Erosions in inflammatory polyarthritis are symmetrical regardless of rheumatoid factor status: results from a primary care-based inception cohort of patients
M. Bukhari,
M. Lunt,
B. J. Harrison,
D. G. I. Scott1,
D. P. M. Symmons and
A. J. Silman
ARC Epidemiology Unit, University of Manchester Medical School, Oxford Road, Manchester M13 9PT and
1 Norfolk and Norwich Hospital, Norwich, UK
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Abstract
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Background and aims. Symmetry is considered an important criterion for the differentiation of rheumatoid arthritis (RA) from other forms of inflammatory polyarthritis (IP), particularly those that are seronegative. Because of the inclusion of symmetry in the diagnostic and classification process, however, its true occurrence in RA cannot be assessed. As a surrogate, peripheral inflammatory arthropathies associated with rheumatoid factor production may be more likely to be symmetrical. We examined the degree of symmetry of erosions in an unselected cohort of patients with IP and tested the hypothesis that the presence of rheumatoid factor (RF) is associated with greater symmetry.
Methods. All patients registered with The Norfolk Arthritis Register (NOAR; a UK primary-care based cohort of patients with IP with annual follow-up) and who had radiographs performed at the fifth anniversary from notification were included in the analysis. Radiographs of the hands and feet were read using the Larsen method; a score of 2 or more in any particular joint indicated an erosion. Log-linear modelling was used to determine the symmetry of erosions between right and left for the following joint groups: wrists, metacarpophalangeal joints, proximal interphalangeal joints and metatarsophalangeal joints. Log-linear modelling was also used to determine the influence of RF on symmetry.
Results. Five hundred and thirty-seven patients contributed to the analysis. The median time to performing radiographs was 69 months (interquartile range 65.574.8) from the onset of symptoms. A total of 212 (39%) patients had erosive disease. Overall, IP was found to be a symmetrical disease. Despite there being more erosions in RF-positive patients, there was no greater excess of symmetry in RF-positive compared with RF-negative patients.
Conclusion. Radiographically, IP is a symmetrical disease irrespective of RF status. The use of symmetry as an important feature in identifying subgroups of patients with IP, such as RA, is challenged.
KEY WORDS: Inflammatory polyarthritis, Erosions, Symmetry, Modelling, Rheumatoid factor.
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Introduction
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Rheumatoid arthritis (RA) is generally considered by clinicians to be a symmetrical arthritis. As part of the process of developing criteria, attempts have been made to model clinical opinion (gold standard), and it is therefore not surprising that clinical symmetry is a criterion both in the 1958 American Rheumatism Association (ARA) classification criteria for RA [1] and the revised 1987 ARA criteria [2]. Symmetry is also frequently used as an important distinguishing feature in clinical diagnosis. Nevertheless, clinical symmetry is difficult to define precisely. Three issues have to be addressed. First, what is meant by joint involvement? The 1987 ARA criteria define this as joint swelling or effusion observed by a physician. Others have argued that classical rheumatoid deformities, such as ulnar deviation, even in the absence of swelling, should constitute involvement [3]. Secondly, which joint areas are included? The 1987 ARA criteria include only 14 joint areas when considering symmetry: the proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, wrists, elbows, metatarsophalangeal (MTP) joints and the ankle and knee joints on both sides of the body. Yet many RA patients have involvement of additional joint areas which could contribute to the assessment of symmetry. Thirdly, there is the question of the definition of symmetry itself. The American College of Rheumatology (ACR) definition [4] requires that more than 50% of the joint areas (of the 14 listed above) involved (swollen or with effusions) should show simultaneous involvement on both sides of the body. Absolute symmetry between, for example, the MCP joints is not required. Thus, the likelihood of symmetry is related to the number of joint areas involved; for example, any patient with involvement of more than 10 joint areas will be defined as having symmetrical arthritis.
