Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome

J. C. Packham and M. A. Hall

Oxford Regional Paediatric Rheumatology Unit, Wexham Park Hospital, Slough SL2 4HL, UK

Abstract

Objective. To examine the clinical and functional outcome of adults with juvenile idiopathic arthritis (JIA) using the recent World Health Organization/International League Against Rheumatism (ILAR) classification.

Patients and methods. Two hundred and fifty-nine adults with long-standing JIA (average disease duration 28.3 yr) were eligible for the study; 246 (95%) attended for an interview, clinical examination and notes review and 231 (89.2%) returned a comprehensive functional and psychosocial self-assessment questionnaire.

Results. Of all patients, 43.3% had active arthritis clinically and 54.4% on laboratory measures (C-reactive protein). Clinical inflammation was less common in systemic-onset JIA. The percentage of all patients with severe disability (Health Assessment Questionnaire score >1.5) was 42.9. Uveitis occurred frequently in the oligoarticular-onset and enthesitis-related subsets. Over 30% of the extended oligoarticular group with uveitis developed glaucoma compared with none of the enthesitis group.

Conclusions. Adults with JIA often have significant levels of disability, often related to continuing active disease over prolonged periods. There is a clear need for good transition from paediatric to high-quality adult rheumatology care.

KEY WORDS: Juvenile idiopathic arthritis, Physical disability, Outcome, Disease activity, Health Assessment Questionnaire (HAQ), Mobility, Growth defects, Uveitis, Long-term follow-up.

Juvenile idiopathic arthritis (JIA) is often self-limiting; about 60% of patients reach adulthood with no active synovitis or functional limitation. However, many patients experience detrimental effects, including joint deformity and destruction, growth abnormalities and retardation and osteoporosis, resulting in pain, impaired psychological health or difficulty with daily living. The course of disease is unpredictable and fluctuating. Exacerbations are characterised by recurrence of synovitis in previously involved joints and/or an increased number of joints involved. The cumulative effect of continuing active arthritis into adulthood increases the degree of functional limitation and joint destruction.

Long-term outcome studies of JIA show that between 30 and 56% of patients have severe functional limitation (Steinbrocker classes III and IV). Fourteen of these studies have followed patients for at least 10 yr [17] and seven have a follow-up of at least 15 yr [814]. The length of follow-up is extremely important in identifying the long-term outcome. Scott et al. [15] prospectively followed 112 adult patients with rheumatoid arthritis at 5, 10 and 20 yr who were treated aggressively with disease-modifying drugs. Although function initially improved, it deteriorated considerably between 10 and 20 yr. These findings are mirrored in JIA: Laaksonen [4] demonstrated that the number of patients in functional classes III and IV increased from 12% at 3–7 yr from onset to 48% after >=16 yr.

Generalized growth failure is seen in JIA secondary to prolonged severe disease (previously described as most severe in systemic JIA) aggravated by treatment with corticosteroids. Active disease may cause premature epiphyseal closure and lead to short stature or localized growth defects, including micrognathia and shortening of the fingers, hands, forearms, toes or feet. Localized overgrowth also occurs classically at the knee, causing leg-length discrepancy.

Five studies with disease duration of over 10 yr have used psychological, social or functional assessment measures in addition to the crude, poorly validated and physician-centred Steinbrocker classification [16], which assigns patients to one of four functional classes on the basis of the physician's assessment.

Doherty et al. [8] assessed 25 patients with a mean duration of disease of 13 yr, but only included those who were functionally independent (Steinbrocker I and II). Even in this group of patients with a good functional outcome, significant impairments were observed in mobility, physical activity, household activity, depression, and pain and health perceptions measured by the Arthritis Impact Measurement Scale [17].

Wirrell et al. [18] reviewed the social outcome of 61 patients with a mean duration of disease of 16.8 yr, by telephone interview and questionnaire. Scores for physical and social function were lower than those of the normal population measured by the RAND 36-Item Health Survey. The deficit in function was not related to disease subtype and there were normal scores for pain, emotional well-being and employment. These findings contrast with those found when reviewing most work in this field and may reflect differences in study design and population.

