Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, University of Manchester Medical School, Manchester M13 9PT, UK.
Correspondence to: W. Thomson. E-mail: wendy.thomson{at}man.ac.uk
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Abstract |
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Methods. Electronic databases were searched for major studies publishing outcome data in the past 10 yr in juvenile idiopathic arthritis, juvenile rheumatoid arthritis and juvenile chronic arthritis, and 21 studies were selected. The proportions of children in the different categories of the outcomes of interest are described. Data were stratified where possible by disease subtype.
Results. There were major differences between the studies reviewed in terms of study design, case selection and the results obtained. In general, children with systemic- or polyarticular-onset disease were much less likely to go into remission than those with oligoarticular onset, although the remission rates in the latter group ranged from 36 to 84%. Several different approaches were used to assess functional outcome but the pattern of results between the different subgroups was the same as with remission. Similarly, children with polyarticular disease in all the cohorts reviewed were substantially more likely to have erosive radiological damage on follow-up. The rates of individual outcomes, even within a subgroup, varied considerably between studies and this does not appear to be explained solely by differences in methodology.
Conclusions. There remains a considerable lack of clarity in the prognosis following onset of juvenile idiopathic arthritis for the major outcomes considered, although those with oligoarthritis at presentation have the best outcome. The ability to offer accurate prognosis is particularly important to both reassure parents and guide treatment at disease onset. To achieve this, large definitive prospective studies will be required.
KEY WORDS: Juvenile arthritis, Outcome, Remission, Function, Bone erosion
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Introduction |
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Outcome following arthritis onset is multidimensional as the disease can not only cause joint damage but can also affect extra-articular structures, such as the eyes and viscera. In relation to structural damage, there is a significant detrimental effect on function. The above factors and the associated psychological aspects of chronic disease will have generalized consequences on all aspects of quality of life.
There have been several studies assessing outcome but comparison between studies has been hindered by the lack, until recently, of a universally accepted classification method, given the differences in inclusion and exclusion criteria for the two previous widely used classification systems: EULAR (European League Against Rheumatism) and ACR (American College of Rheumatologists) [4, 5]. Most outcome studies therefore did not use the recently agreed ILAR (International League of Associations for Rheumatology) classification criteria [6] and its subsequent revisions [79]. Furthermore, older studies may be no longer relevant, given the shift towards earlier use of disease-modifying anti-rheumatic drugs and modulators of cytokines (biological agents), with a view to controlling disease activity, before the joint pathology becomes permanent [1017]. Accurate estimation of outcome is of value not only for individual patient prognosis but also for rational service planning, as well as for providing a guide for those designing studies evaluating potential new interventions.
We have therefore reviewed the major published outcome studies in juvenile arthritis over the past 10 yr with the aim of providing the best estimates of the proportion of children achieving (i) disease remission, (ii) functional impairment and (iii) structural damage, after stratification into the main disease subtypes. With regard to variation in results, we have attempted to consider the impact of different methodological approaches, the magnitude of the latter precluding formal meta-analysis.
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Methods |
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Inclusion criteria and subgroup classification
Consideration was restricted to studies of outcome in childhood inflammatory arthritis, published in the last 10 yr. This interval was selected to restrict inclusion to those studies which observed children exposed to current therapeutic practices.
We also restricted inclusion only to those studies which provided data on disease subtype according to one of the recognized classification schemes. Thus, studies using ILAR, ACR and EULAR criteria were included. (It should be noted that the EULAR criteria stipulate persistence for 3 months whereas the first two require only 6 weeks.) In order to make the available results from different studies more comparable, we limited analysis to data from the following subtypes, which are common to all three classification systems:
Methodological description
We distinguished three types of studies: (i) true prospective cohort studies, which were designed ab initio to follow up all diagnosed children from disease presentation; (ii) retrospective cohort studies, which were able to identify an inception cohort of children from past records and assessed their current status but relied on standard medical records as opposed to standardized information on their status at presentation; and (iii) cross-sectional studies, which captured information only on those currently attending or known to the investigators. The majority of the studies reviewed fell into the last two categories, and by restricting their attention to those children under current follow-up, or a previous period of hospital attendance, would be biased towards those with more severe disease.
Outcome measures assessed
We identified data for three major outcomes: remission, function and structural damage. There was considerable heterogeneity in the approaches used to define all these, particularly for remission and functional loss. Remission was defined using a variety of criteria (e.g. ACR, EULAR, self-report). The proportion in remission for the chosen criteria was used. Health status, including measurements of quality of life, was not dealt with in great detail by most of the studies. Function, however, as one of its many facets, was reported more frequently. Functional limitation was derived from the inability of the patient to carry out activities of daily living, and vocational or educational tasks, as appropriate. Most of the studies used specific tools, such as the health assessment questionnaire (HAQ), the childhood HAQ (CHAQ) or Steinbrocker functional class. Given the variability in the approach to data presentation, we identified for each study the proportion with a disability index below a specific threshold or functional class. The major measures of structural outcomes were the presence of radiological damage and joint deformity, but other structural outcomes reported included joint surgery/replacement, uveitis and linear growth retardation. For the purposes of comparison all these features were also expressed dichotomously, based on their presence or absence at follow-up.
