Early inflammatory polyarthritis: results from the Norfolk Arthritis Register with a review of the literature. II. Outcome at three years

B. Harrison1,2 and D. Symmons2,3,

1 Withington Hospital, Manchester,
2 ARC Epidemiology Unit, University of Manchester Medical School, Manchester and
3 East Cheshire NHS Trust, Macclesfield, UK


    Introduction
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 Introduction
 Background
 Disease outcome at 3...
 Predicting disease outcome using...
 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 
This paper is the second in a series of two reviews which focus on the work of the Norfolk Arthritis Register (NOAR), a register of primary care-based inception cohort patients with inflammatory polyarthritis (IP). The first paper examined genetic and environmental risk factors for the development of IP and of its subset, rheumatoid arthritis (RA) [91]. This paper summarizes the outcome of those patients recruited in 1990–1993 and followed for 3 yr in terms of remission of synovitis, the development of physical disability and radiological erosions. We have also examined prognostic indicators. Most of these results have not been published previously and this is the first time we have looked at all three outcomes in the same group of patients. The NOAR data are presented in the context of a detailed review of previous studies of IP and RA.


    Background
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 Introduction
 Background
 Disease outcome at 3...
 Predicting disease outcome using...
 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 
The ability to predict disease outcome in patients newly presenting with inflammatory polyarthritis (IP) would be useful from a variety of perspectives [1], not least that of the patient. For example, there is mounting evidence that, to achieve their maximum potential, disease-modifying anti-rheumatic drugs (DMARDs) should be given as soon as possible after disease onset, before the disease process has become established and irreversible damage has occurred [29]. In order to target treatment appropriately and to avoid exposing patients with mild disease to potentially toxic drugs, it would be helpful to know which patients with IP are likely to go on to develop severe rheumatoid arthritis (RA).

Many studies are confined to patients who satisfy the 1987 American College of Rheumatology (ACR) classification criteria for RA [10]. These criteria do not perform well in identifying patients with early IP who will later develop RA [11]. Nevertheless, they do give some consistency in patient selection between studies and so we have used them in this paper. Thus RA is a subset of IP.

Previous prospective studies investigating predictors of outcome in early IP
Table 1Go lists all prospective studies which have included at least 50 patients with early (disease duration <3 yr) IP and which have investigated clinical and/or genetic predictors of outcome. Most are from European centres, probably because differences in the delivery of health care make it difficult to perform such studies in North America. Over 75% of these reports used the ACR criteria for RA to select patients for study.


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TABLE 1. Prospective studies investigating clinical and/or genetic predictors of outcome in patients with early (<3 yr) IP

 
An accurate picture of disease outcome in IP is best obtained by recruiting patients soon after symptom onset and following them prospectively [68]. The studies listed in Table 1Go were all based in hospital clinics, although some tried to recruit patients more widely from the local population [29, 33] or by invitation to attend early arthritis clinics [50, 54]. Compared with community-based studies, hospital-based studies are easier to establish and maintain, and offer greater diagnostic certainty. However, left censorship is a major problem in hospital-based studies, particularly those that recruit using classification criteria for RA, because they exclude patients with mild disease and who enter remission early. The Norfolk Arthritis Register (NOAR) aims to recruit all patients with a new onset of IP who present to primary care [69]. Details of the referral and assessment procedures were presented in the previous paper in this series [91].

In this paper we examine disease outcome and predictors of prognosis among patients newly presenting with IP/RA, with emphasis on data from patients referred to NOAR.

NOAR study population used in this review
Between January 1990 and February 1993, 635 patients were referred to NOAR. Of these, 56 were later excluded because of an alternative diagnosis. Of the remaining 579 patients, 486 (84%) were followed for 3 yr, 24 (4%) died, 41 (7%) declined further participation and 28 (5%) were lost to follow-up. The baseline characteristics of the 486 patients who completed 3 yr of follow-up are shown in Table 2Go. Almost half (47%) satisfied at least four of the six ACR classification criteria (excluding X-rays) at baseline. Over the 3-yr follow-up period, 357 (73%) patients were referred to hospital for their arthritis.