David et al. [9] assessed 43 patients with a mean duration of disease of 19.7 yr, but only included patients with polyarticular disease, thus excluding a number of subsets and skewing the patient group towards those with a poor outcome. The limited numbers of patients in each subgroup probably account for some unexpected findings in this study.

Peterson et al. [12] performed the only population-based long-term outcome study, on 44 patients with a mean duration of disease of 24.7 yr. Because it was a population-based study, a high proportion of oligoarticular arthritis (73%) was found in the study group. This makes assessing the small numbers of patients in other subgroups difficult. Even in this group of patients, the majority of whom were in a group with comparatively good outcome, over 35% had abnormal function.

Zak and Pedersen [10] reviewed a group of 65 patients with an average 26.4 yr of disease. This is a thorough review of function, disease activity and symptomatic outcome, but does not include any psychological parameters. Active disease was present in 37% of patients, 11% had severe disability and 22% had undergone JIA-related major surgery. The same group had also been reviewed after 10 yr of disease; increased physical disability, handicap and requirement for surgery had developed in the intervening 16 yr. No reduction in the proportion of patients with active arthritis was noted in the later study.

This is the first study giving detailed clinical and functional information on adult patients with long-standing JIA using the recent World Health Organization/International League Against Rheumatism (ILAR) classification. [19] It documents the patients' functional, psychological and social support needs, highlighting areas which commonly affect patients' function and independence. The objective of this research is not to undertake cohort-based epidemiological research, but to describe the functional and psychosocial outcome of those individuals at the more severe end of the disease spectrum, requiring continuing adult rheumatology care.

Methods

Patients
When the National Centre for Juvenile Arthritis at the Canadian Red Cross Hospital, Taplow, closed in1985, patients within the Oxford region and those on a surgical programme were transferred to the rheumatology service at Wexham Park Hospital. They are not a true cohort, but are skewed towards patients with severe JIA. However, they do represent those patients most likely to be encountered in an adult rheumatologist's clinical practice.

Patients with JIA over the age of 18 yr were identified, who were either still attending clinics or had continuing contact with Wexham Park Hospital in the form of shared care. Patients were identified on a computerized database by manually searching patient lists and by reviewing patient notes. Local ethics committee approval was obtained. Patients eligible for study entry were sent letters describing the aims and requirements of the study and were asked to return a signed consent form. Non-responders were sent a second study letter and subsequently contacted by telephone to ensure that their contact address was correct.

Patient assessment
Patients were assessed individually by interview and clinical examination. Subsequently, a full review of the patient's clinical notes was performed. Each patient was assigned to a disease subtype using the World Health Organization/ILAR classification [19]. Previous medical history was recorded, including medication use, concurrent diseases and surgery. Information was gathered on height, weight, marital status, offspring, education, employment, discrimination in the workplace, social activities, sexual function, housing and social service support. Laboratory tests included haemoglobin, white cell count, platelets, erythrocyte sedimentation rate (ESR; Westergren method), C-reactive protein (CRP), antinuclear antibodies (ANA) and immunoglobulin G. Joint inflammation was measured using the Thompson–Kirwan (TK) [20] index and the range of joint movement was recorded in all joints. A modified Steinbrocker [16] functional class was allocated to allow comparison with older studies; class II, functional ability to conduct normal activities, was split into IIa (despite discomfort) and IIb (despite limited mobility or fixed flexion deformity) [9]. A history of medication use and adverse reactions was taken. Surgical procedures and any subsequent complications were also recorded.

Patients completed a self-report psychological, functional [Health Assessment Questionnaire (HAQ)] [21, 22] and handicap questionnaire. If patients were unable to attend hospital for review, they were seen in local clinics or in their homes. All assessments were carried out by one individual (JCP), eliminating intra-observer error.

Statistical analysis
For assessment of differences between groups, the Mann–Whitney U-test and the {chi}2 test were used. Univariate associations were expressed as Spearman correlation coefficients due to the non-normal distribution of disease variables. In all analyses P <= 0.05 was considered to be statistically significant. All calculations were performed using the statistics package SPSS for Windows (Chicago, IL, USA).

