Predicting erosive disease in rheumatoid arthritis. A longitudinal study of changes in bone density using digital X-ray radiogrammetry: a pilot study

A. Stewart1, L. M. Mackenzie2, A. J. Black2 and D. M. Reid1

1 Osteoporosis Research Unit, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK and 2 Department of Rheumatology, NHS Grampian, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK.

Correspondence to: A. Stewart, Osteoporosis Research Unit, Victoria Pavilion, Woolmanhill Hospital, Aberdeen AB25 1LD, UK. E-mail: a.stewart{at}abdn.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Longitudinal results
 Discussion
 References
 
Objective. Periarticular osteoporosis is one of the first radiological signs of rheumatoid arthritis (RA). Osteoporosis is now quantified using dual-energy X-ray absorptiometry (DXA), although it was originally assessed by radiogrammetry. A new updated system of radiogrammetry has been developed: digitized X-ray radiogrammetry (DXR). We used this DXR system to identify whether changes seen in hand X-rays of RA patients can predict those who subsequently develop erosions.

Methods. We enrolled 24 patients with early RA and they attended for hand radiographs at baseline, 12, 24 and 48 months. The hand radiographs were analysed using a Pronosco X-Posure system which measures bone mineral density, and other parameters using DXR. DXA of the hand was also performed to measure bone mineral density. Sharp and Larsen radiographic scores were calculated and other disease activity markers were measured.

Results. DXR bone mineral density fell significantly throughout the study. The group of RA subjects were divided according to the change in erosive status. Change in DXR bone mineral density after 1 yr was very specific (100%) and highly sensitive (63%) in predicting those who either became erosive or whose erosions significantly worsened. In contrast, of the other disease activity markers, only baseline ESR (sensitivity 67%, specificity 80%) significantly predicted the erosive status of subjects at 4 yr

Conclusion. Computerized radiogrammetry from digitized images can predict at 1 yr those patients with RA who will become erosive at 4 yr. A larger prospective study is required to confirm these findings; however, these results show some promise as a method of targeting those patients who require more aggressive, expensive therapy.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Longitudinal results
 Discussion
 References
 
It is recognized that the earliest radiological feature of rheumatoid arthritis (RA) is periarticular osteoporosis [1, 2]. This predates erosive change on X-ray and therefore could be used to identify individuals with more aggressive RA at an earlier stage. Dual-energy X-ray absorptiometry (DXA) is an established tool for assessing osteoporosis, measuring bone mineral density (BMD) classically at the spine and hip sites, but also at specific sites such as the hand. It has been shown previously that measuring BMD, of the hand in particular, by DXA may be useful as a measure of long-term disease activity [3, 4].

Recently it has become possible to assess BMD using new software and digitized radiographs, providing an updated method based on radiogrammetry: digitized X-ray radiogrammetry (DXR) [5–7]. At the present time DXR has been seen as an alternative to DXA of the hand or wrist in the assessment of osteoporosis [8, 9]. It has been shown to correlate well with DXA [10–12]. This DXR method provides measurements of bone mineral density, porosity, cortical thickness and metacarpal index, and we have assessed this in a novel population of early RA subjects over a period of 4 yr. Previously it has been shown that DXA of the hand is associated with disease activity [3, 13–19]. Since DXR is strongly correlated with DXA (of the spine, hip and radius), we assessed the ability of DXR to predict erosive change in comparison to disease activity markers and DXA of the hand. Therefore the aim of the study was to assess whether DXR measurements of the hand are associated with disease progression in RA subjects.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Longitudinal results
 Discussion
 References
 
We conducted a longitudinal study examining the use of the technique in patients with early RA (within 1 yr of diagnosis). Twenty-four patients (16 females, eight males) were included in the study. RA was diagnosed according to the American College of Rheumatology (ACR) criteria by the attending physician. This was an observational study, and these patients were therefore managed according to routine clinical care. Nine patients were not taking any disease-modifying anti-rheumatic drugs (DMARDs) at baseline and eight were still not taking DMARDs at 12 months. The remaining patients were on DMARDs at standard dosage regimes, as follows: hydroxychloroquine, n = 4 at baseline and n = 1 at 12 months; methotrexate n = 1 at baseline, n = 6 at 12 months; penicillamine, n = 1 at baseline, n = 0 at 12 months; sulphasalazine, n = 9 at baseline and n = 9 at 12 months. At baseline these subjects were also on the following drugs: thiazides, n = 3; non-steroidal anti-inflammatory drugs, n = 19; hormone replacement therapy, n = 3; oral corticosteroids, n = 6 (duration 3–10 months). Four individuals had had a single intramuscular 80 g triamcinolone acetonide injection in the past year and 11 individuals had had one to three steroid injections in the past year. These patients attended at baseline and then at intervals of 12, 24 and 48 months. All patients gave written informed consent.