By contrast, less attention has been paid to radiological damage as an indicator of symmetry. The assessment of radiological involvement has some advantages over clinical examination. Unlike joint swelling, radiological change is not reversible [5, 6] so it is easier to assess cumulative involvement.
We examined the prevalence of radiological symmetry in an unselected cohort of patients who presented with inflammatory polyarthritis of two or more joints, irrespective of any later classification as having RA. All were X-rayed 5 yr after presentation. In order to avoid the tautology of exploring symmetry in a disease defined as symmetrical (i.e. RA), we compared the prevalence of radiological symmetry between seropositive and seronegative patients. Our hypothesis was that peripheral inflammatory arthritis is more likely to be symmetrical when associated with RF.
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Subjects and methods
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We examined an incident cohort of new patients with IP. Radiographs of the hands and feet taken 5 yr from the onset of IP were examined for the presence of erosions. The symmetry of erosive disease was ascertained in all patients and then stratified by RF status.
Subjects
The radiographs of subjects recruited by the Norfolk Arthritis Register (NOAR) were used in this analysis. The NOAR is a primary-care based cohort of patients with incident undifferentiated IP. Details of the NOAR have been described elsewhere [7]. Briefly, adult patients with swelling of two or more joints that has lasted 4 or more weeks are reported to the NOAR by their general practitioner or the hospital. Patients who are later given a consultant diagnosis other than inflammatory polyarthritis, RA or psoriatic arthritis are then excluded.
Patients are examined in a standardized way by trained research nurses and 51 joints are evaluated for swelling and tenderness. Serological status is ascertained using a latex dilution technique and a titre of 1:40 or more is taken as a positive result.
Radiological examination
Patients in the NOAR are followed annually. At the fifth follow-up visit, all patients are asked to attend for radiographic examination of their hands and feet. Radiographs are read by two investigators, with adjudication by a third in case of disagreement on the presence or absence of erosions. Thirty joints are assessed radiologically: in the hands all PIP joints and the thumb interphalangeal joint, all the MCP joints and both wrists are assessed, and in the feet MTP joints 25 are assessed. The Larsen method is used to read the films [8]. A Larsen score of 2 or more for an individual joint indicates erosive change in that joint.
Statistical analysis
Clinical symmetry was said to be present at a particular assessment if 50% or more of the joint areas involved (i.e. with tenderness or swelling or both) were involved symmetrically. Eight joint areas were examined for symmetry of erosive change: PIPs, MCPs, wrists and MTPs on each side. Similarly, radiological symmetry was said to be present if 50% or more of the joint areas with erosions were affected symmetrically.
To determine whether there was more symmetry in the pattern of erosions than would be expected by chance, after taking into account the prevalence of erosions, log-linear modelling was used [9]. A detailed discussion of this is given in Appendix A. In brief, to assess symmetry at each of the four joint sites (PIP, MCP, wrist, MTP), a 2x2 table was constructed and the ratio or symmetry factor calculated. This was the ratio of the observed frequency of subjects with bilateral involvement to the expected frequency calculated from the numbers of subjects with either no erosions or unilateral erosions. The 95% confidence interval (CI) was calculated around this symmetry factor. Each table was then stratified by RF status and the ratio of the symmetry factor in RF-negative subjects to that in RF-positive individuals was calculated, together with the 95% confidence interval, this latter ratio being analogous to an interaction term between RF status and symmetry for that site.
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Results
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In all, 537 consecutive subjects with fifth anniversary X-rays were included in this analysis. The characteristics of these patients are shown in Table 1
. As shown, 69% of the patients were female. The mean age at study onset was 53 yr (S.D. 14.7 yr). Thirty-eight per cent of the patients were seropositive at any time during the follow-up period. Three-quarters of the patients cumulatively satisfied the ARA criteria for RA and 62% had evidence of clinical symmetry at any point in the follow-up period. Radiographs were performed a median of 69 months from onset of symptoms [interquartile range (IQR) 65.574.8 months]. Erosive disease had developed in 212 patients (39%) by the time of their fifth anniversary radiographic examination.