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TABLE 2. Baseline characteristics of the NOAR study population used in this review (n = 486)

 


    Disease outcome at 3 yr in the NOAR cohort: frequency of occurrence and univariate associations
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 Disease outcome at 3...
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 Predicting outcome in the...
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We assessed outcome in three ways: (i) remission of synovitis; (ii) functional disability according to the Health Assessment Questionnaire (HAQ) score [70]; and (iii) radiological damage, using the grading system of Larsen et al. [71]. To aid comparison with previous studies, we also assessed outcome in the subset of 231 patients who satisfied the classification criteria for RA at baseline.

Remission of synovitis
The first systematic approach to the definition of remission in RA was carried out on behalf of the American Rheumatism Association (ARA) [72]. To fulfil the ARA criteria for remission, a patient must satisfy at least five of the following criteria for at least two consecutive months: morning stiffness lasting <= 15 min; no fatigue; no joint pain by history; no joint tenderness or pain on motion; no soft tissue swelling in joints or tendon sheaths; and erythrocyte sedimentation rate (ESR) <30 mm/h for men and <20 mm/h for women. Although these criteria have been used in other studies, the proportion of patients satisfying them is usually very low and there is still no universally accepted definition of remission [66]. We could not use the ARA remission criteria in the NOAR study [66] since we did not see patients in two consecutive months and did not measure the ESR or fatigue. Only 6% of the NOAR patients satisfied the remaining four criteria cross-sectionally at 3 yr, and only 11% satisfied them cross-sectionally at any time point during follow-up. We therefore classified patients as being in ‘remission off treatment’ (as opposed to being in ‘treatment-induced remission’) if they had no soft-tissue joint swelling and had not been treated with DMARDs or steroids within the previous 3 months. The proportion of patients classified as being in remission at 1, 2 and 3 yr is shown in Table 3Go. Only 55 (11%) patients were in remission at 1, 2 and 3 yr and could be classified as having complete resolution of their disease.


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TABLE 3. Proportion of patients categorized as in remission off treatment at 1, 2 and 3 yr in the NOAR cohort

 
These remission rates are similar to those from other studies of IP. Woolf et al. [42] found that 30% of 88 patients with early synovitis were in remission at 5 yr. Nissilä et al. [27] reported a remission rate of 38% at 3 yr in 268 patients with definite RA or undifferentiated arthritis. Higher remission rates (54% at a mean of 6.9 yr) were reported in a North American study of 532 patients classified as having undifferentiated IP when first seen [57]. Patients classified as having RA have much lower remission rates [27, 33, 57]. In the ERAS study, only 15% patients with a clinical diagnosis of RA were in ‘sustained clinical remission’ after 3 yr [40].

We found a significant association between remission and younger age at disease onset: 62% of patients aged 16–25 yr at disease onset were in remission at 3 yr compared with only 30% of patients over 25 yr of age. Remission rates at 3 yr were slightly higher in males (37%) than in females (29%); [8% difference: 95% confidence interval (CI) 0, 18]. There was no association between symptom duration at presentation and future remission.

Functional disability
We defined ‘moderate’ functional disability as an HAQ score of 1. Disability scores were highest at baseline, with an improvement at 1 yr (Fig. 1Go). A similar pattern has been observed in some previous studies [39, 58] but not in others [35]. In the NOAR cohort, the median HAQ score was 0.63 after 3 yr in the whole NOAR group, and 0.88 in patients classified as having RA. The proportion of patients with a HAQ score 1 was 36% in the whole group and 47% in patients classified as having RA. Similar results are found in most other studies of early RA [30, 58]. In the ERAS study, Young et al. [39] reported that 33% patients had an HAQ score >1 after 3 yr. An exception is the study by van der Heijde et al. [46], in which patients were reviewed every 4 weeks and had a mean HAQ score of only 0.35 at 2 yr.