Plain radiograph of their hands were undertaken at each visit and were scored using both Larsen [20] and Sharp/van der Heijde [21] scoring methods. The X-rays were also scanned for DXR using the Pronosco X-Posure system, which gives measurements of bone mineral density in the second to fourth metacarpals (DXR BMD) of both hands, as well as a score for porosity (Por), metacarpal index (MCI) and cortical thickness (CT). Precision was calculated using 10 single sets of X-rays each measured five times, which were selected from this population; the coefficient of variation and standardized coefficient of variation were then calculated [22]. Hand BMD of the dominant hand was measured using a Lunar Expert (GE Medical Systems, Madison, WI, USA) scanner.

Disease activity markers were also measured at each visit. These were erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire (HAQ), C-reactive protein (CRP), early morning stiffness (EMS), Ritchie articular index (RAI), swollen joint count, tender joint count, pain as assessed with a 10 cm visual analogue scale (VAS) and the physician's global disease activity score using a VAS scale. In addition, disease activity scores (DAS) were calculated [23]. The study was approved by the Grampian Research Ethics Committee.

Statistical methods
All statistics were performed using SPSS v. 9 (SPSS, Chicago, IL, USA) or Medcalc v. 4 (F. Schoonjans, Mariakerke, Belgium). Pearson correlation was used. When examining serial longitudinal measurements we used a One-way repeated measures analysis of variance (ANOVA). We divided the subjects into two groups according to their erosion status at 4 yr. Group 1 (n = 10) was a group of subjects who were non-erosive at the beginning of the study and remained non-erosive throughout. Group 2 (n = 12) were non-erosive at baseline but at 4 yr were erosive, or were erosive at baseline and their erosions worsened (score increased by 5 or more) throughout the study. ANOVA was used when examining changes in bone mass measurements across the different erosion status groups. Receiver operator characteristic (ROC) analysis was performed to determine the sensitivity and specificity of a technique, and areas under the ROC curve (AUC) were calculated. For the ROC analysis the changes in bone mass measurements were continuous variables, while group 2 was used as the positive disease state and group 1 as the negative disease state.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Longitudinal results
 Discussion
 References
 
Relationship between bone measurements and anthropometric measurements
The baseline characteristics of the patients used in this study are shown in Table 1. When considering the relationships between hand BMD and the demographic characteristics of the patients, age was significantly correlated with MCI (r = –0.479, P = 0.018). Height was only significantly correlated with DXR BMD (r = 0.643, P = 0.001), CT (r = 0.561, P = 0.004) and hand BMD (r = 0.545, P = 0.007). Weight was only correlated with DXR BMD (r = 0.678, P = 0.001), CT (r = 0.613, P = 0.001) and hand BMD (r = 0.479, P = 0.021). Baseline Larsen and Sharp scores did not significantly correlate with any of the baseline bone measurements.


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TABLE 1. Demographic characteristics of study group

 
Precision of DXR technique
The coefficients of variation (root mean square method) for the Pronosco X-Posure system in the hands were 0.21% for DXR BMD, 10.8% for Porosity, 0.25% for MCI and 0.31% for CT. The standardized co-efficient of variation (SCV) was also calculated where the biological range of measurements were used instead of the mean value to calculate precision. The SCVs were 0.30, 1.68, 0.35 and 0.36% respectively. The least significant changes were 0.59, 3.29, 0.69 and 0.70% for DXR BMD, Por, MCI and CT respectively.

Dominant versus non-dominant hands
We conducted an analysis comparing dominant and non-dominant hands. There was a significant decrease in porosity in the non-dominant hand [mean of dominant hand = 3.96 (S.D. 1.45), non-dominant hand = 3.73 (SD 1.53): P = 0.019]. There was no significant difference between the hands for MCI and CT (P = 0.680 and 0.134 respectively), and there was a trend towards an effect of dominance on DXR BMD (P = 0.093). For all subsequent analyses we therefore used the dominant hand.


    Longitudinal results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Longitudinal results
 Discussion
 References
 
When examining our longitudinal results using one-way repeated measures ANOVA, DXR BMD, Por, MCI and CT did not change significantly over the period of the study (Table 2). We also compared the erosion status at just 1 yr with the changes seen in the bone measurements at 1 yr. Comparing those who remained non-erosive in the first year with those who either became erosive or whose erosions worsened, we found significant differences between DXA hand BMD (P = 0.013), Por (P = 0.038), MCI (P = 0.046) and CT (P = 0.048). DXR BMD showed a trend towards significance (P = 0.052).


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TABLE 2. Mean values over period of study, with P value for one-way repeated measures ANOVA

 
Ability to predict erosion status at 4 yr
We examined the changes in bone mass measurements across the erosion status groups. Table 3 shows the comparison across the groups using ANOVA. When we considered group 2 as a group of patients whose erosion counts deteriorated and compare them with group 1 (non-erosive throughout study) we found no significant differences for all the changes in bone measurements except for change in Por at 1 yr.