In addition to the variation in definitions used, for both cases and outcomes, there was also variability in the duration of follow-up from 4 to over 25 yr. These differences in the observation period added to the above-mentioned methodological differences between studies, making meta-analysis of their results very difficult.
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Results |
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As stated, remission rates in the other subgroups were lower but the variation in remission rates was even greater in both the polyarticular (12.565%) and systemic (076%) subtypes. These two subgroups are more infrequent than the oligoarticular group and hence some of this variation will be random. In several of these studies, despite the small sample sizes, the differences between subgroups were statistically significant [18, 20, 29, 30].
There were, of course, other approaches adopted for measuring disease activity amongst the above studies, which included individual clinical and laboratory indices of disease activity. There was no consistency, amongst studies, in the markers used and hence comparisons are impossible.
Functional outcome
Table 3 summarizes the findings of 16 studies which reported on functional outcomes or disability indices (DI). There was variation in how function was measured, 11 studies using CHAQ or the adult HAQ and eight (including four that also used the HAQ/CHAQ) using Steinbrocker functional classification. The remaining study [24] used the Numeric Rating Scale (NRS-11), a patient/parent self-reported tool for measuring function and pain, based on using a discrete numerical scale (0 = very good, 10 = very bad). Not surprisingly, there were correlations between the scores between the Steinbrocker classification and the more discriminatory HAQ/CHAQ when both were evaluated [27, 28, 31, 32].
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Even within the systemic group there may be differences in outcome. Thus, in a small study of 90 children Lomater et al. [35] separated three types of systemic disease according to severity at baseline: (i) single-episode disease (n = 9) (ii) intermittent fevers and arthritis interspersed with periods of remission (n = 27); and (iii) persistent disease activity (n = 44). These groups also differed in their outcomes at follow-up. Thus, all nine patients with subtype I disease were in functional class I compared with 78 and 61% in subtype II and III cases, respectively. Similar findings were observed by Spiegel et al. [36], who reported 85% of their low risk and 50% of their high risk systemic patients to have DI < 0.75. Eleven studies reported function in the polyarticular subtype. In two studies polyarticular onset had significantly worse functional outcome than oligoarticular course [20, 31]. This observation included both RF+ and RF polyarticular subtypes in the former, a large Norwegian study, though the difference in the latter study was limited to the RF subgroup. This was probably due to lack of power rather than any obvious difference between these two RF-derived subgroups. In another study [32] polyarticular onset was also associated with an increased likelihood of a worse function; however, this was only observed in the female cases.
Structural outcomes
Table 4 presents the proportions with radiological erosion reported in the small number of the above studies with available data. Given the paediatric nature of the population, it was not surprising that radiological examination was not carried out routinely in any study, but only when clinically indicated or before intra-articular corticosteroid injection [26]. There was a variation in the radiographic classification systems used: the Dale was adopted in three reports [18, 20, 26], whilst Steinbrocker was used in one [29]. One of the remaining studies employed a two-class system based on the early (class I) or late (class II) radiological changes [23], whilst the remaining study did not use a predefined system. As with the other outcomes, oligoarticular disease was consistently found to have a lower risk of erosions, this difference being highly significant in three studies [18, 20, 22]. The prevalence of erosions in the oligoarticular group was very low in most, but not all, of the studies. By contrast, the RF+ polyarticular group was associated with high prevalence of erosive disease, which was 100% in the admittedly small Norwegian study [18]. The cumulative prevalence of erosive disease in systemic onset is unclear, with substantial variation amongst predominantly small sample sizes, precluding useful comment.
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Discussion |
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The available data vary widely and this variation is likely to be explained, perhaps not surprisingly, by differences in case definition, method of outcome assessment and duration of follow-up. In addition there are likely to be differences in patient selection, especially within subgroups, and in therapy and management policies, all of which could have influenced outcome.
The absence of universal remission criteria suitable for use in a paediatric population makes comparison between studies very difficult. The two remission criteria more commonly used amongst the studies reviewed were those formulated by EULAR and ACR. The ACR criteria, if strictly applied, can be more difficult to meet. Remission is defined by the presence of subjective reports, such as less than 15 min early morning stiffness, no fatigue, no joint pain, and no joint tenderness, but it does not take into account the presence or absence of drug treatment. The presence of remission using the EULAR criteria is determined from the active joint count, the presence of extra-articular manifestations of arthritis, and the nature of drug treatment. These latter criteria, therefore, use more objective information.