Results

We identified 261 adults with JIA who were eligible for the study. Two patients could not be included in the study as they did not meet the ILAR criteria for JIA (one with adult-onset systemic arthritis, one with juvenile dermatomyositis). Of the remaining 259 patients, 246 (95%) participated in the study. Self-report questionnaires were completed and returned by post by 231 (93.9%) of the patients interviewed. Fifty-two patients (21%) were reviewed either in local clinics or at home.

A total of 246 patients were included in the study (176 females and 70 males), with a gender ratio of 2.5:1. This is consistent with other comparable studies. The mean patient age was 35.4 yr (range 19–78, S.D.=11.1). The mean age at disease onset was 7.1 yr (range 0.8–15.9, S.D.=4.5). The mean disease duration was 28.3 yr (range 8–73, S.D.=10.8) (Fig. 1Go). Less than 3% of patients had a disease duration below 10 yr and 9% below 15 yr. Apart from one Asian and one Afro-Caribbean, all patients were of Caucasian descent.



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FIG. 1. Duration of disease on review.

 

JIA subsets
The frequency of each JIA subset is shown in Table 1Go. This is contrasted with the overall frequencies of each subset based on data from the British Paediatric Rheumatology Group database [23].


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TABLE 1. Diagnostic frequency of JIA subsets in adult and paediatric populations

 
Table 2Go shows that, as expected, the age at disease onset was significantly lower in the oligoarticular, extended oligoarticular and polyarticular (rheumatoid factor-negative) JIA subsets and significantly higher in the polyarticular (rheumatoid factor-positive), enthesopathy-related and psoriatic JIA subsets. Patients in the oligoarticular subset were also significantly younger and had shorter disease duration.


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TABLE 2. Age at onset, duration of disease and age at review of each JIA subset

 
Clinical inflammation and raised inflammatory markers
In previous outcome studies the proportion of patients with active disease has ranged between 31 and 55% [4, 9, 10, 13, 14, 24] depending upon the selection and severity of the population studied. In the present study, disease activity was separated into clinical inflammation determined with the TK scale [25] and the presence of raised inflammatory markers (CRP and ESR) (Table 3Go).


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TABLE 3. Degrees of clinical and laboratory inflammation

 
There was no significant correlation between inflammation and length of disease and no correlation between laboratory-measured inflammation (ESR/CRP) and JIA subset. However, high levels of clinical inflammation (TK index) were most commonly found in extended oligoarticular arthritis (P=0.001), and rarely in systemic JIA (P < 0.02). There was no relationship between physical function (HAQ) and clinical inflammation (TK index). However, HAQ was strongly related to all laboratory-based measures for inflammation (CRP, P< 0.001; ESR, P < 0.001).

Growth
The mean male and female heights were shorter than those of the general population [26]. The standard deviations were increased, indicating greater variation in height than in the general population (Table 4Go). There was a significant association between the length of time on oral steroids and both final male (P=0.001) and final female height (P < 0.01), implicating steroids in growth retardation. However, steroids are usually reserved for use in severe inflammatory arthritis, which itself has a negative effect on growth. Physical disability (HAQ) was strongly associated (P < 0.001) with height. The mean male and female weights were similar to the predicted mean weight in the general population, but the standard deviation was increased, indicating greater variation in weight in the patient population.


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TABLE 4. Patients' height and weight compared with the general population

 
There was a significant association between leg-length discrepancy over 2 cm and systemic JIA (P < 0.001). In the systemic subset, 16/52 patients (30.8%) had leg-length discrepancy, but all of them had previously undergone total hip replacements, 11/16 (68.8%) having had revision of a hip prosthesis. Across all subsets, 23/28 (82.1%) with leg-length discrepancy had a hip prosthesis. This indicates that in adults with JIA the main cause of leg-length discrepancy is surgical.

Micrognathia, evidenced by a small mandible, an overbite and poor mouth opening, was more frequently seen in systemic JIA (32.7%) than in the other subsets (P < 0.05). Associated long-term temporomandibular joint (TMJ) damage was shown by the surrogate measurement of TMJ movement, measured as mouth aperture between the teeth. The percentage of all patients with restricted TMJ movement (mouth opening less than 3.0 cm) was 40.2%. In the systemic subset, this was more common, involving 53.8% of individuals (P < 0.05).