Table 2
shows the observed and modelled frequencies at each of the four paired sites and the expected number of subjects with bilateral erosions, given the number of subjects with either unilateral or no erosions. Details of how this number is calculated are given in Appendix B (note that it differs from the conventional expected value calculated using the marginal totals). For all joint sites, log-linear modelling found no significant difference between the prevalence of erosions between the left and right sides (P>0.1). The modelled frequencies, including the influence of symmetry, were close to the observed values. The statistic G2 is an estimate of the goodness of fit of the models and together with the P value shows the difference between the data modelled and data observed. The table shows that there was a marked increase in symmetry for all sites, the number of concordant subjects being much greater than expected. The symmetry factor was higher in the PIP joints as the observed frequency of concordant erosions was much more than expected from the marginal totals.
The increased symmetry between sites may, however, be an artefact measuring a general tendency to erosiveness. Thus, erosions in the right wrist may be associated with increased erosions generally and any increased occurrence in the left wrist is not a manifestation of symmetry. Indeed, when this was modelled, erosions at any one site increased the risk of erosion at other sites by a factor of 12 (95% CI 6, 26), 4.3 (95% CI 2.9, 6.4) compared with that expected by chance. We therefore attempted to determine whether there was a site-specific symmetry effect after allowing for the general effect. As the number of interactions involved in this approach is very large, we assessed this using a simple model restricted to the MCP and PIP joints. Thus, the presence of erosions in the PIP joints at one side increased the risk in the contralateral PIP joints by a factor of 29 (95% CI 16, 53) over and above the increase at other sites. This effect was the same for the MCP joints, and did not differ significantly between RF-positive and RF-negative patients; previous parameter estimates were uninterpretable because of higher-level interactions. These estimates are from a model that fits less well, but means something.
A comparison of patients who were seropositive and those who were seronegative is shown in Table 3
. Seropositive patients were significantly older (difference 4.1 yr, 95% CI 1.5, 6.6) and more seropositive patients satisfied the list criteria for RA when applied cumulatively. As expected, there were significantly more seropositive patients who had evidence of nodules. There were larger numbers of patients with psoriasis in the seronegative group (7 vs 3%), but this difference was not statistically significant. The numbers of swollen and tender joints were not different in the two groups. Clinical symmetry of joint swelling at any point during the follow-up period was seen equally in seropositive and seronegative patients. There were significantly more patients with erosive disease in the seropositive group. Figure 1
shows the cumulative percentage of joint sites affected in patients in both groups who had erosions. Patients who were RF-positive had more joint groups affected.
The models stratified by RF are summarized in Table 4
. After adjusting for RF status, erosions on one side were still associated with a greatly increased risk of erosions in the same joint area on the opposite side. As shown, the increase in risk did not differ significantly between RF-positive and RF-negative subjects at any site. The symmetry difference statistic was significant between RF-positive and RF-negative groups if the confidence intervals did not include unity. Indeed, the greater symmetry in RF-negative patients than RF-positive patients at the PIP approached statistical significance (P>0.06). This marked difference, however, was due to the difference in prevalence between seropositive and seronegative patients. As the prevalence of erosions on each side in the seronegative patients was very low, the expected number with bilateral erosions was extremely small (0.03). Thus, the observed excess (6), whilst being small in absolute terms, was extremely large relative to the expected number; hence the symmetry factor was also extremely large. The number of degrees of freedom differed depending on the model used to predict the numbers of concordant pairs. Again, there was no evidence of differences in the strength of this symmetry effect between RF-positive and RF-negative subjects (P>0.5).
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Discussion
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This analysis has demonstrated that IP in general is a symmetrical disease in terms of the occurrence of erosions. Importantly, it has shown that RF status does not unduly influence symmetry.
