City Hospital, St Albans AL3 5PN,
1 Orthopaedic Hospital, Oswestry TF6 6TF,
2 Royal Hants Hospital, Winchester SO22 5DG,
3 Broomfield Hospital, Chelmsford CM1 6ET,
4 Selly Oak Hospital, Birmingham B29 6JD,
5 Rheumatology Research Unit, Leeds LS2 9NZ,
6 CORU, UCL, London WC1E 6BT,
7 Diana Princess of Wales Hospital, Grimsby DN33 2BA,
8 North Hampshire Hospital, Basingstoke RG24 9NA,
9 Medway Hospital, Gillingham ME7 5NY and
10 Nether Edge Hospital, Sheffield S11 9EL, UK
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Abstract |
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Methods. The inception cohort of RA patients was recruited from rheumatology out-patient departments in nine National Health Service (NHS) hospital trusts in England. All consecutive patients with RA of less than 2 yr duration, prior to any second-line (disease-modifying) drug treatment were recruited and followed-up for 5 yr. Standard clinical, laboratory and radiological assessments, and all hospital-based interventions were recorded prospectively at presentation and yearly. The outcome measures were clinical remission and extra-articular features, functional ability [functional grades IIV and Health Assessment Questionnaire (HAQ)], use of aids, appliances and home adaptations, orthopaedic interventions, and loss of paid work.
Results. A total of 732 patients completed 5 yr of follow-up, of whom 84% received second-line drugs. Sixty-nine (9.4%) had marked functional loss at presentation, compared with normal function in 243 (33%), and by 5 yr these numbers had increased in each group, respectively, to 113 (16%) and 296 (40%). Home adaptations and/or wheelchair use by 5 yr were seen in 74 (10%). Work disability was seen in 27% of those in paid employment at onset. One hundred and seventeen (17%) patients underwent orthopaedic surgery for RA, 55 (8%) for major joint replacements. Marked functional loss at 5 yr was more likely in women [odds ratio (OR) 1.63, 95% confidence interval (CI) 1.042.5], patients older than 60 yr (OR 1.94, 95% CI 1.32.9), and with HAQ > 1.0 at presentation (OR 4.4, 95% CI 2.87.0).
Conclusions. Clinical profiles of RA patients treated with conventional drug therapy over 5 yr showed that a small proportion of patients (around 16%) do badly functionally and in terms of life events, whereas around 40% do relatively well. The details and exact figures of cumulative disability are likely to be useful to clinicians, health professionals and patients. The rate of progression and outcome in these patients can be compared against future therapies with any disease-modifying claims.
KEY WORDS: Rheumatoid arthritis, Function, Outcome, Work disability, Orthopaedic surgery
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Introduction |
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Most of the published studies on outcome have also investigated potential predictive factors, and again the wide variation in results has depended on study design, duration of RA and choice of outcome measure [4]. Many studies have reported that women and older patients do worse functionally and seropositivity and acute-phase reactants are related to radiological damage, but the influence of these features on eventual outcome is not universally agreed [4].
The Early RA Study group (ERAS) was formed with the primary aim of monitoring the progress, treatment and outcome of early onset RA in the setting of routine out-patient departments, using standardized assessments. Compiling data on a large sample of patients over a long follow-up period gives the opportunity of characterizing with greater precision the typical course of RA and its treatment, for establishing differences in disease progression and possible differences between centres, and evaluating early prognostic features. With such a large sample, the less common outcomes which are at either end of the spectrum of RA (i.e. very good or very poor outcomes, orthopaedic interventions, work disability) can be more clearly defined. This paper reports on functional outcome, and on the direct effects of functional loss on the lives of early RA patients observed for 5 yr.
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Patients, materials and methods |
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Clinical and laboratory assessments
Standard clinical assessments were made by trained metrologists at presentation and yearly. The features chosen when the study commenced in 1987 included those in fact recommended both by the British Society of Rheumatology/Royal College of Physicians working group in 1992 for specialist supervision of RA [9] and the OMERACT conference in 1993 [10]. Assessment of joint disease included the number, distribution and symmetry of joints involved. Joint activity was scored according to both Ritchie [11] and a simple joint score allowing for both swelling without pain or tenderness and for the number of actual joints involved to include individual metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints (0 or 1 per joint with maximum 59) [12]. Features of extra-articular RA were recorded (nodules, Sjögren's, pulmonary, neuropathy, Felty's, localized vasculitis as in scleritis or cutaneous lesions, or systemic vasculitis). Function was assessed by the clinician according to Steinbrocker's functional grade (FGIIV) [13], all patients completed the disability index of the modified Stanford Health Assessment Questionnaire (HAQ, range 03) [14], including a visual analogue pain scale, and grip strength was measured in both hands. Yearly radiographs of hands and feet were assessed for the presence of bony erosions [15]. Routine haematology tests included the erythrocyte sedimentation rate (ESR) measured according to Westergen, and routine serology included rheumatoid factor and antinuclear antibody. Disease activity (DAS) was based on the adaptation of the American Rheumatism Association (ARA) remission criteria [16] allowing for partial and therapeutic (patients still on second-line drugs) remission, and combines the articular index, morning stiffness and ESR.
