What factors influence functional ability in patients with rheumatoid arthritis. Do they alter over time?

M. J. Plant, M. M. O'Sullivan1, P. A. Lewis2, J. P. Camilleri3, E. C. Coles4 and J. D. Jessop3

The James Cook University Hospital, Middlesbrough TS4 3BW, 1 North East Wales NHS Trust, Wrexham, North Wales, 2 Department of Mathematical Sciences, University of Bath, Bath, 3 Department of Rheumatology, University Hospital of Wales, Cardiff and 4 Department of Epidemiology, Statistics and Public Health, Cardiff University, Cardiff, UK.

Correspondence to: M. J. Plant, Department of Rheumatology, The James Cook University Hospital, Middlesbrough TS4 3BW, UK. E-mail: michael.plant{at}stees.nhs.uk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To describe the changes in functional ability (FA) taking place over 5 yr in patients with rheumatoid arthritis (RA) starting disease-modifying anti-rheumatic drug (DMARD) therapy, to investigate the factors having most influence upon FA and to compare these factors at baseline and after 5 yr of treatment.

Methods. Three hundred and sixty-six patients with active RA were studied as part of a 5-yr randomized controlled study of DMARD therapy. FA was assessed by Health Assessment Questionnaire (HAQ) score every 6 months. Multiple linear regression was used to identify factors affecting FA at baseline and at 5 yr. The independent variables used were age, sex, visual analogue scale (VAS) pain, Ritchie articular index, C-reactive protein (CRP), Larsen score and log-transformed morning stiffness (EMS).

Results. Mean HAQ score was 1.64 at baseline, improved by 21% at 1 yr and gradually returned towards baseline levels by 5 yr. At baseline only 34% of variance in HAQ score could be explained; the most significant explanatory variables were the Ritchie articular index and CRP. At 5 yr the variance explained was 60%. The Ritchie articular index remained the strongest factor followed by VAS pain, log10 EMS and Larsen score.

Conclusions. Improvement in function did occur after commencement of the first DMARD therapy but was not maintained to 5 yr. The most consistent factor affecting function was joint tenderness. Global pain and duration of EMS were of lesser importance. Disease activity measures such as the CRP exerted an influence in the earlier, more active stages of disease: radiographic damage assumed greater importance as the arthritis progressed.

KEY WORDS: Rheumatoid arthritis, Follow-up studies, Functional ability, HAQ, Radiography


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
From the perspective of the patient with rheumatoid arthritis (RA), control of symptoms and the prevention of disability are key indicators of successful treatment. Evidence of changes in function can be difficult to identify and monitor, but the development of the self-report Health Assessment Questionnaire (HAQ) [1], has enabled the subject of disability to be examined in quantitative detail in large groups of patients. The need for prospective studies of functional ability (FA) has been emphasized, not just over the short term of 1 or 2 yr but more importantly over the medium and long term [2].

The first prospective studies of functional disability using HAQ over at least 5 yr were reported in 1991. Disability was found to be an early feature, generally followed by a slow but steady deterioration [3–12]. Since 1995, investigators have concentrated on early RA cohorts [13–27]: some of these studies have demonstrated stable function or improvement.

Interpretation of data concerning function is complicated by the fact that many factors influence the degree of disability expressed by the patient. Some of these factors are related to the rheumatoid disease itself. Such intrinsic factors include the degree and extent of tissue inflammation (disease activity) and the amount of structural damage that has accumulated over time (usually assessed by radiography). The correlations between function and radiography are inexact [28]. Serial measures of the disease activity marker, C-reactive protein (CRP), do correlate with changes in FA, but again the correlation is only modest [29]. Therefore, it seems likely that additional factors operate that are extrinsic to the rheumatoid process. Such variables include age, morbidity from coexisting medical conditions and psychosocial variables [30]. Some disease parameters may have both intrinsic and extrinsic components. For instance, pain arises from inflammation and from structural damage and is modulated by central processing and psychological factors. The relative importance of these factors may vary according to the stage of disease. Recent reports have suggested that disease activity exerts a greater influence on FA than does structural damage, particularly during the early stages of RA [13, 28].