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FIG. 1. Distribution of HAQ scores from baseline to 3 yr (n = 477).

 
In the NOAR cohort, baseline HAQ scores were related to the number of swollen joints (Spearman's {rho}, 0.52) and the number of tender joints (Spearman's {rho}, 0.50). There was a linear relationship between age at disease onset and HAQ scores for all years (test for linear trend, P < 0.01). Women had significantly higher HAQ scores at all time points.

Radiological damage
Three hundred and ninety (80%) of the 486 patients in the NOAR study satisfied the study criteria to be X-rayed. X-rays were available for 335 patients. The median time from symptom onset to the latest available X-ray was 22 months. Due to the selection criteria, the 335 patients X-rayed had slightly more severe disease than the whole NOAR cohort. For example, 207 (61%) satisfied classification criteria for RA at baseline and 38% had a positive test for rheumatoid factor (RF). One hundred and thirty-seven (41%) of the patients X-rayed had developed erosions, with a slightly higher prevalence (46%) among those who satisfied classification the criteria for RA at baseline. The median Larsen score was 3 (range 0–73) in all patients X-rayed, 15 (range 2–73) in the subset with erosions, and 4 [range 0–73] in those who satisfied the classification criteria for RA. The prevalence of erosions was slightly higher in men (46%) than in women (39%) (difference of 7 percentage units, 95% CI -5, 19). There was a significant relationship between the development of erosions and older age at disease onset (test for linear trend, P = 0.01). The prevalence of erosions was also higher in patients with a longer symptom duration before initial presentation (test for linear trend, P = 0.03).

Overall disease outcome
The overlap between disease persistence, functional disability and radiological erosions in the NOAR group is illustrated in Fig. 2Go. Among the 335 patients X-rayed, 74 (22%) had erosions, persistent synovitis and a HAQ score 1, whereas only 44 (13%) had none of these. Patients with erosions did not necessarily have high disability scores, and vice versa. These two outcomes may become more closely related in later disease [73].



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FIG. 2. Overlap of different facets of disease outcome in 335 patients with IP referred to NOAR who had X-rays taken.

 


    Predicting disease outcome using clinical variables measured at presentation: methodological issues
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 Introduction
 Background
 Disease outcome at 3...
 Predicting disease outcome using...
 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 
Many investigators have tried to predict disease outcome in IP and RA using clinical variables obtained when the patient is first seen. Although some consistent predictors have been identified (principally RF), the results have differed widely, in terms of both the accuracy of prediction and which factors are associated with an adverse prognosis. The results of studies using multivariate analysis are shown in Table 4Go. The reasons for the differences in study conclusions are complex, and are discussed below.


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TABLE 4. Studies using multivariate techniques to investigate clinical prognostic variables in patients with early IP

 
Study design
Studies of hospital-based RA patients are likely to find different predictors from studies of primary care-based patients with IP because factors such as age, gender, social class, psychological status, education, occupation, disease duration and disease severity influence hospital referral. For example, older patients with IP may be more likely to have persistent disease than younger patients. However, once patients are seen in a hospital clinic with confirmed RA, age may have no influence on disease severity. Therefore, age may be identified as a predictor of erosions in a study based in primary care, but not in a hospital clinic. The size of the study is also important. Large studies are more likely to yield robust prediction models, assuming that they are conducted rigorously, without substantial misclassification and measurement error.

Definition of disease outcome
Although most studies have investigated broadly similar outcomes, they have used different methods of assessment. For example, radiological outcome can be measured as the presence/absence of erosions, an overall score of radiological damage, or the number of eroded joints. In addition, outcome is reported at different times after disease onset.

Methods of analysis
Most studies have used multivariate techniques such as multiple logistic regression, multiple linear regression and discriminant analysis. These can produce different results depending on how the independent variables are categorized and the rules used to retain/remove variables from the models.