Physical disability
The disability of the patients was measured with the modified Steinbrocker score and the HAQ and was related to JIA subset (Table 5Go). Systemic JIA and seronegative polyarticular JIA were related to poor functional outcome. Conversely, both oligoarticular and enthesitis-related JIA patients tended to have relatively few functional problems. The level of disability (HAQ score) deteriorated as the duration of disease increased (P < 0.001).


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TABLE 5. Disability related to JIA subset

 

Eye pathology
Uveitis had affected 22% of the study group at some time in their disease course, with significantly higher levels within the oligoarticular and extended oligoarticular groups and significantly lower levels within the systemic and rheumatoid factor-positive polyarticular groups (Table 6Go).


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TABLE 6. Percentage of patients with JIA-related eye pathology

 
Glaucoma was relatively uncommon, occurring in only 4.1% of patients. It only occurred in patients with previous uveitis and was most commonly seen in those patients with extended oligoarticular arthritis and uveitis, involving 31.8% of patients in this group. It was not associated with the uveitis found in enthesitis-related or psoriatic JIA despite uveitis being found commonly in 26.6% of the patients in these groups.

The percentage of patients who had required eye surgery was 10.6 and the percentage with cataracts was 10.2; both conditions were more commonly seen in the extended oligoarticular group. In the systemic onset JIA group, all of the cataracts were in patients with previous steroid use. The enthesitis-related JIA group had a significantly lower incidence of cataracts than all other groups. Sicca syndrome had an overall incidence of 15% and was significantly more common in patients with rheumatoid factor-positive JIA, involving 29.7%.

The relationship between ANA and uveitis is described in Table 7Go. Uveitis was significantly related to ANA positivity in patients with extended oligoarticular JIA (90.5%) and rheumatoid factor-negative polyarticular JIA (30%). None of the patients with uveitis in the spondyloarthropathy subsets (enthesitis-related and psoriatic JIA) were ANA-positive.


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TABLE 7. Frequency of uveitis and ANA positivity related to JIA subset

 
Amyloidosis
The percentage of patients with amyloidosis was 8.9, diagnosed by either rectal biopsy or serum amyloid protein scan and presenting with either proteinuria or a CRP out of proportion to disease activity. Patients with systemic JIA were most commonly affected (Table 8Go). Men were affected more commonly (14.1%) than women (5.2%). A further seven patients with amyloidosis under the care of Wexham Park Hospital (not included in the study group) had died in the preceding decade. Five of these deaths could be directly attributed to amyloidosis and a further two were related to leukaemia, occurring after chlorambucil therapy for amyloid.


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TABLE 8. Frequency of amyloidosis related to JIA subset

 
Chlorambucil had been given to all but two individuals, who at review had well-controlled amyloidosis on methotrexate only. Fifteen out of 21 remained well-controlled, having discontinued chlorambucil after a mean time of 4.46 yr, and 4/21 remained on chlorambucil for a mean time of 2.59 yr. Two women treated with chlorambucil for amyloidosis had subsequently become parents. All of the men who had received chlorambucil and subsequently had sperm counts (5/9) were azoospermic. Two of the eight women (25%) who had received chlorambucil had undergone an early menopause an average of 17 yr later, suggesting a long-term effect from this cytotoxic agent.

Medication use
NSAIDs.
All of the patients had required non-steroidal anti-inflammatory drugs (NSAIDs) at some stage of their illness; 72.4% of patients still required NSAIDs, while 30.1% used simple analgesics. In total, 79.7% of patients required some form of analgesic support.

Adverse reactions to NSAIDs necessitated their withdrawal at least once in 59% of patients. Of all NSAIDs, 12.7% were discontinued because of adverse gastrointestinal side-effects, including nausea, vomiting, abdominal pain, gastrointestinal bleeding and iron-deficiency anaemia. Gastrointestinal protection from a combination of antacids, H2 antagonists, proton pump inhibitors, misoprostol and bismuth had been used by 53.7% of patients. Iron supplementation (other than during pregnancy) had been prescribed for iron deficiency anaemia in 53.3% of patients.

