significant cataract requiring surgery, and any visual loss reducing best corrected Snellen visual acuity to 6/24 or less, or any combination of the three. The second end point was disease remission defined as a period of inactive uveitis, lasting a minimum of 6 months, off all topical and systemic treatment. We present the rates of complications and remission overall. The subgroup of patients treated from the onset of disease in our institute, and who were compliant with treatment, were designated the standard cohort. The majority of patients were originally referred for assessment of their arthritis and automatically undergo ophthalmological screening. A minority of patients are referred for ophthalmological assessment alone or for severe arthritis or other systemic inflammatory disease. In order to assess the effect of patient recruitment resulting from these variations in referral source and initial presentation, the following were excluded from the standard cohort: those undergoing uveitis treatment outside our unit for at least 6 months at the onset of disease; those known to have poor compliance with treatment; those with systemic disease other than JIA; JIA patients who first presented with uveitis rather than arthritis. These were designated the non-standard cohort.

Patient treatment and follow up

The treatment of all patients was with topical dexamethasone 0.1%, doses ranging from twice a week to hourly. Patients received cyclopentolate 1% at night when the disease was sufficiently active that they were at risk of synechiae. The dose of steroid was titrated against the number of anterior chamber cells as determined by slit lamp examination and the patients were reviewed at 4–8 weekly intervals during periods of active disease. Occasionally, subconjunctival injections of triamcinolone were given under general anaesthesia if topical steroids fail to provide adequate disease control. Systemic treatment was rarely given for eye disease alone during the greater part of the period examined, but the majority of patients required such treatment for their arthritis. This consisted mainly of non-steroidal anti-inflammatory drugs, with methotrexate as a second line immunosuppressant. The majority of patients were given weekly low dose oral methotrexate according to standard protocols of trials and were in the range of 10–20 mg/m². In patients with poorly controlled uveitis or arthritis, doses of up to 40 mg/m² were given. Some patients were given other immunosuppressants in the earlier part of the study period.

Statistical analysis

All time variables are given as median and range. Significant differences between patient groups were initially tested by χ² (for the non-continuous variables) or Kruskal-Wallis tests. Significant factors were entered into a multivariate Cox proportional hazard model.

RESULTS

Demographic variables

There were 163 (275 eyes) patients in the study with 123 and 40 patients in the standard and non-standard cohorts respectively. Some patients had multiple reasons for inclusion in the non-standard cohort. There were 21 initially treated elsewhere and two who were non-compliant with treatment for extended periods. Ten patients developed uveitis before arthritis or had idiopathic uveitis, seven patients had systemic disease other than JIA including three with psoriatic arthritis, one with sarcoidosis, one with Reiter's disease, and one with ulcerative colitis.

The median follow up was 4 years. Twenty five per cent (40) were male and 12% (20) were non-white; 129 (79%) patients were seen after 1990 and 124 (124/155, 80%) were ANA positive. Fifty one patients (31%) had unilateral disease and 76 (76/161, 47%) had uveitis at their first slit lamp examination. Thirty patients (18%) received methotrexate during the course of their disease and 26 (16%) had severe uveitis at presentation. Twelve patients had other immunosuppressants including 10 with oral prednisolone, three with gold injections, three with penicillamine, and three with hydroxychloroquine. The median age of arthritis onset was 28 (2–140) months and the median age of uveitis at 50 (4–149) months and a median gap of 13 (0–128) months. In 15 patients (five with and 10 without complications) the records of the original visit were lost and the severity of disease presentation was unknown. The demography for the standard/non-standard cohorts and patients with and without complications are given in Table 1.

Factors associated with complications

Thirty four (21%) patients developed complications. Complications were significantly more common in the non-standard cohort (47% v 12%) (Fig 1), those with uveitis found at their initial visit (28% v 14%), and those with severe disease at presentation (65% v 10%) (Fig 2). Complications were less common in those with oligoarticular JIA (18%) compared with other diagnoses (39%). Those with complications were older at the onset of arthritis (49 months v 36 months, p = 0.024) but there was no significant difference in the age at onset of their uveitis. There was no significant association with race, sex, date of onset, use of systemic immunosuppression, ANA status, or whether disease involved one or both eyes (Table 2).

