This analysis provides further evidence for the longitudinal relationship between radiographic damage and physical function. As shown, progression of radiographic damage over short periods of time is associated with worse physical function, which is independent of the effects of inflammatory disease activity (DAS). In addition, patients who had negative radiographic progression tended to have better physical function than patients with zero or low positive progression scores. This finding gains importance in the light of the low radiographic progression rates that were found in the 2-year TEMPO trial.14
Despite these low progression rates, this (sensitive) longitudinal analysis suggests that any type of radiographic progression has repercussions for physical functioning. It may be argued that DAS and CRP inappropriately reflect disease activity and that the proposed association between radiographic progression and physical function would disappear if a variable that better reflects inflammatory activity were used. This is, however, highly unlikely. The contribution of radiographic progression to the HAQ score was similarly high before and after adjustment for DAS and CRP, so that both effects are truly separated (data not shown).
In a 10-year longitudinal study,18
we have previously observed that radiographic damage and disease activity independently contribute to changes in physical function in RA regardless of disease duration. Others have reported the longitudinal relationship between joint damage and physical function after adjustment for disease activity.19
In that particular study, performed on an inception cohort of patients with RA followed up for many years while receiving standard conventional antirheumatic treatment, the main driver of physical function was determined to be disease activity. But Welsing et al
also found a significant contribution of joint damage (measured by van der Heijde’s modification of the Sharp score) to explain the variation in physical function.19
There are important differences between these previous studies18 19
and our current study: First, we analysed a trial population using highly effective treatments. In our study, radiographic progression was minimal, although the level of baseline damage was, on average, substantial. Apart from that, the active trial treatment resulted in very low levels of disease activity in the majority of the trial population. Even with such a low level of variation in the determinants of function (disease activity and radiographic damage/progression) a relationship between radiographic damage progression and the HAQ score was suggested by this analysis. Second, in our study, we investigated the contribution of radiographic progression itself, rather than radiographic damage at any particular time point. Our analysis suggests that both the level of damage, and the progression rate, although very low, contributed to variation in physical function. Third, our observations were made in a 2-year follow-up study, whereas the previous studies18 19
investigated function over a period of 9–12 years, in which deterioration of physical function is likely to be far more substantial. Taken together, however, the longitudinal studies provide evidence that physical function in patients with RA is determined not only by disease activity but also by radiographic damage and the rate at which radiographic damage increases over time. Fluctuations in the progression rate and in the disease activity cause demonstrable effects on physical function within very short time intervals. These data add to the ever-growing evidence that it is important not only to suppress disease activity but also to halt radiographic progression to maintain physical function.
It is not a coincidence that studies using longitudinal data analyses are consistent with the existence of a relationship between radiographic damage and physical function. It has been hypothesised that this relationship exists, but it has turned out to be rather difficult to confirm it statistically in studies using cross-sectional analytical approaches.20 21
A longitudinal data analysis provides far more statistical power because it uses all available data of a prospectively followed cohort in an aggregated manner, while adjusting for spurious intra-patient correlation. Apart from that, longitudinal data analysis provides insight into how changes in disease activity and radiographic progression—for example, as a result of effective treatments, influence physical function.
Physical function is often considered to be a rather static outcome. However, recent experience from randomised clinical trials evaluating highly effective treatments has shown that impairment of physical function in patients with RA is reversible to some extent. In a recent analysis, Aletaha et al
reported that the irreversible part of the HAQ score was between 0% and 33%, increasing with the duration of RA.22
We hypothesise that this irreversible impairment is caused by structural damage, while the reversible impairment is primarily inflammation. If true, early effective intervention to limit structural damage may be helpful in decreasing irreversible physical impairment.
Many studies support the use of early treatment of RA. Landewé et al
showed that the best way to prevent radiographic damage is to start treatment before such damage has occurred.23
If this is not possible, aggressive treatment should be started within 12–24 months after the diagnosis of RA to limit radiographic progression over time.23
Anderson et al
showed that the rate of radiological progression is set during the early stages of RA and suggested resetting this progression rate through pharmacological treatment as soon as possible after the disease is recognised.24
Other studies support the finding that radiographic damage occurs early in the onset of RA and progresses throughout the disease.2 3 25–27
A recent meta-analysis showed that starting treatment early has a long-term benefit on inhibition of structural damage.28
This analysis demonstrated that the association between radiographic progression and physical function was similarly important in relatively early RA (disease duration
3 years) as compared with more advanced RA (disease duration >3 years), which emphasises the importance of minimising radiographic progression at all stages of the disease.
Rheumatologists frequently question whether the small differences in radiographic progression between trial arms are clinically meaningful. This analysis supports the view that subtle differences in radiographic progression have a measurable impact on physical function, although most probably at a level that is not truly clinically meaningful for the patient over a relatively short period. The question, however, is how physical function would be influenced if mild progression were allowed for years and years, using the argument that small fluctuations are not clinically meaningful.