Treatment profiles
All centres followed the framework of the published UK guidelines for management of RA [9], which include the provision of therapy services, appropriate orthopaedic interventions, and sequential use of second-line [disease-modifying anti-rheumatic drugs (DMARDs)] drugs together with symptom relieving measures, with judicious use of steroids when required. Combination therapy was used in severe and non-responsive RA. The DMARDs used were chosen according to the physician's preference, although dosage schedules employing graduated regimens were previously agreed according to standard practice for each drug. Reasons for discontinuation were based on clinical judgements and coded according to loss or lack of effect, to adverse events, both reasons, remission, or miscellaneous (e.g. pregnancy).
Outcome measures
These included clinical (disease activity and remission, extra-articular features of RA); functional (functional grade and HAQ); therapy interventions (physiotherapy, occupational therapy) and use of standard aids and appliances (e.g. wrist splints, walking aids) and any major appliances (wheelchair more than once per month) or major home adaptations (e.g. alteration to stairs, bathrooms and toilets); type of tendon or joint surgery as a result of RA; and loss of or changes in paid employment. The latter was based on interviews with patients and details of social security allowances. All these items were collected prospectively in a standard way.
Statistical analysis
Summary statistics have been used to demonstrate the differences in clinical features between categories of the outcome measures. Because of non-Gaussian distributions of continuous variables, and for ordinal variables, median values (with interquartile ranges) are shown. Categorical variables are expressed as counts (and percentages) for the clinically relevant categories. Differences between centres are shown as percentage ranges. The odds ratio (OR) with 95% confidence intervals (CI) have been used to demonstrate the association between eventual outcome measures at 5 yr and three clinical features at presentation (gender, age at onset >60 yr, initial HAQ greater than the median for the whole group i.e. > 1.0). Where appropriate, 2 analysis and MannWhitney with test for significance (P value < 0.05) are shown.
Patient sample
A total of 941 patients recruited before January 1994 were due for their 5 yr follow-up. Figure 1 summarizes the patient sample and reasons for those lost to follow-up; 746 (80%) patients were followed for at least 5 yr, of whom 14 were unable to attend their 5 yr follow-up visit (e.g. for other medical or surgical reasons, temporary move, etc.). Table 1
summarizes the clinical characteristics of the cohort at study entry. The characteristics of the patient sample at presentation were fairly typical of early RA cohorts, with differences between centres being generally on a minor scale. The duration of symptoms of RA prior to presentation to a rheumatologist and entry to study was less than 12 months in 81%, with an overall median of 6 (411) months, and a mean of 8.1 (S.D. 6.1) months, thus indicating early RA. Overall, 33% were in FGI at entry (2252%), compared with 57% in FGII (4987%) and 9% in FGIII (015%). By 5 yr, 617 (84%, 6593%) patients received at least one DMARD at a median of 7 weeks from first presentation to rheumatology clinics (68% within 3 months and 77% by 12 months). Preference for the first DMARD was sulphasalazine in 73%, intramuscular gold in 10%, D-penicillamine in 7%, oral gold in 3%, antimalarials in 3%, methotrexate in 3%, and various others (azathiaprine, cyclosporin, cyclophosphamide). Thus, 16% used non-steroidal anti-inflammatory drugs (NSAIDs) only, 42% received only one DMARD, two DMARDs were used in 25% and three or more were used in 17%. Oral steroids in doses of
7.5 mg daily for
12 months were used in 16% (640%).
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Results |
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Functional ability
At presentation 52 (7%) patients already had marked functional loss (FGIII/IV), compared with normal function in 243 (33%), and by 5 yr these numbers had increased in each group to 113 (16%) and 296 (40%), respectively (Table 4). Severe functional restriction (FGIII/IV) at 5 yr was more likely in women (OR 1.6, CI 1.032.5), patients older than 60 yr at presentation (OR 1.9, CI 1.32.9), and with initial HAQ > 1 (OR 4.4, CI 2.87.0). To illustrate the importance of the association of HAQ in early stages of RA with eventual functional grade at 5 yr, Fig. 2
shows the change in HAQ over the observation period of 5 yr in patients destined to be in FGI, II or III/IV at 5 yr.
