EXPERT ANALYSIS FROM ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES
Structural damage in axial and peripheral ankylosing spondylitis is the result of a combination of destruction and new bone formation, which can be halted if treated early and for long enough, according to Dirk Elewaut, MD, PhD.
“There is a longstanding paradox in the field of ankylosing spondylitis, as to whether there is a strict relationship between the inflammation that leads to the signs and symptoms in patients, and the structural progression,” said Dr. Elewaut, who spoke at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “An overwhelming amount of evidence supporting the link between inflammation and new bone formation in ankylosing spondylitis has accumulated in recent years. ”
Early studies of anti–tumor necrosis factor (TNF)-alpha therapy over 2 years showed no structural progression of ankylosing spondylitis (AS) on radiography. However, more recent data indicated that a strong relationship exists between disease activity and structural progression ( Ann Rheum Dis. 2014;73:1455-61 ). “If you have inactive disease, it’s a relatively flat line, but if you have very high disease activity, there’s a very striking relationship between disease activity and the Ankylosing Spondylitis Disease Activity Score,” said Dr. Elewaut of the department of rheumatology at Ghent (Belgium) University Hospital. “We were missing something in the early clinical studies of anti-TNF alpha agent, and there are a few explanations as to why.”
One key reason why the early TNF inhibition trials showed no effect of treatment on structural progression stemmed from inadequate study design. “The original studies were underpowered, and the patients used NSAIDs,” he said. “We also know that the anti-inflammatory effect [of TNF inhibition] is not 100%. So you have a clear drop in inflammation with biologics, but it’s not completely stopped. This led to a lot of speculation as to whether inflammation and ankyloses are coupled or not.”
More recently, researchers have honed in on the transition from acute inflammatory lesions visible on MRI by bone marrow edema to so-called fatty lesions, which are also visible on MRI. They have observed that fatty lesions are associated with new bone formation. “Lesions containing more fat are thought to be more difficult to modulate by biological therapy,” Dr. Elewaut said. “Once you have a fatty lesion, you have some kind of metabolic disease of the bone, and it’s a one-way road to the development of new syndesmophytes. So in other words, it is essential to assess the relationship between inflammation and new bone formation with both the STIR [short tau inversion recovery images] and T1-weighted MRI.”
A working hypothesis among AS researchers is that the effect of anti-TNF therapy on radiologic progression depends on the relative number of acute and mature inflammatory lesions that individual patients have. “Early diagnosis is a prerequisite for advances in disease modification,” he said. At least three “windows of opportunity” for disease modification exist, Dr. Elewaut continued. One is that the link between inflammation as measured by clinical parameters and new bone formation will be more evident in early AS. The second is that early treatment of patients with axial AS and spinal inflammation with anti-TNF agents will prevent new bone formation. The third is that reduction of new bone formation in established AS will be observed only with long-term anti-TNF therapy after mature lesions have resolved/repaired, and no new inflammatory lesions are being formed. One study found that patients with a delay of more than 10 years starting anti-TNF therapy were more likely to progress, compared with patients who received therapy earlier (odds ratio, 2.4; P = .03; see Arthritis Rheum. 2013;65:645-54 ). “The message here is quite clear,” Dr. Elewaut said. “The earlier we treat intensively, the better impact you have on structural outcomes.”
In a trial known as CRESPA (Clinical Remission in peripheral SPondyloArthritis), researchers including Dr. Elewaut evaluated the efficacy and safety of golimumab (Simponi) to induce clinical remission in patients with early, active peripheral AS ( Ann Rheum Dis. 2017;76:1389-95 ). In all, 60 patients were randomized to golimumab or placebo for 24 weeks. At week 24, a significantly higher percentage of patients receiving golimumab achieved clinical remission, compared with placebo (75% vs. 20%, respectively; P less than .001). At week 12, similar results were observed (70% vs. 15%; P less than .001).
“These were very striking results in this early disease population,” Dr. Elewaut said. In a follow-up analysis, the researchers withdrew therapy in patients who reached clinical remission, to see what would happen. “At 1.5 years of follow-up, 57% of patients are in drug-free remission,” Dr. Elewaut said. “This is interesting and suggests that at least in a fraction of those patients, you can actually achieve a drug-free remission.” Predictors for relapse included pre-existing psoriasis and having more than five swollen joints.
Dr. Elewaut disclosed that he is a member of the speakers bureau for AbbVie, Novartis, Pfizer, and UCB. Global Academy for Medical Education and this news organization are owned by the same parent company.