There are some methodological issues that need to be addressed in this analysis. First, patients with seropositive disease will have more and worse erosions [10, 11] and therefore we were comparing patient groups with differing prevalences of erosion. In our cohort, 47% of seropositive patients were erosive and only 15% of seronegative patients were erosive. The statistical approach used in this study adjusted for this and showed no difference in symmetry between the two patient groups.
Secondly, there may have been reader bias. Thus, there may have been a tendency for increasing ascertainment of an erosion on the contralateral side if one was found on the ipsilateral side. Ideally, reading of radiographs should have been performed by examining the right and left films independently. All X-rays were read by two observers, however, which should have minimized such a tendency.
Thirdly, we addressed the issue of disease symmetry by examining the occurrence of erosions. Traditionally, disease symmetry is considered on the basis of clinically overt joint involvement, but this may not necessarily be reflected in erosive damage. It is difficult to assess clinical symmetry cumulatively and current clinical status could be influenced by local therapy. The underlying assumption behind the current analysis is that radiographic damage is a more robust measure of symmetry. The conclusion reached, however, may not be applicable to the distribution of non-erosive joint involvement. The relationship between synovitis and erosions in individual joints has been reported as strong by a few investigators [1214], but Kirwan [15] reported a low correlation between clinical synovitis and erosive progression in individual joints.
Fourthly, there were inevitably losses to follow-up as a result of death, migration and other factors. It seems unlikely that there would have been selective loss such that the relationship between RF status and symmetry was different between participants and non-participants.
There have been a few reports in the literature which have described conflicting answers to the question of symmetry: a study comparing 50 RF-positive with 50 RF-negative patients showed no significant differences in symmetry [10]. However, in that study the seropositive patients had more symmetrical pairs of clinically involved joints, though not erosions, compared with the seronegative subjects. A further study of 17 RA patients who were seronegative, matched with seropositive controls, showed similar global symmetry, although seropositive patients tended to have more and larger erosions [16]. By contrast, in the study by Burns and Calin [11], symmetry in hand radiographs was more marked in the 30 seropositive patients (93%) than in the 16 seronegative cases. However, this was a comparison of global symmetry and did not assess individual joints or joint groups or the feet.
A larger study of 200 patients with RA [17], using an analysis similar to that used in the present study, illustrated that RF status did not influence symmetry. Patients were classed as symmetrical, partially symmetrical and non-symmetrical depending on whether exactly the same joint was affected on both sides or whether it was the same group of joints but not exactly the same joint. There were more patients with erosions in the seropositive group, and this might have influenced their estimates. Finally, Thould and Simon [18] reported that the more severe the radiological involvement in the feet, the less likely was asymmetry in their cohort of 109 patients with definite RA according to the 1958 criteria. There was no comparison of symmetry of the hand joints in that study.
Helliwell et al. [19], using mathematical binomial modelling, also found that clinical symmetry was a function of the number of joints involved. This was in an analysis of the difference between early and late psoriatic arthritis and rheumatoid arthritis.
Our findings are different from those observed in the literature in that we ignored the ARA criteria for RA in which symmetry would be a foregone conclusion and used an unselected cohort of patients with IP. We deliberately chose to study a group unselected by a diagnostic process influenced by the presence of symmetry. We have thus demonstrated that erosive joint damage is more frequently symmetrical than expected by chance, and this is the case irrespective of RF production.
Finally, a biological explanation for the symmetry of erosions has not been forthcoming, although there are some data to support neurological influence on inflammation. In one experiment [20], the electrical stimulation of C fibres in experimental animals produced a symmetrical inflammatory response despite being applied unilaterally. Other reports have shown that the injection of inflammatory crystals in one footpad of rats produces swelling in the other footpad [21]. This indicates that a mechanism exists whereby afferent nerves from one joint can induce an inflammatory response in the contralateral joint by inducing the release of inflammatory mediators.