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Aids, appliances and home adaptations
Physical assessment and treatment by therapists was provided in 83% with some centre variation (6499%). There was less variation in the requirement for major aids. Seventy-four patients (10.4%, 616%) needed major adaptations or appliances which included stair adaptations, stair lifts, major bathroom and toilet changes, or regular use of wheelchairs (Table 5), and a further 83 patients (18%) required walking aids (special shoe wear and calipers). Such measures were more likely in women (OR 2.4, CI 1.34.5), patients older than 60 yr at presentation (OR 2.7, CI 1.74.5), and patients with initial HAQ > 1.0 (OR 3.5, CI 26).
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Joint surgery
Orthopaedic surgery was required in a total of 117 (16.2%, 1028%). Major joint replacement was performed for RA in 55 patients (8% overall, 511%). A further 21 (3%) underwent excision arthroplasty or synovectomy (Table 5). Trends only were seen for older patients and worse initial HAQ for orthopaedic intervention. Medical in-patient treatment for RA or its complications varied considerably between centres (overall 21%, 442%) because of differences in in-patient facilities.
Work loss
A total of 353 patients (48%) were in paid employment at presentation, of whom 211 (60%) remained working at 5 yr and 79 (22%) retired mainly because of RA. Of the 142 who stopped working, 32 (23%) retired at their expected ages or for reasons other than RA (e.g. redundancy), 79 (56%) retired early because of their rheumatoid disease, and in a further 19 (13%), RA was one of several factors responsible for early retirement, the others being mainly co-morbidity and/or social reasons. In 12 patients, this information was missing (Fig. 3). Loss of full-time work due to RA was more likely in those with a definite manual component to their work (OR 2.97, 1.266.9).
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Patients without 5 yr of follow-up
A total of 193 patients did not attend their 5 yr follow-up assessment for reasons shown in Fig. 1. The same presentation features as shown in Table 1
(for 5 yr of follow-up) are shown in Table 6
for all these patients, in those who died and those who declined to attend further because they were in remission and no longer troubled by their disease. Comparisons have been made with the main cohort of 732 patients who did complete 5 yr using the MannWhitney and
2 tests where appropriate (P values are shown if <0.05). The main findings at presentation were more severe disease (functional grade, HAQ, erosions), proportionally more men, and older age in patients who died within 5 yr. In contrast to this, those who withdrew from the study because of remission were younger, less seropositive and had fewer ACR criteria at presentation.
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Discussion |
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The clinical profiles of RA patients treated with conventional drug therapy over the first 5 yr in this study show that 40% of patients do relatively well (13% were in fact in clinical remission), 44% follow a relapsing/remitting course with variable but definite functional impairment, in comparison with a small proportion (around 16%) who do badly in terms of the effects of RA on functional ability and life events. Women, older age at onset (60 yr or more) and worse initial HAQ (>1.0) were each associated with worse outcomes. However, disease outcome at 5 yr in an individual patient with very early RA cannot be predicted with accuracy using simple clinical measures. A future study from this group examining genetic markers and detailed radiological scores is near completion and may improve on this.
These results were based on aggregated data from nine rheumatology units in different regions of England, but collected prospectively and in a standard format, and with the numbers included it is a reasonable assumption that these figures represent the variation in patterns of presentation and outcome at 5 yr found in early RA. Some of the differences seen between centres could be explained on the basis of minor differences in clinical practice (e.g. choice of second-line drugs), although some reflected major differences in availability of certain services (e.g. medical/rheumatology in-patient beds and physical therapy interventions). Others were due to population differences (e.g. employment). We have previously reported the adverse effects of lower socio-economic status on functional scores in RA [17], and these findings were broadly similar to published work in other countries [5, 18, 19].
The main strengths of this study include the chance to study RA from its earliest stages prior to the use of second-line drugs; the relatively few exclusion criteria (which are so restrictive in clinical trials), thus reflecting actual clinical practice, but which still allows valid comparisons using the appropriate subgroup analysis; regular yearly follow-up using standard assessments has ensured that data have been collected prospectively, and those lost to follow-up kept to a minimum but at least accounted for; little variation in disease duration because all patients have the same follow-up (5 yr from entry). Possible sources of bias in this study arise as a result of left censoring (milder RA not being referred to hospital out-patients and relatively more patients in remission who were lost to follow-up), right censoring (more severe RA not surviving 5 yr), and treatment effects. Five year follow-up has been achieved in 80%, and the 10% mortality at 5 yr was similar to comparable studies and only slightly increased when compared with population expected rates [20]. None the less, mortality was responsible for 10% of the original sample not included in the 5 yr outcome analysis, compared with 2.4% lost to follow-up because of very mild disease or remission. The severity of RA at 5 yr is likely to be underestimated in our study because the patients who died prior to 5 yr of follow-up did have worse disease at presentation. In three patients the cause of death was thought to be related to complications of RA or its treatment. Most patients received at least one DMARD, 84% within the first year, at a median of 7 weeks, and in 72% the same first drug was used, as was common practice in England in the late 1980s and early 1990s. Thus, although the subtle effects of different DMARDs tried first and subsequent changes cannot be accounted for, patients were being treated early in a conventional manner.