DMARDs.
Of the patients, 74.4% had received disease-modifying anti-rheumatic drugs (DMARDs) to control their disease process and 36.3% of patients were still taking a DMARD. There was an association between the length of DMARD use and JIA subset, patients with enthesitis-related JIA (P < 0.005) and oligoarticular JIA (P < 0.001) being prescribed DMARDs for a smaller percentage of their disease duration. Patients with systemic-onset JIA (P < 0.005) and rheumatoid factor-positive JIA (P < 0.005) received DMARDs for a larger proportion of their disease course. The percentage of patients taking each DMARD at some time in their disease course is described below (Table 9Go).


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TABLE 9. Use of DMARDs in long-term JIA

 

Steroids.
The percentage of patients who had previously taken oral corticosteroids was 58.9, and 24.4% of patients were still taking oral steroids. The average duration of steroid use was 11.6 yr, but with wide variation (range 0.2–46.1 yr, S.D. 10.35 yr). Systemic-onset JIA patients took steroids for longer than other subsets (14.4 yr, P < 0.01). The risk of corticosteroid-induced osteoporosis had been at least partially addressed by the use of anti-osteoporosis agents, including bisphosphonates, calcium/vitamin D preparations and hormone replacement therapy, used in 25.2% of patients.

Orthopaedic intervention
The inflammation related to juvenile arthritis is sufficient to cause such severe joint damage that patients require prosthetic joint replacement, often at a young age. Prosthetic joint replacement was common in the study group, total hip joint replacement being most frequent. Of the patient group, 51.2% had at least one major prosthetic joint replacement.

The percentage of patients in each subset with prosthetic joints and prosthesis revisions are shown in Table 10Go. Other joints (shoulder 4.9%, elbow 3.3%, wrist 1.6% and ankle 1.6%) were replaced infrequently and revision of these joints was unusual.


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TABLE 10. Percentage of patients in each subset with prosthetic joints

 
Of the patients with total hip replacements and the patients with total knee replacements, 15.4 and 2% respectively had undergone revision of their joint prosthesis at least once. The total number of joints replaced in individual patients was related to a number of factors. The risk of requiring a joint replacement was particularly increased in the systemic subset (P < 0.001). Other predisposing factors with significant effects (P < 0.001) were disease duration, poor function, height retardation and continuing active inflammation. The presence of growth defects was less strongly associated (P < 0.01). Patients in the oligoarticular and psoriatic subsets required prosthetic joint replacement much less frequently.

Discussion

The long-term follow-up of patients with such chronic disease highlights the impact of chronic arthritis starting in childhood. The accurate and objective assessment of disability is an important component in measuring outcome in JIA. However, it should not be considered separately from other aspects of outcome, such as mortality, pain, economic impact and the psychosocial effects of disease.

The majority of previous studies have not separated the disease subsets, which are known to affect prognosis and outcome. This study is the first to apply the recently introduced ILAR criteria [19] instead of the EULAR criteria [27] to patients with longstanding disease. The main difference between these classifications is an expansion in the number of subsets recognized, as shown in Table 11Go.


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TABLE 11. Differences between the EULAR/WHO 1977 and ILAR 1995 criteria for the diagnosis of juvenile arthritis

 
Retrospective classification is potentially unreliable, but the documentation of clinical findings at onset of disease was felt to be sufficiently detailed to allow clear classification. The classification of patients in the study benefits from the long follow-up period, as individuals may change their classification with time after the initial diagnosis at 6 months (Table 12Go). This is particularly true for the oligoarticular onset group, who often develop disease involving five or more joints and enter the extended oligoarticular subset. The systemic onset subset does not change with time, as this subset is entirely dependent on the clinical features at onset rather than subsequent disease progression.


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TABLE 12. Changes in subset of JIA after 6 months (excluding systemic onset JIA)

 
Oligoarticular-onset patients without dactylitis/psoriatic nail changes in whom a family member develops psoriasis are at present reclassified as ‘other’. This exclusion from the oligoarticular onset subsets has been identified as a difficulty in the classification [28]. Because of this difficulty, family history of psoriasis was not included in the classification parameters for the study. It was also felt that, because of the duration of patient follow-up, any patients with initially occult psoriasis causing their arthritis would have developed skin manifestations. None of the patients reviewed were ‘unclassified’. Specifically, no patient with rheumatoid factor-positive polyarticular JIA had psoriasis and none of the enthesitis-related JIA patients were ANA-positive. This suggests that these subsets are well defined and the exclusion criteria are appropriate.