Validating the results
The statistical significance of a multivariate model can be reported as a P value, but this is not very informative. It is better to assess the ability of the model to identify correctly patients with the outcome using a separate re-test sample. The Middlesex Hospital Study is the only other study to do this [2326]. Large numbers of patients are required for this method, and the performance of the model in the re-test sample is invariably less good than in the original sample. Even if a separate re-test sample is used, the model may still not be generalizable to other patient cohorts.

Selection of possible predictors
The results of a multiple logistic regression analysis are dependent on the variables which are included as possible predictors. If the baseline HAQ score is not entered as a possible predictor, then it will not be selected!

Presentation of the results
Most studies have presented their results in terms of the amount of variance explained or the overall accuracy of the prediction model. However, the most important information for the clinician is the probability that an individual patient, presenting with particular clinical features, will or will not develop the outcome in question. This information can be expressed as positive and negative predictive values (PPV and NPV). The PPV represents the proportion of patients with a positive test (for example RF-positive) who develop the outcome in question, and the NPV represents the proportion of patients with a negative test who do not develop the outcome. The PPV and NPV are affected by the prevalence of the outcome used and so the results will only be generalizable to cohorts with similar basic characteristics.


    Predicting outcome in the NOAR population using multiple logistic regression
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 Introduction
 Background
 Disease outcome at 3...
 Predicting disease outcome using...
 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 
We used multiple logistic regression techniques to identify baseline variables associated with outcome at 3 yr. Some of the results have been reported previously [6466], but not using this particular cohort or with 3 yr of follow-up. The following variables, recorded at presentation, were entered as possible predictors: (i) demographic: age at symptom onset (divided by tertiles: 16–46, 47–61, >61), gender, initial disease duration in months (divided by tertiles: 0–3, 4–7, >7); (ii) clinical: soft-tissue swelling of the individual joint areas; swelling of large joints (elbow, shoulder, knee); individual components of the 1987 ACR classification criteria (excluding X-rays); total number of swollen joints (divided by tertiles: 0–4, 5–11, >11); and total number of tender joints (divided by tertiles: 0–5, 6–14, >14); HAQ score 1; and (iii) laboratory: RF-positive 1:40, RF-positive 1:160. Results were adjusted for use of DMARDs/steroids. Each outcome variable was dichotomized. All variables were entered and then removed manually in a stepwise fashion if they had a P-value of >0.05. Prediction models were generated using a random two-thirds sample of the study population, and tested in the remaining one-third. The results presented relate to the accuracy of prediction in the separate re-test sample.

Table 5Go shows the variables selected by the model as important predictors of outcome, an estimate of the variance explained (pseudo r2), the overall accuracy of the model, and the PPV and NPV. We obtained a relatively high accuracy (77%) for correctly categorizing patients as having an HAQ score of >=1. This figure is higher than that obtained in most previous studies (Table 4Go). The accuracy was also reasonably high for identifying patients who would develop radiological erosions (70%). Other studies which attempted to predict remission of disease [32, 33, 40, 52, 57] also obtained poor results.


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TABLE 5. Results of multiple logistic regression analysis to predict disease outcome at 3 yr among patients referred to NOAR

 
We have also developed simple algorithms (Table 6Go) which can be employed easily in clinical practice. This was straightforward for erosions, since only two predictors (RF and initial disease duration) were selected. To predict functional disability, we used recursive partitioning [74] to reduce the number of variables in the model from five to two.


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TABLE 6. Simple algorithms to categorize patients according to probability of (i) erosions; and (ii) HAQ >=1 at 3 yr

 
The clinical usefulness of a prediction model depends on the setting in which it is to be employed. In primary care, it is important that the model is simple to apply and includes variables which are readily available. If such a model is used to decide whether patients should be referred to hospital, then high NPVs are more important than high PPVs. For example, if patients who have a negative test result are not referred to hospital, it is important that few of them develop an adverse outcome. However, if prediction models are being used to select patients for more aggressive therapy, the PPVs need to be higher in order to give an acceptable risk:benefit ratio. The results in Table 5Go show that, whereas PPVs were relatively low (63 and 61%), NPVs were higher (74 and 81%). However, these NPVs may still be too low to be clinically useful. Our data may be used as a guide in management/referral decisions but should not be used to replace clinical judgement.


