It has been long understood and well accepted that inflammation and structural damage are tightly connected in rheumatoid arthritis and that the degree of structural damage will be controlled if the inflammation is controlled.
Eric M. Ruderman, MD, associate professor of medicine at Northwestern University Feinberg School of Medicine in Chicago, moderated the session on the apparent disconnect between inflammation and disease progression in ankylosing spondylitis (AS) at the 2009 ACR/ARHP Annual Scientific Meeting in Philadelphia.
“Once TNF [tumor necrosis factor] blockers entered the arena, the link between inflammation and what was occurring structurally was found not to be so tight. Even though we are treating the symptoms, we may not in the long run be having any impact on the structural outcome of the disease,” he said.
A chronic inflammatory disease, AS preferentially affects the axial structure, with peripheral arthritis and extraarticular manifestations common. Inflammation of the enthesis is also common, with insertion of bone into tendons and ligaments, Dr. Ruderman said.
Effect of TNF Agonist Therapy
Desiree M.F.M. van der Heijde, MD, PhD, professor of rheumatology at Leiden University Medical Center in Leiden, The Netherlands, reviewed recent research that has investigated the efficacy of TNF blockers on progression of structural damage in AS. One trial used etanercept therapy; another, infliximab; and the third, adalimumab. In the trial with etanercept, Davis et al showed a sustained response in improvement of signs and symptoms of AS in patients receiving twice weekly doses of the agent.1 The Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) trial examined efficacy of infliximab versus placebo and found that the therapy decreased spinal inflammation as assessed by MRI.2
The two-year results of the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in Ankylosing Spondylitis (ATLAS) trial showed that adalimumab reduced the signs and symptoms of AS and induced partial remission for up to two years. As with etancercept and infliximab, the agent improved patient quality of life.3
Dr. van der Heijde reviewed results of two-year follow-up studies that compared radiographic progression between patients enrolled in those trials and those enrolled in the Outcome Assessments in Ankylosing Spondylitis International Study (OASIS). The OASIS trial began in 1996 at four European centers and is a longitudinal observational study. Patient use of nonsteroidal antiinflammatory drugs was comparable in all trials.
One of these follow-up studies compared progression in structural damage between patients enrolled in either the Canadian AS study or the ATLAS trial and those in the OASIS cohort. In the Canadian AS study and in ATLAS, patients had been treated with the TNF blocker adalimumab; patients in the OASIS trial had not received a TNF blocker. Radiographic progression in the spine at baseline and at two years was measured using the modified Stoke AS Spine Score (mSASSS) method.
Once TNF blockers entered the arena, the link between inflammation and what was occurring structurally was found not to be so tight. Even though we are treating the symptoms, we may not in the long run be having any impact on the structural outcome of the disease.
—Eric M. Ruderman, MD
Mean change in mSASSS from baseline to two years was 0.8 for the patients treated with adalimumab and 0.9 for those who had not received the TNF blocker, a non-statistically significant difference.4 The same was found in other trials that compared radiographic progression between patients treated with a TNF blocker and patients in the OASIS cohort, Dr. van der Heijde said.
Even though there was no effect on structural damage, there were “striking effects of MRI activity of the spine,” leading to questions about whether this contributes to formation of syndesmophytes, she said.
Three independent studies have looked at this correlation, with all patients given an MRI at baseline and over time. The MRI looked at the vertebral edge, with analysis of each vertebra as an independent unit.
Results showed that formation of new syndesmophytes is rare at sites with inflammation. “If there is a syndesmophyte, the majority are not associated with inflammation,” Dr. van der Heijde said.
“What we know now about TNF blockers is that they don’t seem to inhibit structural damage,” she continued. “However, it is still good to use them because they are effective on symptoms and signs of the disease,” and on functioning, spinal mobility, quality of life, inflammation as assessed on MRI, and bone mineral density.
Using Mouse Models
Rik Lories, MD, PhD, of the division of rheumatology at the Laboratory for Skeletal Development and Joint Disorders in KU Leuven, Belgium, said that progression of AS is characterized by spine or joint ankylosis due to new cartilage and bone formation that originates from extra- or intraarticular entheses.
His research has used mouse models of AS to understand the mechanisms of new bone formation in spondyloarthritides (SpAs). Dr. Lories and colleagues have proposed that bone morphogenetic protein is a critical player in the early phases of ankylosis in SpA and that WNT signaling through beta-catenin plays a crucial supportive role in this process, in particular in the progression of endochondral bone formation.
Their research, reported in Arthritis Research and Therapy, has culminated in an hypothesis about how the disease develops. “Activation of entheseal cells could lead to a double phenomenon: triggering of new tissue formation and production of proinflammatory molecules. The former can lead to restoration of tissue integrity or tissue remodeling. The latter phenomenon can develop into a chronic inflammatory process in which cytokines such as TNF play a pivotal role,” Dr. Lories and colleagues noted.
“A number of known factors may contribute to chronicity: the structural properties of HLA-B27, activation of the immune system by the presence of inflammatory bowel disease or infection, and polymorphisms in cytokines and cytokine processing molecules that lead to either more severe inflammation or delayed clearance of inflammation,” they said.
Development of SpA, therefore, is dependent on a complicated process resulting in chronic or recurrent inflammation, “but also to the triggering of new tissue formation, completely or partially independent of inflammation,” Dr. Lories and colleagues wrote.5
Current evidence from animal models suggests that “inflammation and new bone formation are linked but are largely molecularly uncoupled processes,” he said. The triggering of inflammation clearly leads to tissue destruction.
“The relationship between biomechanical stress, micro damage, acute inflammation and chronic activation of the immune system should be high on the research agenda,” Dr. Lories said. Current therapies only target the pain and symptoms of the disease.
Molecular Level
Dominique Baeten, MD, PhD, associate professor in Academic Medical Centrum in Amsterdam, said that much is still not known about bone formation and destruction in AS. “We don’t really know what is happening at the molecular level, and we can’t really connect it to the clinic right now.”
In his presentation of several hypotheses, Dr. Baeten suggested that there may be different kinds of inflammation that have implications for connective tissue, cartilage, and bone. “Triggering of inflammation clearly leads to tissue destruction. Perhaps by slightly different cytokines or inflammatory mediators, it can lead to tissue formation.”
There may also be another pathway through stromal activation directly to tissue formation, he said. “Very importantly, the mechanism may be completely different if you look at the synovial joint as we do in rheumatoid arthritis, or at the sacroiliac joint or peripheral joints.”
Kathy Holliman is a medical journalist based in New Jersey.
References
- Davis JC, van der Heijde DM, Braun J, et al. Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks. Ann Rheum Dis. 2005;64:1557-1562.
- van der Heijde D, Landewe R, Baraliakos X, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 2008;58:3063-3070.
- van der HD, Schiff MH, Sieper J, et al. Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: Long-term results from the ATLAS trial. Ann Rheum Dis. 2009;68:922-929.
- 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:R127.
- Lories RJ, Luyten FP, de Vlam K. Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis. Arthritis Res Ther. 2009;11:221.