The impact of tumor necrosis factor α inhibitors on radiographic progression in ankylosing spondylitis

Abstract

Objective: To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS).

Methods: All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model.

Results: TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching.

Conclusion: Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.

Figure 1. Smoking and Rate of Radiographic Progression

Comparison of the rate of mSASSS progression in patients who smoked compared to those who do not. The rate of progression was significantly different from the group of patients who either did not smoke or smoked less than 10 pack-years. A clear increase in progression rate is seen with increasing total burden of smoking.

Figure 2. TNF-inhibitors and rate of radiographic progression

This shows the effect of duration and point of starting therapy among AS patients on TNF-inhibitors. (A) The duration of therapy in relation to the total duration of disease is plotted against the rate of progression. As patients remained on therapy for a greater proportion of their disease duration, the rate of radiographic progression decreased. There was a significant difference in the rate of progression in those patients who remained on the drug for more than 50% of their disease duration compared to others. (B) The delay in starting TNF-inhibitors was significant in determining the effect it had on the rate of progression of radiographic damage. The earlier the therapy was initiated, the better the results. (C) Cumulative probability plots show a striking difference in radiographic progression, with patients who got TNF-inhibitors within 10 years of onset of disease progressing at a much slower rate compared to those who received the drug after 10 years.

Figure 3. Zero-Inflated Negative Binomial Model for change in mSASSS scores over time

There were several patients who did not progress during the follow up period. Zero- inflated negative binomial model is conducted to account for many portions of zeros (55.4%) in over dispersed delta mSASSS. TNF-Inhibitor use was significantly associated with less progression (defined by change in mSASSS), when patients were followed up for more than 3.9 years. There was no significant difference between two groups during early time period. The expected decrease of delta mSASSS in the TNF-inhibitor user group compared to non-user group was 58% (Relative Ratio (RR)=0.42, 95% CI= [0.18, 0.98], p=0.044).