NEW YORK – Late initiation of tumor necrosis factor inhibitors in patients with ankylosing spondylitis more than doubles their risk of radiographic worsening, according to a prospective study that provides insight into the natural history of this disease.
"We are probably looking at a window of opportunity. If we capture patients with more acute lesions, we may be able to inhibit the processes that drive progression that cannot be reversed once the lesions are more mature," reported Dr. Nigil Haroon of the division of rheumatology at the University of Toronto.
Dr. Nigil Haroo
The data presented by Dr. Haroon were characterized as the first to show a clear association between reduced ankylosing spondylitis (AS) damage and tumor necrosis factor (TNF) overall and early initiation of TNF inhibitors specifically. According to Dr. Haroon, earlier studies have not shown this association because of inadequate follow-up.
"AS is slowly progressive. Two years is not enough to see an effect," said Dr. Haroon, who noted that most TNF inhibitor trials have not exceeded this period. He believes at least 4 years of follow-up are needed.
Long follow-up is particularly relevant for showing benefit from anti-inflammatory therapy if, as described by Dr. Haroon, sustained inflammation is required to induce vertebral fat infiltration and if, in turn, this infiltration promotes formation of syndesmophytes. However, from the clinical perspective, there is now at least some evidence that early is better than late initiation of TNF inhibitors in AS patients at risk for progressive disease.
The clinical evidence is drawn from a five-center study with 334 patients published late last year and updated by Dr. Haroon at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (Arthritis Rheum. 2013;65:2645-54). However, Dr. Haroon primarily focused on the significance of these data as they relate to the natural history of AS.
In the study, the goal was to evaluate the impact of TNF inhibitors on spinal damage in AS. Overall, TNF inhibitors, vs. no TNF inhibitors, were associated with a 48% reduction in the odds of radiographic progression (P = .02), but the timing of TNF inhibitors was an independent predictor of benefit. In those who initiated TNF inhibitors 10 or more years after disease onset, the odds of progression was increased 2.4-fold (P = .03) relative to an earlier start. Duration of TNF inhibitor therapy was also inversely correlated with progression.
These findings are highly consistent with an independent series of studies conducted by Dr. Haroon and others who have linked sustained inflammation with vertebral fat infiltration. Visible on MRI, fat infiltration at the vertebral corners has been linked to metaplasia and the de novo syndesmophyte formation that characterizes radiographic progression.
"We are not 100% sure that inflammation and new bone formation are linked, but the evidence is accumulating," Dr. Haroon reported. The theory supported by the clinical study is that early control of inflammation aborts the pathologic process that leads first to vertebral fat infiltration and then to syndesmophyte formation.
Not all AS patients may benefit equally from TNF inhibitors from the perspective of disease progression. In the five-center study data presented by Dr. Haroon, only 30.5% of the patients experienced progression, defined by having at least a one unit per year increase in the mSASSS (modified Stokes AS Spine Score). Elevated baseline inflammatory markers, such as C-reactive protein, and smoking, for which there was a dose effect, were associated with progression after researchers controlled for baseline mSASSS totals. Other factors, particularly genetics, have also been strongly linked to risk of progression in AS.
Dr. Haroon reported no relevant financial relationships.