In this study, we evaluated the association between disease activity and radiographic spinal progression in axSpA patients receiving TNFi who were included in a Spanish national registry (REGISPONSERBIO). Our results showed that disease activity measured by ASDAS is clearly associated with radiographic spinal progression in patients on TNFi treatment.
The duration of biologic treatment is an important factor in assessing its effect on spinal progression in axSpA. As previous studies showed a potential association between the duration of TNFi treatment and risk of progression (7, 9, 21), with no TNFi effect being observed within a follow-up period of 2 years (9, 22). Moreover, the potential long-term effect of TNFi on new bone formation is thought to be due to an effective suppression of inflammation. In this regard, new evidence suggests that inflammatory changes are followed by the replacement of subchondral bone marrow by repairing tissue which then stimulates osteoblasts, leading to new bone formation (1). Based on these observations, the association between disease activity and radiographic spinal progression was evaluated separately for patients receiving long-term treatment (TNFi ≥ 4 years) and patients treated for a shorter period. Our results showed that patients on long-term treatment with a mean sustained average of low disease activity measured by ASDAS over time show significantly less progression rates than those with high ASDAS averages. Conversely, in patients treated for less than 4 years who experimented radiographic progression presented a progressive increase of ASDAS mean score compared with those without progression. Such differences, however, did not achieve statistical significance until the third year of follow-up. Hence, our data supports previous studies that suggest a slowdown effect on radiographic progression associated to the maintenance of disease control in patients with axSpA treated with TNFi (3, 22).
To our knowledge, this is the first study suggesting that low disease activity is an appropriate target in the inhibition of radiographic spinal progression. As stated in the recent ASAS-EULAR management recommendations for axSpA, a treat-to-target approach is recommended (10, 23). Nevertheless, there is no absolute consensus about which specific target to use. Molnar et al. (9) suggest that inactive disease (ASDAS < 1.3) might be an adequate target for the inhibition of spinal radiographic progression. However, it might be quite challenging to achieve inactive disease in standard clinical practice, as only 25%-35% of patients achieve inactive disease status, according to previously published studies (18, 24). These observations are in line with those of our own cohort, in which only 23% of patients had inactive disease at the time of recruitment, while 52.1% of patients achieved low disease activity. Nevertheless, our findings suggest that low disease activity (ASDAS < 2.1) might be an appropriate target for preventing radiographic progression and a more reasonable treatment objective to achieve in clinical practice.
In our data, disease activity measured by BASDAI and CRP showed similar trends to ASDAS, although the association with progression status was weaker and did not show statistical significance. These findings are in line with previous publications, where despite an acceptable concordance between patient groups defined by BASDAI ≥ 4 and ASDAS ≥ 2.1 (25, 26), ASDAS is the preferred tool for assessing disease activity (10). As reported by previous authors, a longitudinal relationship between ASDAS and subsequent syndesmophyte formation was found, while such a relationship between BASDAI and syndesmophytes was far weaker (3, 27). Furthermore, ASDAS shows a better correlation than BASDAI when measurements of disease activity assessed by patients and physicians are compared (28). Finally, ASDAS cutoffs for disease activity and response criteria are well established and are based on a thorough validation process, in contrast to the BASDAI scale where thresholds have been defined in a more arbitrarily manner (24).
Our study had several limitations. First, not all REGISPONSERBIO patients could be included in the current study due to the unavailability of suitable radiographs. This point has negatively affected the final number of patients available for inclusion and further analysis. Secondly, conventional radiography might be an insensitive tool for detecting radiographic spinal progression compared to other imaging techniques. Low-dose CT has the potential to become the primary method used to detect radiographic spinal progression in axSpA in the future, as it has been shown to detect more progression in the form of new and growing syndesmophytes in patients with r-axSpA (29). Currently, conventional radiography requires a radiographic interval of at least 2 years to detect a relevant change, so long-term treatment is necessary before radiographic progression can be detected. Finally, although readers were blinded to all clinical data, radiographic scoring was performed with readers being aware of the chronologic order. However, this approach appears to be more sensitive for detecting change than reading with paired time order (30).
One of the strengths of our study is the prospective nature of the cohort used in our study, which provided disease activity data every 6 months over a follow-up period of 3 years. This amount of disease activity data offered an accurate picture of disease status in patients treated with TNFi. Additionally, this design allowed the use of statistical tools to analyze the data as an experiment of repeated measures (linear-mixed effects model). Finally, disease activity was assessed with ASDAS-CRP, BASDAI score and CRP serum levels, allowing comparison in terms of radiographic implications.