    A review of the influence of individual predictors on disease outcome
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 Background
 Disease outcome at 3...
 Predicting disease outcome using...
 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 
Demographic variables
Age.
The relationship between age and disease outcome is complex. The median age of patients referred to NOAR (55 yr) was similar to that reported in recent hospital-based studies [33, 40, 46, 54, 58]. This suggests that age per se does not influence referral to hospital. We found that younger patients were more likely to enter ‘remission off treatment’. However, age had no influence on ‘treatment-induced remission’ rates. Tunn and Bacon [52] and Young [40] noted higher remission rates in younger patients, whereas Eberhardt et al. [33] and Pease et al. [75] did not. We found that older patients were more likely to be disabled according to the HAQ. Although we previously reported that age was an independent predictor of moderate disability at 1 yr [64], in the present analysis it was not selected as an independent predictor of the HAQ at 3 yr. Others have also reported that age is not independently associated with disability at 1 yr [58], 2 yr [33, 46] or 3 yr [39]. However, age has been independently associated with disability at 8 and 16 yr [26, 29], perhaps because older people without arthritis may have higher HAQ scores. Finally, we found that older patients were more likely to develop radiological erosions. This is in accordance with some previous reports [28, 46] but not with others [24, 37, 59].

In summary, in the NOAR study, older patients had a worse prognosis. In contrast to one other study [76], we found that the prevalence of RF positivity rose with age (test for linear trend, P = 0.04). It may be that age was not selected as an independent predictor of outcome in the multivariate analysis because of its association with RF.

Gender.
Many previous studies reported an adverse prognosis in females, and none reported that outcome is worse in males. In the NOAR cohort, men were more likely to enter remission. This is in accordance with previous reports [32, 40]. Disability scores were higher in women. This may be related to differences in perceived ability between males and females, since van den Ende et al. [77] reported that males were more likely to overestimate their functional ability according to the HAQ. However, Deighton et al. [78] felt that higher HAQ scores in women were explained entirely by disease severity. Gender had little influence on the development of radiological erosions or the total Larsen score. Only two previous studies have reported that females have a worse radiological outcome [17, 37].

There are a number of biological reasons why females may have an adverse prognosis. It is also possible that men with milder disease are more likely to be referred to hospital for occupational reasons. Other intriguing possibilities include different responses to DMARDs in males and females and different prescribing practices. In the NOAR study, a higher proportion of men had been treated with DMARDs (54%) than women (46%).

Mortality studies in RA suggest that two groups, younger men and older women, have a particularly reduced life expectancy. The literature on early RA suggests that, while most young men with RA go into remission, those who do not have a poor outcome.

Disease duration at the time of presentation.
We found that the duration of symptoms at presentation was an independent predictor of future disability and radiological damage. Only a few other studies have examined initial disease duration as a predictor of outcome. Some reported that patients with a longer disease duration did worse [9, 39, 52, 57] whereas others did not [12, 18, 19, 32, 33, 37].

There are a number of possible explanations for the association between disease duration and outcome. First, patients who present earlier may have self-limiting disease. However, remission rates at 3 yr were not influenced by the time to presentation. Secondly, patients who have had the disease for longer have had a longer time in which to develop, for example, erosions. However, the relationship persisted when, in the multivariate analysis, we entered time from disease onset to X-ray as one of the independent variables. Finally, patients who present later to medical care may have a worse prognosis. This could be either because delay in presentation is a confounder for other factors associated with a poor prognosis, such as social class, psychological factors and type of disease, or because patients have missed the opportunity for early treatment with DMARDs. Some workers have reported that patients with an insidious disease onset (who are likely to seek medical care later than those with an explosive onset) have a worse prognosis [24, 33, 79]. However, this was not the case in other studies [12, 29, 30, 80]. We favour the last hypothesis, that the association is due to the missed opportunity for early DMARD therapy. In the NOAR study, the period of 3 months from symptom onset was selected because we divided disease duration into tertiles, the lowest of which was 3 months. However, others have also suggested that this period of 3 months is critical [81].