The only significant variables on multivariate analysis were severity of disease onset—relative risk (RR 6.60 (2.51–17.4), p = 0.001), and membership of the standard cohort (RR 0.40 (0.15–1.07), p = 0.068) (Table 3). The majority of complications in those presenting with severe disease developed within the first 18 months. Complications in those with mild onset disease developed at a constant rate over the first 9 years (Fig 2). The actual complication rate in the standard cohort was 12% (13/110) and 47% (18/38) in the non-standard cohort (Fig 1). The individual end points of poor vision, cataract extraction, and glaucoma were all associated with severe uveitis at onset and membership of the non-standard cohort (all p<0.001).

Subgroup analysis of the standard cohort confirmed that uveitis severity at onset was the most significant independent risk factor for the development of complications (RR 16.2 (4.3–61.0), p = 0.001). Male sex was also found to be independently associated with a higher complication rate (RR 4.3 (1.1–16.6), p = 0.032), and the rate appeared to be higher in the first 4 years when compared with females (Fig 3). After 8 years the complication rate was 38.4% for males and 9.7% for females. There was no association of complications with sex in the non-standard cohort.

Associations with disease remission

Factors significantly associated with disease remission on univariate analysis were similar to those associated with lack of complications (Table 2). Multivariate analysis (Table 3) found that mild onset, a long interval between the onset of arthritis and uveitis, and white race were independent predictors of remission. In the standard cohort mild onset and female sex were independent predictors of remission (Fig 4).

Frequency of complications and remission in the standard cohort

The group with the highest rate of complications and lowest rate of remission were those with severe onset in the standard cohort (71% and 0%). Females in the standard cohort had the most benign disease with 5% complication rate and 54% remission rate (Table 4).

Rates of blindness

The overall rate of severe visual loss (<6/60) was 6% (17/275 eyes), and in the standard cohort 8/203 (4%) suffered severe visual loss. The overall rate of moderate or severe visual loss was 30/275 (11%) and 13/203 (6%) in the standard cohort.

DISCUSSION

JIA associated uveitis is the most common cause of chronic anterior uveitis in childhood and is associated with significant ocular morbidity (Tables 5 and 6). Screening in JIA uveitis appears to be successful in decreasing prevalence and the rate of blindness in one population based study.¹ However, a subset of patients still progress onto severe disease and complications. Their identification is necessary in order to plan effective methods of reducing visual loss. There is a wide range of visual loss reported even in the last decade (Table 6) from 0¹¹ to 25%⁷ and this reflects the importance of accounting for varying follow up and referral patterns when assessing temporal changes in disease severity. In Table 6 blindness rates do show a decline but the exact reasons for this are not clear as screening, surgical technique, and referral patterns have changed over this period.

Kanski¹² estimated 25% of the JCA uveitis population to have severe disease and found those presenting with uveitis to have a particularly poor outcome. These patients range from 7%⁶ to 31%¹³ of the published cohorts. Both authors found a poor visual outcome with the latter noting 66% rate of visual loss in this subgroup. Wolf et al⁵ found that the degree of final visual loss correlated well with the degree of visual loss at onset and the risk of ocular complications correlated well with the severity of inflammation observed at the initial examination. Chalom et al¹⁴ found, as we did, that there was an increased complication rate in uveitis associated with a short gap between the joint and eye disease onset and that uveitis developing after a long gap from the onset of arthritis had a more benign outcome.