In conclusion, patients with inflammatory polyarthritis display symmetry of erosive disease course independently of their RF status.
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Appendix A: Log-linear modelling
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Log-linear modelling is a method of modelling the frequencies in each cell of a contingency table. The natural logarithm of the cell frequency is modelled as a linear function of a number of parameters. If the frequency in the jth column and ith row is nij and we are fitting two parameters,
and ß, then the log-linear model would be
where xij and yij are variables which are specific to each cell.
If the contingency table to be fitted contains n cells, then n parameters can be fitted to provide a perfect fit to the data: this is called a saturated model. If fewer parameters are fitted, the difference between the fitted model and the saturated model can be tested with a likelihood ratio statistic (G2); if the difference between the models is not statistically significant, the simpler model is an adequate fit to the data.
To assess symmetry in a single joint, a 2x2 table needs to be modelled. Thus, up to four parameters may be fitted. The parameterization we used is shown in Table 5
. Parameter µ is a nuisance parameter, analogous to the constant term in a linear regression. Parameter
measures the overall prevalence of erosions, because it has a multiplier of 1 in each cell where there are erosions on one side and 2 in the cell with erosions on both sides. Parameter ß measures the difference in the prevalence of erosions on the left and right sides, as it has a multiplier of 1 in each cell in which there are erosions on the left side and 0 in each cell in which there are no erosions on the left side. If erosions on the left side occurred independently of erosions on the right, the expected frequency with erosions on both sides would be e(µ+2
+ß). The observed frequency is e(µ+2
+ß+
)=e(µ+2
+ß)xe
. Thus, the parameter
measures the relative excess of bilateral erosions that would be expected given the frequency of erosions on the left and right sides alone. The value of e
is referred to as the symmetry factor.
If we wish to model the effect of RF on symmetry, we need to stratify by RF status and model a 2x2x2 table. The parameters fitted are all of the above parameters and their interactions with RF status. Thus, we get a measure of overall symmetry from parameter
and the ratio of the symmetry effect in RF-positive patients to that in RF-negative patients from its interaction with RF status.
However, these models only measure the increased risk of erosion in a joint given erosions in the corresponding joint on the opposite side. This may be due to erosions occurring symmetrically, or it may simply be due to the fact that, given erosion at a particular site, the risk of erosions at all sites is increased. Strictly, symmetry implies that the elevated risk in the corresponding joint on the contralateral side is greater than the elevated risk in other joints. To test this, more complex models involving more than one joint site are required. However, the number of parameters required increases exponentially with the number of joint sites, and modelling all four sites simultaneously would require a table with 512 cells. Not only would this be prohibitively complex, but many cells would be empty, making inference problematic. Therefore a model containing only PIP and MCP joints was fitted to test whether the increased risk of erosion, given an erosion at one site, was greater at the contralateral site than elsewhere.
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Appendix B: Calculating the expected number of subjects with bilateral erosions
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Suppose that the probability of developing an erosion on one side is p and that this probability is same on each side. Then, if we assume that the erosions on one side are independent of erosions on the other side, the probability of no erosions is (1-p)(1-p), the probability of one erosion is 2p(1-p) and the probability of two erosions is p2. If a sample of n subjects is investigated, the observed and expected numbers of subjects with erosions on each side would be as in Table 6
.
We want to fit a model to the observed numbers a, b and c, and calculate the expected value of d from this model. The symmetry factor is then observed/expected. This amounts to calculating p2n in terms of a, b and c. The number of subjects with no erosions&!hairsp;=a=(1-p)2n and the number of subjects with erosions on one side=b+c=2p(1-p)n.
Now,
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Notes
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Correspondence to: A. J. Silman, ARC Epidemiology Unit, University of Manchester, Oxford Road, Manchester M13 9PT, UK. 
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Submitted 19 October 2000;
revised version accepted 7 August 2001.