We have undertaken a longitudinal descriptive study over 5 yr of RA patients starting their first disease-modifying anti-rheumatic drug (DMARD). Annual changes in functional ability are documented. The main objective was to explore which factors most influence patients' functional ability. Candidate factors were demographics, clinical and laboratory measures of disease activity and radiographic damage. In particular, we aimed to compare the relative contribution to disability of disease activity measures and radiographic damage, both at baseline and after 5 yr.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This investigation comprised a secondary analysis of 541 patients who took part in a 5-yr randomized controlled trial of DMARD therapy [31]. Patients were recruited through the Rheumatology Department at the University Hospital of Wales between 1981 and 1989. The study design and flow of participants through each stage have been described in detail in a previous report [31]. All patients had active disease defined by the presence of at least three of the following criteria: six painful joints, three swollen joints, erythrocyte sedimentation rate (ESR) >28 mm/h, morning stiffness (EMS) >45 min, radiological progression. The HAQ was not introduced to the United Kingdom until 1983. This current investigation is restricted to 421 patients with HAQ scores at baseline and after 5 yr (range 4.6–5.4 yr).

Patients were randomly allocated to receive one of four DMARDs: D-penicillamine, hydroxychloroquine, sodium aurothiomalate or auranofin. In the event of adverse effects or lack/loss of efficacy, patients were randomized to one of the alternative DMARDs.

Clinical, laboratory and functional assessments were made every 6 months. Clinical assessments included: pain visual analogue scale (VAS) (0–10 cm), duration of EMS, Ritchie joint tenderness index [32], grip strength, painful joint score. The painful joint score was devised locally to denote the number of joints that were painful on active movement (range 0–17).

Functional ability was assessed by HAQ [1, 33]. HAQ is a 24-point self-report questionnaire covering eight domains of daily activity. Laboratory assessments included haemoglobin, ESR, CRP and rheumatoid factor.

Annual radiographs of the hands/feet were scored by an experienced musculoskeletal radiologist [35]. Each film was graded according to the method of Larsen [34] with reference to previous films. Thirty-two joints were scored using a 0–5 scale. The Larsen score was modified by exclusion of grade 1 [35].

Statistical methods
The aim of the statistical modelling was to fit two robust and parsimonious multivariable models with HAQ, at initial recruitment and at 5 yr, as dependent variables (see Table 2). As well as demographic factors (age, sex), candidate explanatory variables were those covering radiographic damage (modified Larsen score) and a number of indicators of disease activity (VAS pain, Ritchie index, CRP, EMS) at the appropriate time period (baseline or 5 yr). Table 1 shows these variables with their bivariate correlations with the relevant HAQ score. Those submitted as candidate variables are indicated with a.


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TABLE 2. Multiple linear regression models of factors affecting functional ability at baseline (top) and at 5-yr follow-up (bottom)

 

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TABLE 1. Baseline characteristics of the cases included and excluded from the multiple regression analysis

 
Care was taken to avoid inclusion of pairs of variables with high internal correlations. Thus, CRP was included instead of ESR (correlation 0.61) and Ritchie index was included instead of painful joint score (correlation 0.46). Given the substantial positive skew of the distribution of EMS, a log-transformed version was used.

Case selection was by exclusion of the 55 cases with missing values for the chosen candidate explanatory variables. Multiple linear regression models were fitted for the 366 cases using the stepwise procedure in SPSS. The probability for a variable to enter the model was set at 0.01: probability for removal was set at 0.02. Residuals were checked for normality after the addition of each explanatory variable.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Table 1 compares the baseline characteristics of the study group with the patients excluded because of incomplete data: no important differences were evident. Mean disease duration was 4.2 yr: 10% of patients had a disease duration >10 yr.