Detailed information from inception cohorts of RA with longitudinal follow-up of 5 yr or more with adequate numbers is sparse. There are, however, several published accounts of outcome in RA based on longitudinal studies with large numbers but with very variable disease duration at the time of recruitment, and these have reported progressive decline in clinical [21], radiological [22], physical function and health status measures over time [22, 23]. The major part of this decline occurred early (in the first 5 yr from first observation), followed by a more gradual decline [23], but late rapid deterioration has been described [24]. Wolfe and Cathey [19] found a trend towards improvement in some patients within the first years of observation in a longitudinal study, but that the underlying trend was towards progressive functional decline. None of these studies evaluated the time course of function in the early stages of RA, and so it is difficult to make valid comparisons, but all suggested major functional loss in most patients. Although the HAQ varied widely over time, functional outcome in our patients was better overall, and evidence for the rapid deterioration and marked reduction in functional capacity in early RA reported by Sherrer et al. [25] was fortunately only seen in small numbers. However, a small proportion of our patients did have poor 5 yr function (FGIII/IV 16%), and most of these patients already had poor HAQ scores at presentation (Fig. 2). In contrast to the above-mentioned studies, there was overall improvement in most clinical and laboratory measures in the first 3 yr of RA in our patients, which remained more or less stable at 5 yr.
Most of the few reported inception cohorts of RA from single centres with good follow-up used Steinbroker's functional grading as a measure of outcome. This may lack sensitivity for change (especially between FGII and III) but has been the most widely used in the past. The study from Memphis [26] reported on 50 early RA patients at 35 yr of whom 13 (26%) were in FGI and 10 (20%) in FGIII. Both the Middlesex [27] and Bath [28] studies reported on 100 patients each recruited within a year of onset of RA, with functional outcomes of around 60% in FGI and 13% in FGIII (at a mean follow-up of 4.5 and 3 yr, respectively). Our results are closest to a report of outcome in a small cohort of 63 Swedish patients [5], and in a study of second-line therapy in Scotland [29], although in the latter patients were highly selected on the basis of inclusion in clinical trials. Better outcomes have been noted in prospective studies of early RA compared with cross-sectional studies [4]. A recent editorial by Pincus and Callahan [30] reinforced the importance of properly conducted prospective studies of early onset RA which give a more complete picture of this condition.
Joint replacement or excision arthroplasty for RA was required in 11% of our patients by 5 yr of follow-up, with little difference between centres. Comparisons with other longitudinal studies are difficult because of differences in disease duration and changes in the type of and threshold for orthopaedic intervention in recent years, but a Swedish study in 1994 [5] reported a subgroup of 14% (nine patients) who required joint replacement within 5 yr.
Work disability has been addressed in studies mainly from the USA (cross-sectional studies) and northern Europe (longitudinal), most reporting work disability of 2950% by around 5 yr [6, 7, 3133]. The variation in results reflects the differences in study designs, social security arrangements and methods of ascertainment. In our patients, most patients in paid employment at presentation were still working (60%), work disability by 5 yr due to RA was 22%, and was higher in manual workers.
The identification of factors indicative of poor outcome early in the course of RA is crucial for tailoring treatment and supporting coping mechanisms. The strength and reliability of prognostic factors depend largely on the choice of outcome measure, with radiological damage more consistently predicted than function [4]. We have used clinical features most consistently associated with functional outcome, and although women and older age were both related to poor function at 5 yr, the HAQ at presentation had the strongest association.
The exact figures detailed in this report are derived from a true to life setting of standard rheumatological management and drug treatments offered to early RA patients in hospital rheumatology departments in England in the 1990s. By illustrating the magnitude of functional change attributed to RA, these figures are important in planning for the kind and extent of services required for managing RA in early stages. Is it possible to compare and contrast RA outcomes in current practice in other parts of the UK and Europe, and even set targets for these when planning the management of RA? If all patients are followed-up regularly using registers (as with management of diabetes), and standard measures (e.g. HAQ) are recorded prospectively, valid comparisons could be achieved. The assessment of drug treatment effects is limited in observational studies because of non-random assignment of therapy. None the less, newer agents can only be described as disease-modifying if they can be shown to alter cumulative disability in the long term. The ERAS database will permit a comparison of these new drugs with a well-described historical standard reflecting management and costs of RA during the 1990s.
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Acknowledgments |
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Notes |
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References |
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