There was a wide range in the reported remission rates within the oligoarticular subtype, although the numbers studied in all of the above reports were very small. The two lowest reported rates (36 and 47%) were those from studies [26, 29] using onset subtypes to categorize their patients, their groups almost certainly containing mixed cases of persistent and extended oligoarticular disease. In those studies restricted to persistent oligoarticular cases, the lowest remission rate (43%) was observed in the only study using self-defined remission criteria [25]. Interestingly the latter were less stringent, requiring duration of remission of only 6 months compared with the 2 yr used in the other reports. The two highest remission rates (84 and 81%) were reported by studies [18, 27] with relatively long follow-up periods (10 and 26 yr, respectively). This was not a universal observation as one study with 15 yr of follow-up [20] reported a lower (57%) remission rate. The differences between the four studies reporting remission rates amongst the extended oligoarticular cases could not be explained by the remission criteria used, as the highest rate corresponded to the study with the most restrictive criteria. It is possible that the relatively high loss to follow-up rate in the study with higher remission rate [27] may be responsible. Indeed, in another study there was a significantly lower remission rate in their study cases compared with those lost to follow-up [25].
Wide variation in the reported remission rates was not limited to the oligoarticular onset subtype, and was seen in both the polyarticular and systemic onset subgroups. The lowest remission rates in systemic disease (0%, 20%) were also only reported in the two studies [18, 27] with tiny numbers of cases: four and five, respectively. Small case number may not be the only reason for the inconsistency, as the two studies [20, 35] with the largest numbers (29 and 80) also showed a substantial variation in their remission rates (36 and 76%). One possible explanation for this is the difference in the definitions used for remission, the former study using ACR and the latter using EULAR remission criteria.
The majority of the studies used CHAQ or HAQ to assess functional outcome, with the Steinbrocker functional classification system used in only a few studies. This latter system clearly lacks discrimination in terms of both the type of functional impairment and identifying small changes in disability, making comparisons with other studies or even within the same study speculative at best. The systemic disease subgroup had significantly greater impaired function [18, 31, 34], although, the actual disability levels varied substantially between studies. The highest rate of disability reported [31] is probably attributed to a high selection bias, that study being based upon prevalent cases; hence patients with more severe disease were more likely to continue to have been seen at the hospital. In only one study was polyarticular onset found [18] to have significantly better function than extended oligoarticular and systemic subtypes.
Variability was also observed in the reported erosion rates in the studies examined. The highest overall rate of erosive disease in one study [26] is probably the result of including a disproportionately high number of extended oligoarticular cases (50%). This is in contrast to the study with the lowest erosion rate, which included only 5% with polyarticular disease [29]. Subtype distribution alone could not explain the disparity in results, given the wide variation observed when the rates of erosive disease were compared within subtype between studies [18, 20]. Thus the erosion rate in one study [20] was considerably lower in the systemic compared with the polyarticular subgroups, whereas no difference was observed between these same two groups in another study.
Some of the variability observed between studies may, of course, be real, reflecting true differences in genetic and environmental factors between the cohorts studied. Furthermore, the influence of therapy was not assessed in these observational studies but is likely to have had some influence on the outcomes measured. There remains, therefore, a considerable lack of clarity about the prognosis following the onset of JIA, both in total and by subgroup.
We deliberately restricted our consideration to publications from the past 10 yr in an attempt to make the conclusions relevant to modern therapeutic regimes. However, there has been a recent proliferation in the use of new biological agents, such as tumour necrosis factor (TNF-
) inhibitors, which might be expected to influence the outcome in children in those subtypes with poor prognosis. Thus, further studies are required to consider the impact of such regimes on disease outcome.
In summary, for all the reasons stated above there is a need for studies that are (i) prospectively designed, with cases ascertained soon after disease onset to enhance data quality in terms of standardization and completeness of both predictors and outcomes; ideally, such studies should aim to capture all incident cases within a target geographical population; (ii) of appropriately large size to provide numbers in each of the subtypes of interest to provide sufficient statistical power; this will probably require multicentre recruitment; (iii) use standardized classification schemes to ensure homogeneity of the selected cases and allow comparison with other studies; and (iv) use well-validated instruments and universally accepted criteria to measure remission, radiological damage and health status outcomes, including function and quality of life.
The onset of inflammatory arthritis is a major source of anxiety for the affected child and the family and it is particularly important to be able to give accurate information, both to provide reassurance where appropriate and guide the targeted use of effective but potentially toxic therapies to those most at risk.
The authors have declared no conflicts of interest.
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