In this study we have confirmed that severe disease at presentation is a major factor in determining the outcome of uveitis. We have also examined the influence of referral patterns and modes of presentation and demonstrated the large effect that patient selection and length of follow up has on the reported outcomes of this condition. A study from Boston, USA¹⁵ reports an unusually elderly cohort whose uveitis started at the age of 11 and who were seen 5 years after disease onset and the complication rates compare with our non-standard cohort. Similarly, another referral cohort reported from the same unit had an exceptionally high complication rate.¹⁶ In contrast, others^1,11 have noted much smaller complication rates which are similar to those found in our standard cohort after a similar follow up period. Our non-standard cohort was necessarily heterogeneous and numbers of each group are too small to determine whether systemic diagnosis or late referral truly affect outcome. It is encouraging that complication rates of our standard cohort for cataract and glaucoma are lower than in other series (Table 5) but the rate is unlikely to be reduced significantly until the percentage of late presentations can be reduced

Kanski³ found that most uveitis was inactive by 7 years. Chylack et al¹⁷ found that 41% required treatment for more than 6 months. We found that just over half of those in low risk groups went into remission. We could not determine in this study the incidence of very long term complication and remission rates of those who have very persistent disease but who escape the initial complications found in the first 9 years. Unfortunately, these patients are a difficult to group to follow as they have usually been discharged from the care of specialist rheumatologists by their teens. In this study we have used the initial complications as the end point. Late complications in the aphakic eye are likely to continue for decades and the risk factors for late visual loss may be very different from those found in this study, but are likely to be confined to those who have already incurred at least one complication in the duration of this study.

The proportion of females developing uveitis have ranged from 62%¹⁸ to 83%.¹⁷ Kanksi¹⁹ found that girls were at higher risk of severe disease, and the female sex has been found to be a risk factor for severe arthritis in JIA.²⁰ We unexpectedly found in the standard JIA cohort that boys were at much higher risk of developing complications. The reasons for this are unclear. There were no significant differences in the delay in diagnosis and no sex difference in the demographic or HLA associations (unpublished data). These findings may suggest a lower threshold for the admininstration of systemic immunosuppression in males with JIA uveitis.

In this study it was not possible to demonstrate any effect of systemic immunosuppression on the ocular complication rate. The major impact of disease severity at onset and the variable indications and timing of systemic treatment during the period of this study may have hidden any significant effect. It is important to account for these factors in the design of future studies on the effect of treatment.

The significance of signs noted at the diagnosis of uveitis are twofold. Firstly, they may represent a prolonged period of untreated disease and, secondly, they may represent the rapid onset of signs of aggressive disease. New posterior synechiae rarely occur once the patient is on treatment and our experience of poorly compliant patients suggests that it takes at least 1–2 months for synechiae to develop in untreated patients. The high rate of complications in those with posterior synechiae suggests that short periods of untreated disease at onset may cause irreversible anterior segment changes increasing the chance of cataract and glaucoma for several years despite apparently adequate control of subsequent anterior uveitis. Phakic patients with persistent flare in the absence of cellular activity rarely achieve full remission and anecdotal reports claim the flare itself places the eye at increased risk of glaucoma. It is therefore logical to treat this group very aggressively as soon as they are diagnosed in order to reduce further risks of complications accumulating. Initiating aggressive immunosuppression once complications have started to develop may be too late to reduce the risks of long term visual loss from post-cataract surgery, macular oedema, and phithsis.

Twelve of the 29 patients developing complications were known to have mild disease at onset. The only way to reduce severe disease at presentation is by earlier diagnosis of JIA, earlier referral for slit lamp examination and, ultimately, by universal screening of vision in childhood. These strategies alone will not eliminate the complication rate as nearly half our patients with complications initially had mild disease and their outcome can only be improved by initiating more effective immunosuppression. The low rates of severe disease in the majority of patients cannot justify the universal use of toxic systemic treatment and we require further studies to characterise more accurately those who start with mild disease but then go on to develop persistent disease and a high risk of complications. Only with a dual strategy of improving early screening and developing more effective treatment can the complication rate be significantly reduced.