Ankylosing spondylitis (AS) is a chronic rheumatic inflammatory disease of the axial skeleton, large peripheral joints, and entheses. AS is a member of the spondyloarthritides, a group of disorders that share common clinical, serologic, radiographic, and genetic features, including enthesitis, presence of the human leukocyte antigen-B27 antigen, and radiographic progression that may restrict spinal mobility and potentially evolve into complete spinal ankylosis [1]. Tumor necrosis factor (TNF), a proinflammatory cytokine, is present in biopsies of sacroiliac joints of patients with active disease, suggesting TNF involvement in the inflammatory process of AS [2].

The TNF antagonists etaneracept [3] and infliximab [4] have been shown to reduce the signs and symptoms of active AS and improve disease-related quality of life. In the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) and Canadian AS (M03-606) studies, adalimumab also demonstrated a reduction in signs and symptoms and improvement in disease-related quality of life in patients with active AS [5, 6]; these benefits were maintained over 2 years of treatment [7].

Treatment with adalimumab [8], etanercept [9, 10], and infliximab [11] has also been shown to reduce inflammatory activity, inhibiting the progression of radiographic damage in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). In vitro and in vivo models indicate that the bone destruction is mediated by TNF activation of osteoclasts [12–14].

Although TNF antagonists are effective in treating the signs and symptoms of AS, a clear relationship between TNF and spinal bone formation in patients with AS has not been established. Recently published studies have reported that neither etanercept [3] nor infliximab [4] inhibits structural progression in the spine of patients with AS after 2 years of treatment, suggesting that osteoproliferation in AS is independent of TNF. To further assess the relationship between TNF and spinal bone formation with adalimumab, we compared the radiographic progression in patients with AS treated with adalimumab for 2 years with that of TNF antagonist-naïve patients in a separate historical control group previously treated with conventional nonbiologic therapy.

In the present study, radiographic progression in patients with AS treated with adalimumab 40 mg eow was compared with radiographic progression in patients in the OASIS historical control group. There was no difference between the adalimumab and OASIS cohorts in the mean change in mSASSS from baseline to year 2 based on the primary efficacy analysis of patients' radiographs. Similarly, no difference between the adalimumab cohort and the OASIS cohort was observed when the analysis included only the subset of OASIS patients (OASIS-Eligible set) who satisfied the minimum baseline disease activity requirements of the adalimumab studies. Additional sensitivity analyses were performed to investigate other factors that could have potentially affected the results (for example, vertebral imputation), but these analyses did not reveal significant differences in radiographic progression between adalimumab-treated patients and the control cohort.

Intra- and inter-reader reliability was evaluated using ICC values. In AS studies, ICC values generally range from 0.6 to 0.7 [20]; ICC values in the present study were within expected ranges and did not contribute to the negative results.

The OASIS and adalimumab cohorts were heterogeneous with respect to baseline demographic and disease characteristics. Adalimumab-treated patients had significantly greater disease activity and mSASSS values compared with the OASIS cohort. In addition, a greater percentage of adalimumab-treated patients were taking NSAIDs at baseline. NSAID therapy has been reported to inhibit syndesmophyte formation and structural progression of AS; however, this finding needs to be confirmed [21]. Differences in baseline characteristics between the adalimumab and control cohorts had no apparent effect on radiographic progression. A more direct and stringent comparison between adalimumab and control cohorts would ideally be performed in a randomized, double-blind, placebo-controlled trial. However, owing to the rapid effectiveness of TNF antagonists in the treatment of AS, it would be unethical to conduct a 2-year, placebo-controlled trial to assess radiographic progression. Thus, the historical control OASIS cohort is the best available comparator for adalimumab-treated patients.