Clinical variables
A large number of clinical variables have been proposed as predictors of outcome (Table 4Go). Some of these are discussed below.

Baseline HAQ score.
The baseline HAQ score was by far the most important predictor of future disability in NOAR. A logistic regression model including only the HAQ score (>=1; <1) as an independent predictor was almost as accurate as the model which also included all other baseline variables. The importance of functional ability at baseline has been reported by other studies using multivariate techniques [29, 33, 35, 38, 58], with one exception [23]. Baseline HAQ was also the most important predictor of future work disability in NOAR [E. M. Barrett, D. G. I. Scott, D. P. M. Symmons, submitted for publication]. However, there was no association between baseline function and radiological outcome.

Rheumatoid factor.
In the NOAR study, a positive RF test was an important predictor of an adverse outcome, particularly radiological damage. The PPV for erosions in patients who were RF-positive at baseline was 71%. However, as 26% of seronegative patients also developed erosions, it is important not to withhold treatment in this group. All but one [37] of 18 previous studies investigating radiological outcome in early RA have confirmed the importance of a positive RF test [12, 17, 18, 2325, 28, 29, 32, 33, 42, 46, 48, 54, 59, 82, 83]. The association with functional disability was less marked, and was only apparent for RF at a higher titre of 1:160. Some previous studies have indicated that RF positivity is an important predictor of early disability [30, 38] but others have indicated that it is not [17, 33, 39, 46, 58]. However, there is greater consistency for studies investigating later disability (5–25 yr after onset): all but one [12] identified a positive RF test as being important [23, 26, 29, 35, 42]. In the NOAR study, we identified a positive RF test as being an important predictor of disease persistence, with a PPV of 93% compared with 59% for a negative RF test. Other studies have also noted that seronegative patients are more likely to enter remission.

Genetic factors
Many studies have investigated genetic predictors, principally HLA-DRB1 alleles, in prospective studies of early RA. Of seven studies investigating radiological erosions in early RA, four report a positive association [45, 51, 54, 62] and three report no association [36, 56, 61]. There is also disagreement about the influence of HLA-DRB1 alleles on functional disability and disease persistence [32, 36, 53, 54, 60, 84]. We performed detailed typing for HLA-DRB1 alleles using PCR based methods in 532 patients who were followed up for 2 yr, 359 of whom had X-rays taken [67]. In brief, we found that HLA-DRB1 alleles had no influence on the development of persistent disease and only a moderate influence on the development of functional disability. However, there was a clear association with the development of radiological erosions. Patients with at least one copy of any shared epitope (SE)-bearing allele were approximately twice as likely to develop erosions as those who were SE-negative: the relative risk was 1.9 (95% CI 1.4, 2.6). Of particular interest, we found that HLA-DRB1 alleles were important only in patients who were RF-negative, and did not influence outcome in seropositive patients (Table 7Go). Thus, knowledge of SE status has little additional benefit over that of RF alone in identifying patients likely to develop erosions. Our data do not support the routine genetic screening of patients with early IP to identify those at high risk of erosions.


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TABLE 7. Prevalence of erosions according to baseline RF and SE status in the NOAR cohort

 


    Limitations of the NOAR study
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 Introduction
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 Disease outcome at 3...
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 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 
Study population
Norfolk was chosen for the study because of the low levels of migration and the good links between primary and secondary care. However, residents of Norfolk may not be representative of the whole UK, being slightly older, less socially deprived and with fewer people at the extremes of the social class categories [85, 86]. Our results may therefore not be generalizable to other populations. However, this is true for all studies, since there are wide variations in sociodemographic characteristics within and between countries.