The degree of disability in our patients mirrors that found in other studies. Severe functional limitation was present in 37.1% (Steinbrocker III or IV) and 42.9% (HAQ score > 1.5) of all patients. Patients with all patterns of polyarticular disease had a higher risk of severe functional limitation, which was most evident in the systemic JIA subgroup.

Patients were referred to Wexham Park Hospital from a wide geographical area. This may have had an influence on the socioeconomic mix of patients' families, higher social class families being more likely to seek tertiary specialist care. However, it is unlikely that this effect differs significantly from that of any other tertiary referral centre.

Because this was a long-term follow-up study and not cohort-based, the frequencies of JIA subgroups in the study group varied from those seen in a paediatric population (British Paediatric Rheumatology Group database). Those subsets with a good outcome, such as persistent oligoarticular arthritis, are under-represented in the study group, as many go into remission, do not require continuing hospital review or are under the care of a local adult rheumatologist. In the paediatric rheumatology population, up to 50% of oligoarticular patients subsequently extend to a polyarthritis [29]. In our study population almost 80% of the oligoarticular subset had progressed to polyarticular disease, indicating the need for continuing medical review in those patients whose arthritis extends. The subsets with the worst prognosis as regards function (systemic and rheumatoid factor-positive polyarthritis) constituted just 14% of a paediatric rheumatology population but 36.3% of our study group.

The concept that JIA becomes less inflammatory with time and ‘burns out’ is not supported by the finding that around 50% of all patients continued to have detectable inflammation late in the disease course. The real level of continuing active disease is probably even higher than 50%, as in the absence of active synovitis on clinical examination deformities may continue to develop and synovitis may be found at operation. The possibility of occult disease activity further increases the potential for poor outcome and the need for aggressive therapy. The systemic subset has the worst functional outcome, and in the paediatric population it has the highest levels of inflammation, sufficient to cause 57% of JIA-related amyloid-A amyloidosis [30]. In contrast, in our study the levels of clinical inflammation (TK index) were lower in systemic-onset JIA than in any other subset. A reduction in the level of inflammation at long-term follow-up in systemic-onset JIA subset has also been described by David et al. [9] and Svantesson et al. [3] and suggests that the concept of arthritis burning out may hold true in the systemic-onset subgroup.

Uveitis was seen commonly, particularly in those subsets with oligoarticular onset. Despite a relatively high frequency of uveitis in enthesitis-related and psoriatic JIA, none of these patients were ANA-positive and none went on to develop glaucoma, suggesting a more benign ocular disease course than in the other subsets.

Because this is a long-term study, the DMARDs used largely reflect historical treatment regimes. More recently, there has been increasing use of methotrexate and sulphasalazine and a coincident decline in the use of gold, penicillamine and chloroquine. Similarly, the patients remaining on corticosteroids are now being initiated on osteoporosis protection, when previously the osteoporotic effect of these drugs was not addressed.

The need for prosthetic joint replacements increases with severity and time. The influence of severe disease in childhood, as evidenced by the correlation between the presence of prosthetic joints with systemic-onset JIA, growth defects and height retardation, highlights the importance of disease control from an early age. With the recent introduction of more effective immunosuppressive agents and earlier aggressive intervention, the proportion of these patients who go on to require surgery may well decline in the future.

Adults with JIA often have significant levels of disability, usually related to severe continuing active disease over a prolonged period. There is a clear requirement for good transition from paediatric/adolescent to adult rheumatology and high-quality ongoing care.

Acknowledgments

This research was supported by a grant from the Arthritis Research Campaign.

Notes

Correspondence to: J. C. Packham, Staffordshire Rheumatology Centre, Haywood Hospital, High Lane, Burslem, Stoke-on-Trent ST6 7AG, UK. Back

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Submitted 6 September 2002; Accepted 18 July 2002