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TABLE 3. Comparison of change in bone measurements at 1 yr according to erosion status at 4 yr

 
An ROC analysis was performed to test the ability of the bone measurements to predict those whose erosions worsened (i.e. group 2) compared with those who stayed non-erosive (i.e. group 1). The sensitivities for changes at 1 yr in DXR BMD, Por, MCI and CT were as follows: 63, 75, 63 and 75% respectively. The corresponding specificities were all 100%. AUCs were 0.91 for DXR BMD, 0.93 for Por, 0.89 for MCI and 0.91 for CT. There were no significant differences between these AUCs.

We also performed ROC analysis on the disease activity markers and hand BMD. Of those measured, only change in Larsen or Sharp score at 1 yr (both AUC 0.90, sensitivity 80%, specificity 100%), ESR at baseline (AUC 0.73, sensitivity 67%, specificity 80%), white blood cell count at baseline (AUC 0.76, sensitivity 78%, sensitivity 67%) and change in total hand BMD at 1 yr (AUC 0.77, sensitivity 70%, specificity 100%) were significant. The DXR measurements were not statistically significant higher than ESR, white blood cell count and total hand BMD.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Longitudinal results
 Discussion
 References
 
To optimize therapy in RA patients, it would be beneficial to identify those patients who are going to suffer joint damage before erosions occur, to allow more potent and expensive therapy to be targeted to those who would benefit most. The scoring systems of Sharp and Larsen are not predictive of erosive change; rather they are measurements of current disease progression. However, they do relate to long-term disability [24–26]. It has been shown previously that hand BMD measured by DXA is associated with radiographic changes in early RA subjects, and there have been tentative suggestions that hand BMD may be a surrogate marker for long-term disease activity [27].

Recently a new method of assessing hand BMD has appeared in the form of DXR, a computerized form of the radiogrammetry [6], which was popular several years ago to measure metacarpal index and cortical thickness. This newer method has been shown to be highly reproducible by ourselves in this current study and by others [5]. This DXR method measures not only metacarpal index and cortical thickness, but also BMD and porosity (an arbitrary index). We found an inverse relationship between MCI and age, as was expected from previous studies [11], since MCI measures cortical thinning. The relationships found between DXR BMD, Por, MCI and CT and dominance have shown decreased porosity in the non-dominant hand. This suggests higher bone strength in the non-dominant hand, which is contrary to findings from other studies. This may simply be a reflection of the small numbers in the study, the arbitrary nature of the Por measurement or the fact that Por is less precise than the other measurements.

In our current study it appears that measurements of DXR are significantly associated with erosion scores in early RA subjects. Indeed it appears that changes seen at 1 yr with DXR BMD or the other measurements are predictive of those who will have erosions 4 yr later. When the least significant change (LSC) for all DXR measurements is calculated for those who remain non-erosive, the percentage change at 1 yr is within the precision of the scanner; however, the percentage changes seen in the erosive group far exceed the LSC. Examining the patients in groups according to changes in their erosion status is applicable, as clinicians would generally group patients into these categories when deciding on treatment. However, we are unable to examine associations simply in the group who were non-erosive at baseline due to small numbers in this pilot study. When an ROC analysis is performed looking at those who were non-erosive throughout the study compared with those whose erosions worsened (i.e. those who became erosive or in whom the number of erosions increased) the measurements were very specific (i.e. 100%) but were also sensitive (ranges from 63% to 75%). This appears to be better than all other disease activity markers which we assessed, of which only baseline ESR showed any predictive capacity. Therefore we may have a tool by which we can target those who require more aggressive management of their RA in order to prevent erosions, which will inevitably lead to disability.

In previous studies examining DXR and disease activity in arthritis subjects it has been shown cross-sectionally that DXR is able to distinguish the severity and progress of the disease [28] and is a useful measure of destructive disease activity in patients with RA and unclassified polyarthritis [29]. In this pilot study we have also shown that the DXR system may be a useful tool, since the measurements only require plain radiographs of the hands, which are used in routine clinical practice at present. The DXR system is also quick and precise (coefficient of variation is less than 1%) and could easily be used within a clinic situation. However, this study was in a small group of subjects and needs to be repeated in a much larger cohort of early RA subjects, and the cost-effectiveness of the procedure should be examined.


    Acknowledgments
 
This work was funded by Arthritis Research Campaign (ARC; grant number SO598/SO645). AS holds an ARC Postdoctoral Fellowship. DMR is thankful for continuing core support from the ARC. Thanks to Rebecca Barr, research assistant, for help in measuring DXR and Joanna Norris for helping recruit the subjects for the study. We are also grateful for the loan of the equipment from Pronosco.

Conflict of interest. DMR has declared that Pronosco loaned and eventually donated the equipment used to carry out this study. The other authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Longitudinal results
 Discussion
 References
 

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Submitted 7 April 2004; revised version accepted 23 July 2004.



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