Introduction
Physical functioning is a key outcome in chronic diseases such as axial spondyloarthritis/ ankylosing spondylitis, and should be closely monitored. There is modest evidence to show that physical functional status in ankylosing spondylitis correlates independently with both radiographic damage and disease activity. However, findings regarding the efficacy of current therapies in preventing radiographic progression of ankylosing spondylitis are sparse, and of limited quality.
In this article, we evaluate the extent to which current pharmacologic therapies for ankylosing spondylitis delay radiographic progression. In order to assess the efficacy of these therapies, however, we must first understand the context of disease progression for ankylosing spondylitis, as assessed by radiographs.
Measuring disease progression in ankylosing spondylitis
Radiographic progression in ankylosing spondylitis is generally assessed via the mean modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Measuring disease progression in ankylosing spondylitis is complicated by highly variable progression rates (even in the absence of immunosuppressants), slow-developing spinal lesions, and suboptimal study design.
Furthermore, syndesmophytes often do not develop until 5 years after baseline conventional radiographs. It is highly likely that therapies may have changed during such a prolonged interval; therefore, when attempting to determine whether current therapies slow radiographic progression, this prolonged interval introduces the possibility of confounding.
Some investigators have demonstrated that disease progression in ankylosing spondylitis is typically linear for cohorts of patients. However, individual patients frequently display nonlinear progression, which can occur at any time during their disease. This variation in individual disease courses manifests as wide standard deviations.
In one study, Ramiro et al found a standard deviation of 16.2 points, over 20% of the total mSASSS scale, when measuring radiographic progression. Similarly, Baraliakos et al found that while 43% of subjects were rapid progressors (showing a fourfold greater rate of progression than the mean), 25% of patients exhibited no progression (<1 new syndesmophyte or an increase of <1 mSASSS unit per year). This variation in individual disease course undermines any attempt to attribute progression to medication exposure.
Current therapies for ankylosing spondylitis
Current therapies typically prescribed for ankylosing spondylitis include nonsteroidal anti-inflammatory drugs (NSAIDs), traditional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologics. Each class of therapy has a fairly limited literature addressing radiographic progression via observational and interventional studies.
NSAIDs in ankylosing spondylitis
Most observational studies of NSAIDs do not evaluate radiographic progression, although Poddubnyy et al did identify retardation of progression with higher doses of NSAIDs, compared with lower doses. However, this evidence was encumbered by a lack of a concurrent control population, instead relying on quasi-controls, and only assessed for deflection of mSASSS scores compared with initial time periods. The effect was most pronounced in subjects with elevated C-reactive protein (CRP) levels and those with syndesmophytes at baseline.
These observational data may suffer from channeling bias, since patients are not randomly assigned to specific therapies; rather, physicians base their clinical decisions on existing patient disease activity. Channeling bias can be circumvented through interventional studies, since these potentially provide more causal information that links therapy with disease progression.
Despite several interventional studies investigating traditional NSAIDs and cyclooxygenase-2-selective NSAIDs in ankylosing spondylitis, radiographic progression has only been evaluated in two of (at least) 39 studies. Wanders et al reported a significant decrease in progression when continuously using NSAIDS (principally celecoxib) compared with intermittent dosages. These results were contingent upon CRP concentration.
The Effects of NSAIDs on RAdiographic Damage in Ankylosing Spondylitis (ENRADAS) trial by Sieper et al also evaluated radiographic progression, but did not find a significant decrease in progression with continuous versus on-demand diclofenac. It is unclear whether differences in study design or the selected NSAID are responsible for these results. Other studies have failed to include radiographic progression as an outcome, precluding any clear general understanding of the role of NSAIDs in slowing radiographic progression.
Traditional synthetic DMARDs in ankylosing spondylitis
Studies of DMARDs in ankylosing spondylitis have principally adopted an interventional study design. Approximately 20 interventional studies of DMARDs have been conducted thus far, but none have included radiographic progression as an outcome. Since the first studies using DMARDs treatment for ankylosing spondylitis were published in 1986, the majority of reports have suggested modest improvements in patients’ peripheral symptoms, but limited improvements in axial symptoms. This includes sulfasalazine, the most closely examined DMARD, which has been investigated in no less than 12 randomized controlled trials, including a recent study by Sharma et al. In light of these findings, it seems unlikely that radiographic progression of spinal disease would be delayed by DMARDs.
Biologics in ankylosing spondylitis
Data on treatment of ankylosing spondylitis with biologics include both observational and interventional trials. Among the observational data, a longitudinal cohort study involving patients from the OASIS study found that there was no association between biologic use and the inhibition of radiographic damage.
However, at least four subsequent studies (Prospective Study of Outcomes in Ankylosing Spondylitis [PSOAS], Follow Up Research Cohort in Ankylosing Spondylitis [FORCAST], Swiss Clinical Quality Management [SCQM], and Groningen Leeuwarden Ankylosing Spondylitis [GLAS]) have challenged this conclusion. These studies demonstrated that the use of tumor necrosis factor (TNF) inhibitors is associated with a reduction in the odds of progression of 50%, and that patients who initiated TNF inhibition treatment 10 years or more after disease onset were more likely to experience radiographic progression. This discrepancy could be explained by the fact that the mean disease duration in the OASIS cohort was 20 years, likely beyond the “window of opportunity” in early disease when biologics could be expected to retard disease trajectory.
Two additional earlier studies of adalimumab and etanercept in ankylosing spondylitis both found that TNF inhibitors were not associated with slower progression. However, these two studies were designed with methodological shortcomings in that the duration of follow up was too short (2 years), and cases and controls were drawn from different populations and therefore potentially subject to substantial bias.
Because this randomized controlled trial radiograph data is not compelling for biologics, the relationship between progression and biologics often must be inferred from magnetic resonance imaging (MRI) data. Studies evaluating the efficacy of infliximab and certolizumab in treating ankylosing spondylitis using MRI to monitor disease progression found a greater mean reduction in the MRI scores for the TNF inhibitor groups compared with the placebo-treated groups.
A similar study employing golimumab produced comparable MRI findings; however, by 4 years, according to radiographs, no difference in mSASSS was discernable when comparing those initially assigned to placebo and crossed over to 50 mg golimumab with those initially randomized to 100 mg golimumab. Lastly, Braun et al evaluated the effect of 150 mg and 75 mg intravenous doses of secukinumab on radiographic progression over 2 years. While the rate of progression was low for both doses of secukinumab, no formal comparisons were reported, and no true placebo group was included.
In both the golimumab and secukinumab studies, the placebo group was re-randomized to receive various doses of the interventional therapy. Since the majority of the observation period used to determine radiograph progression was spent with both arms receiving treatment (including those initially assigned to placebo), it is not surprising that no difference was recognized between the two groups.
Conclusion
In summary, small numbers of studies, methodologic limitations, high variation in patient characteristics, and limited use of radiographic outcomes in published trials prevent us from clearly determining whether existing treatments for ankylosing spondylitis prevent radiographic progression. Observational studies of TNF inhibitors are most consistent in suggesting that agents may retard structural damage. Future studies of NSAIDs, DMARDs, and biologics will likely continue to grapple with this question for some considerable time in the foreseeable future.
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