Disease parameters over the course of the study are shown in Fig. 1. For reference purposes, the details of the dataset are included in an additional table to be found as supplementary data at Rheumatology Online. Mean HAQ score was 1.64 at baseline; it fell by 21% at 1 yr to 1.29 and then gradually returned towards baseline levels. CRP and ESR levels followed a different course. At 1 yr mean CRP and ESR had reduced by half and remained approximately constant thereafter. Larsen score increased linearly by 36% over the 5 yr. VAS pain levels, duration of EMS, Ritchie index and painful joint score all decreased over the course of the study by 17–33%.



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FIG. 1. Changes in HAQ, CRP and modified Larsen score over the course of the 5-yr study. Values are median, 25th and 75th centiles.

 
Spearman correlations between disease variables and HAQ score at the same time point are shown in Table 1. The highest correlations with HAQ were found for Ritchie index, VAS pain and painful joint count. Lesser correlations were seen for haemoglobin (Hb), ESR, CRP, sex and log-transformed EMS. The Larsen score showed correlation at 5 yr but not at baseline. No significant correlation was seen between HAQ and age, disease duration or rheumatoid factor.

Development of functional disability was compared with serial CRP measurements over the period of the study and with change in radiographic score. Spearman correlation between change in HAQ score and time-integrated CRP was 0.23: correlation between change in HAQ and change in Larsen score was 0.20. This relative lack of correlation between functional ability and time-integrated CRP, Larsen score and other parameters prompted us to perform a cross-sectional multivariate analysis to identify the factors associated with functional disability.

Stepwise multiple linear regression models were fitted for the baseline state and 5-yr review, using HAQ as the dependent variable. The seven independent variables used were: age, sex, VAS pain, Ritchie articular index, CRP, modified Larsen score and log-transformed EMS.

At baseline, only 34% of variance (adjusted r2 value) in HAQ score was explained; variables selected were Ritchie articular index, CRP, sex, VAS pain and log10 EMS. Larsen score and age were not selected (Table 2). At 5 yr the variance explained was greater, at 60%. The Ritchie articular index remained the strongest factor followed by VAS pain and log10 EMS. The Larsen score entered the model, replacing CRP.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This prospective study of patients with established RA starting their first DMARD has shown that over 5 yr FA improved initially and then reverted to baseline levels. Patient management reflected the practice of the 1980s and the choice and timing of DMARDs at that time, particularly with regard to attitudes concerning treatment of early, mild and relatively stable disease. All patients were treated with analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroid injections, and were referred for physiotherapy, occupational therapy and orthopaedic surgery as indicated.

The first studies to describe FA using the HAQ score over 5 yr or longer were reported in the early 1990s: the patients included were regular clinic attendees with a wide range of disease duration up to 20 yr [3–12]. Their baseline HAQ ranged between 0.69 and 1.88. All of these studies except two showed a gradual increase in HAQ score [3–10]. The exceptions were the studies by Callahan et al. [11] (no change over 5 yr) and Munro et al. [12] (initial improvement). Our own study was similar to these reports in that our patients had established disease with a relatively high baseline HAQ of 1.64. Our study differed in that a designated level of disease activity was defined, whereas other studies generally required only the diagnosis of RA. Like the Munro et al. study, all our patients were starting DMARD therapy: this might explain why these two studies demonstrated temporary functional improvement. This requirement for our patients to reach a ‘threshold’ of severity may also explain why disease duration did not correlate with HAQ.

Since 1995, investigators have tended to focus on cohorts with early RA inception. Such cohorts tend to have less disability at baseline (HAQ 0.28–1.3). Of these studies, six have shown gradual deterioration [13, 17–21], five showed no change [14–16, 22, 23], two showed non-sustained improvement [24, 25] and two showed sustained improvement [26, 27]. Overall, the more recent publications have observed a better functional outcome. This better prognosis could certainly be the result of earlier treatment and more effective treatment, such as the use of methotrexate alone or in combination with biological therapies; equally it could reflect a less severe natural history for early disease.