The entry criteria for the NOAR study were deliberately broad in order to avoid left censorship. This means that our results are not necessarily applicable to patients seen in hospital clinics, although 73% of NOAR patients were also referred to hospital. The proportion of patients with ‘true’ RA is lower in the NOAR study than in hospital-based studies. We view RA as a subset of IP, or the peak of the IP iceberg rather than viewing ‘non-RA’ IP as a separate condition.

X-ray data
When the NOAR study was designed, we wanted to avoid exposing patients with mild disease, who would be unlikely to have erosions, to irradiation. However, with hindsight, it would have been preferable to request X-rays for all patients, which we are now doing at 5 yr. Sixteen per cent of patients who did not satisfy the criteria to have X-rays taken had erosions after 5 yr. A second concern is that we have used the results of X-rays taken a median of 22 months after disease onset. A number of potentially erosive patients may not yet have developed radiologically visible changes [87]. The data presented here, therefore, refer to the prediction of early erosions.

Clinical and demographic data analysed
We did not measure laboratory indices of inflammation, such as C-reactive protein (CRP) and ESR, at baseline. Other studies have suggested that these measures are important predictors of outcome [55, 88, 89]. Although information on social class was not included in the present analysis, the results of a separate analysis suggest that social class, measured in a number of ways, does not influence the outcome. This is in contrast to some other studies [35, 90]. Data on smoking status, co-morbidities and psychological status are yet to be analysed.


    Conclusions
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 Introduction
 Background
 Disease outcome at 3...
 Predicting disease outcome using...
 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 
Using only three variables (RF, initial disease duration and baseline HAQ) we could identify patients who would develop erosions and/or moderate disability by 3 yr after presentation. It has been suggested that higher PPVs (in the order of 90–95%) may be possible with the addition of genetic and laboratory data and by following research into health status and socioeconomic factors, and new disease markers such as metalloproteinases, anticollagen antibodies and hand densitometry [68]. Our view is that, for both clinical and statistical reasons, higher PPVs are unlikely to be achieved. RA is a heterogeneous disorder whose outcome depends on the complex interaction of genetic, psychosocial, biochemical, hormonal and treatment-related factors. Unless homogeneous disease subgroups are studied, it seems unlikely that it will be possible to predict outcome with a high degree of accuracy in an individual patient. Further, it is impossible to eliminate the measurement error inherent in studying clinical variables such as X-ray damage and joint counts. This reduces the precision, and hence the reported accuracy, of possible prediction models.

In collaboration with other units investigating early arthritis, we are keen to develop classification criteria for early RA which could be used to ensure consistency between studies. At the present time we believe that all patients who have IP with a duration of between 4 and 12 weeks should be regarded as potentially having RA and considered for DMARD therapy, especially if they are RF-positive or have a baseline HAQ score of >=1. Once a patient has had persistent disease for 12 weeks or more an adverse outcome is more likely and the need for aggressive therapy is greater.


    Acknowledgments
 
This study was funded by the Arthritis Research Campaign, UK. We are grateful to the general practitioners and hospital doctors of the Norwich Health Authority for their dedication in referring patients for study. In particular, we thank Professor D. G. I. Scott, consultant rheumatologist, Norfolk & Norwich Hospital. We also thank the current and previous NOAR staff and research nurses for their hard work: J. Barnard, B. Barrett, D. Bunn, J. Chipping, L. Galpin, S. Ivins, A. Langrish-Smith, L. Massingham, P. van Poortvliet, M. Sommerville and S. Whiting. We thank members of the ARC Epidemiology Unit: R. Bradbury, P. Brennan, C. Burt, A. Silman and N. Wiles.


    Notes
 
Correspondence to: D. Symmons, ARC Epidemiology Unit, Oxford Road, Manchester M13 9PT, UK. Back


    References
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 Introduction
 Background
 Disease outcome at 3...
 Predicting disease outcome using...
 Predicting outcome in the...
 A review of the...
 Limitations of the NOAR...
 Conclusions
 References
 

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