In recent years, there has been marked progress in the treatment of ankylosing spondylitis (AS) due to the availability of inhibitors of tumor necrosis factor alpha (TNFα). Treatment with these inhibitors has been shown to decrease serum inflammatory parameters.1 Multiple efforts have been made to characterize whether TNFα inhibitors are able to influence spinal radiographic progression in AS, with no definitive consensus formed to date.1,2

The development of advanced lesions in AS is thought to be influenced, in part, by vascular proliferation, with vascular endothelial growth factor (VEGF) playing a regulatory role in that process.3 Serum levels of VEGF have been shown to be increased in patients with AS, correlating with AS disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP).3 A predictive effect of the serum level of VEGF on the spinal radiographic progression of axial spondyloarthritis has been demonstrated in one study.4


To investigate the association between serum VEGF levels, spinal radiographic progression, and magnetic resonance imaging (MRI)-measured spinal inflammation in response to golimumab (GOL) therapy, Jurgen Braun, MD, and colleagues from the Ruhr-University Bochum, Berlin, Germany, analyzed longitudinal data from a multicenter randomized, double-blind, placebo-controlled trial of GOL in patients with AS (the GO-RAISE study).5  GOL is a fully humanized immunoglobulin G 1 kappa monoclonal antibody that binds to both the soluble and transmembrane forms of TNFα.

Patients with AS who were eligible for participation in the GO-RAISE study were diagnosed with AS according to the modified New York Criteria, had active disease (as defined by BASDAI ≥ 4 and a visual analog scale [VAS] spinal pain assessment score of ≥ 4), and had inadequate responses to current or previous nonsteroidal anti-inflammatory drugs or disease-modifying antirheumatic drugs.

These patients were randomized to receive subcutaneous doses of placebo, GOL 50mg, or GOL 100mg every 4 weeks until Week 16. At that time,  patients receiving placebo who had <20% improvement in VAS scores were re-randomized to receive either placebo, GOL 50mg, or GOL 100mg. At Week 24, all patients who were receiving placebo crossed over and received GOL 50mg. Patients in all treatment arms continued their treatment through Week 100. Long-term extension of the study, in which the GOL dose could be increased or decreased from 50mg to 100mg every 4 weeks, was then conducted at the treating physician’s discretion.

Serum inflammatory markers were collected for enzyme-linked immunosorbent assay at Weeks 0, 4, 14, 24, and 104. Radiographic examination took place at Weeks 0, 104, and 208 and was scored using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) method. Sagittal MRI scans of the cervical, thoracic, and lumbar spine were acquired at Weeks 0, 14, and 104. Radiographs and MRI scans were read by 2 independent examiners who were blinded to the treatment group, and chronology of images was obtained.

The researchers found no significant association between baseline serum VEGF levels and baseline presence of syndesmophytes.5 Furthermore, no difference was found in mean baseline serum VEGF or changes in serum VEGF in patients who did and did not have radiographic progression at Week 104 or Week 208. Absolute serum levels of VEGF or changes in VEGF levels were not associated with further radiographic progression or increased risk of new syndesmophyte formation at week 104 or 208.

“ROC analysis showed that using VEGF at baseline, Week 14, or Week 24 to predict syndesmophyte formation or mSASSS progression at Week 104 or 208 was no different from random chance,” the authors noted.

Summary and Clinical Applicability

In this study, levels of serum VEGF were not predictive of spinal radiographic progression of AS or formation of new syndesmophytes in patients receiving anti-TNFα therapy with GOL. These results suggest that the inflammatory process controlled by TNF inhibition may be partially uncoupled from new bone formation in the pathogenesis of AS.

“While angiogenesis is involved in early/active disease, once inflammation is largely quelled by TNF antagonism, angiogenesis is alsostopped and VEGF levels drop. However, bone formation through syndesmophytes, although initially stimulated by inflammation, continues for several years,” the authors conclude.

References

1.       Braun J, Baraliakos X, Hermann KG, et al. The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial. Ann Rheum Dis. 2014;73(6):1107-13.

2.       Van der heijde D, Salonen D, Weissman BN, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther. 2009;11(4):R127.

3.       Lin TT, Lu J, Qi CY, et al. Elevated serum level of IL-27 and VEGF in patients with ankylosing spondylitis and associate with disease activity. Clin Exp Med. 2015;15(2):227-31.

4.       Poddubnyy D, Conrad K, Haibel H, et al. Elevated serum level of the vascular endothelial growth factor predicts radiographic spinal progression in patients with axial spondyloarthritis. Ann Rheum Dis. 2014;73(12):2137-43.

5.       Braun J, Baraliakos X, Hermann KA, Xu S, Hsu B. Serum vascular endothelial growth factor levels lack predictive value in patients with active ankylosing spondylitis treated with golimumab. J Rheumatol. 2016; DOI: 10.3899/jrheum.150897.