Our main objective was to explore the factors affecting functional ability and to compare these relationships both at baseline when disease was active and after 5 yr of treatment. The Ritchie score was the dominant factor at both the start point and end point of the study. The most striking trend between baseline and 5 yr was that CRP (the second most important variable at baseline) was replaced by radiographic damage, EMS and VAS pain at 5 yr. At this stage, mean disease duration was 9.2 yr in our study. This suggests that radiographic damage becomes an important factor affecting FA as disease progresses and as patients become stabilized on DMARD therapy. Results from three other studies are remarkably consistent. All demonstrated that radiographic damage does exert a significant effect on function but only after 6 to 12 yr [13, 25, 28].

Why is the relationship between function and articular damage not stronger? It is important to understand the strengths and weaknesses of the assessment tools. We have used HAQ as our sole indicator of function as it is well validated and widely used. However, some authors have suggested that HAQ may exaggerate the level of disability and have a bias towards large joints such as the hip, knee and shoulder [36–38]. This latter point is especially relevant to our analysis, as Larsen scoring only encompasses the hands and feet. Furthermore, two groups have challenged whether HAQ is accurate in evaluating progressive changes over time [7, 20].

Radiography is generally used for evaluation of structural damage because it is objective and quantitative. Scott et al. [28] suggest that there may be a threshold effect below which radiographic damage does not lead to functional deficit. Clearly the relationship of the hands and feet to the larger joints is crucial. Although Kuper et al. [39] have shown a correlation between large and small joints for X-ray change, other data suggest that large joint damage actually explains more of the variation in HAQ score [40].

Our multivariate analysis indicated that five factors give the greatest explanation of variance in HAQ score: Ritchie index, VAS pain, CRP, Larsen score and EMS. It was anticipated that age (by reducing functional reserve) and sex might also have significant influence. Neither of these variables was significant, in keeping with observations by Molenaar et al. [41].

Others have found pain to be the most important explanatory variable for function [42], but joint tenderness has not been investigated before in this respect. In our study, the Ritchie index was clearly the most significant variable at baseline and at 5 yr. The Ritchie index is an observer-based assessment of aggregate joint tenderness and seems to convey different information from the patient's own perception of overall pain. It is known that persistently swollen joints tend to develop greater radiographic damage; this accords with the idea that joint swelling is a marker of disease activity. By contrast, tender joints are not strongly associated with radiological progression [29] but are associated with disability. This observation suggests that tender joints may reflect different or additional aspects of a patient's disease. On a more pragmatic level, tender joints are likely to inhibit a patient from using their joints fully, and the very presence of tenderness might induce a patient to report a daily activity as ‘very difficult’ rather than just ‘difficult’ in the HAQ questions. So, it seems likely that joint tenderness is an important phenomenon in its own right, with a major impact upon function, that is independent of disease activity and joint inflammation.

Functional disability in RA patients is clearly a complex and multifactorial phenomenon. Several groups have recognized a link between disability and psychological status [20, 43, 44]. Others have pointed to educational status, socio-economic class and general symptomatology as being important [20, 45].

In conclusion, this prospective study shows that improvement in functional ability did occur after the start of DMARD therapy in the 1980s but was not maintained to 5 yr. It therefore provides a useful comparator for novel therapeutic strategies. The most important and consistent factor affecting functional ability is joint tenderness. Global pain and morning stiffness are of lesser importance. Multivariate analysis suggests that measures of disease activity such as the CRP exert an influence in the earlier, more active stages of disease, whereas structural damage as demonstrated by radiography assumes greater importance as arthritis progresses and as the disease activity subsides.


    Acknowledgments
 
We are grateful to the following who assisted with the study: Mrs D. L. Lougher, Mrs C. E. Vokes (metrologists), Mrs A. M. Jessop (research assistant), Mrs J. A. Bethel (database manager), Mrs C. A. Rowlands (data assistant) and Mrs S. Hopkins (research nurse).

The authors have declared no conflicts of interest.

Supplementary data

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    Supplementary data are available at Rheumatology Online


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 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 4 March 2005; revised version accepted 6 May 2005.



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