It is unclear why TNF antagonist therapy does not appear to inhibit radiographic progression in patients with AS. Given the insidious nature of spinal ankylosis, the 2-year timeframe of the studies may have been insufficient to fully assess radiographic damage and progression. There is one small study suggesting that infliximab slowed the progression of structural damage from 2 to 4 years of therapy [22]. However, that study had notable limitations, including differences in baseline disease activity (that is, BASDAI scores) between patients receiving infliximab versus traditional therapies (OASIS), and differences in scoring methods [22]. Therefore, this effect requires further investigation. It is possible that inhibition of radiographic progression may take even longer periods of continuous TNF antagonist therapy [23].

Initiation of anti-TNF therapy in patients with very early AS or preradiographic spondyloarthritis may prevent radiographic progression in the spine, but there are no data as of yet to confirm this hypothesis. The studies of radiographic progression in patients treated with etanercept, infliximab, or adalimumab included patients with long-standing AS and evidence of at least grade 2 sacroiliitis (satisfying the modified New York criteria [24]). Therefore, studies in patients with spondyloarthritis with preradiographic sacroiliitis or early evidence of sacroiliitis (and who do not yet satisfy the modified New York criteria) may be more likely to demonstrate inhibition of structural damage following TNF antagonist therapy. Adalimumab has been shown to significantly suppress serum concentrations of MMP-3, a biomarker that is a significant independent predictor of structural damage progression in AS [25, 26]. However, we found no significant correlation between change in radiographic progression and change from baseline in concentrations of MMP-3 for adalimumab patients in the Canadian study, which may reflect the small sample size. Longer-term studies will be needed to further assess the full impact of TNF antagonist therapy on radiographic progression.

One possible limitation of this study may be the use of the mSASSS scoring system for quantification of disease progression. This system is limited in that it takes into account the structural changes in the vertebral bodies and related soft tissues of the cervical and lumbar spine without evaluating possible further damage at the posterior elements of the cervical and lumbar spine, the thoracic spine, or the facet joints [20]. However, the mSASSS has been validated for AS and is currently the standard method for scoring radiographic progression [15, 20]. Moreover, because this method was used in the analysis of both the adalimumab and the OASIS cohorts, it is doubtful that the results of this study were influenced by the mSASSS scoring method. Moreover, the method was able to detect changes for more than 40% of the patients.

TNF is associated with inflammation and bone destruction in RA and PsA. TNF antagonists have been shown to reduce disease activity and inhibit the degenerative bone processes in RA and PsA [8–11]. In contrast, TNF antagonists have not been shown to inhibit the bone formation associated with AS despite amelioration of the signs and symptoms of the disease. Consistent with this observation, uncoupling of inflammation and bone formation has been reported in animal models of spondyloarthritis [27–29]. Recent evidence suggests that new bone formation may be more likely to occur at the sites of spinal inflammation in patients with AS; two studies reported that more syndesmophytes developed at inflamed vertebral edges than at noninflamed vertebral edges, although the majority of syndesmophytes developed at vertebral edges without inflammation at baseline [30, 31]. However, one study demonstrated the development of new syndesmophytes even when inflammation had resolved after anti-TNF therapy [31]. It has been proposed that each AS patient is likely to have several spinal lesions at different stages of evolution. In addition, it may be possible that very early lesions resolve with anti-TNF therapy prior to the induction of reparative changes, whereas for more mature inflammatory lesions, reparation is allowed to proceed following resolution of inflammation with anti-TNF therapy. The overall outcome for the individual patient is then little change at the level of the entire spine [32]. The observation that new syndesmophytes also develop where there appeared to have been no prior inflammation at vertebral corners also points to the possibility of non-inflammation-driven pathways of reparation [33, 34]. Further research is needed in this area.

In patients with long-standing AS, 2 years of treatment with adalimumab was effective in improving axial symptoms and reducing spinal inflammation but did not significantly inhibit radiographic progression. These findings are consistent with those reported with etanercept and infliximab. Additional studies that examine longer-term data with TNF antagonists and earlier use of TNF antagonists to inhibit inflammation and syndesmophyte formation are needed to better understand the relationship between chronic inflammation and spinal ankylosis in AS.