Ankylosing Spondylitis: Prolonged Anti-TNF Stops Damage

Janis C. Kelly

July 22, 2013

( UPDATED July 25, 2013 ) — A major observational study in ankylosing spondylitis (AS) published online July 1 in Arthritis & Rheumatism revealed that tumor necrosis factor (TNF) inhibitors significantly reduced the risk for radiographic progression, that the benefit became apparent after nearly 4 years of treatment, and that the benefit was lost if treatment began late.

"Our key finding was that TNF-inhibitor treatment of AS was associated with a 50% reduction in the odds of progression in the overall cohort. If you don't start the treatment early enough, you lose the benefit of decreasing that risk of progression because there is a window of opportunity that would be missed," senior author Lianne S. Gensler, MD, told Medscape Medical News. Dr. Gensler is assistant clinical professor of medicine, University of California, San Francisco.

Three prior studies had reported no radiographic benefit from treating AS with adalimumab, infliximab, or etanercept. Dr. Gensler pointed out that those studies included only 2 years of treatment.

"Not only do you need to begin TNF-inhibitor treatment early but you need to continue it for a long time. The branch in radiographic progression with vs without TNF-inhibitor treatment was at 3.9 years. Clinically, that would mean that it takes almost 4 years of treatment to see the benefit," Dr. Gensler said.

The researchers, led by Nigil Haroon, MD, from the University Health Network, University of Toronto, Ontario, Canada, conducted a prospective study of 334 patients with AS. Patients were treated with standard care including nonsteroidal anti-inflammatory drugs (NSAIDs) and TNF inhibitors. Progressors were defined as having change of more than 1 unit/year by the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS). Because of the high number of nonprogressors, the researchers used a zero-inflated negative binomial model with varying follow-up periods, in addition to univariable and multivariable regression analyses. Multivariable analysis included the Bath AS Disease Activity Index, erythrocyte sedimentation rate, C-reactive protein, HLA-B27 status, sex, age of onset, smoking, and baseline damage.

TNF-inhibitor treatment was associated with a 50% reduction in the odds of progression. Patients who did not begin TNF inhibitors until 10 or more years after disease onset were twice as likely to progress as those who started treatment earlier. TNF-inhibitor treatment significantly reduced progression in the zero-inflated negative binomial model when the gap between X-rays was more than 3.9 years. NSAIDs were not associated with decreased progression risk.

"An important question for future research is whether NSAIDs make a difference in AS or not. It would be useful to have data showing whether the NSAID benefit can be reproduced in patients like our cohort and whether there is a synergistic effect between NSAIDs and TNF inhibitors," Dr. Gensler said.

"These are interesting data, and this seems like a good analysis," Arthur F. Kavanaugh, MD, told Medscape Medical News. Dr. Kavanaugh, who is director of the Center for Innovative Therapy at the University of California, San Diego, School of Medicine, was not involved in the study.

Dr. Kavanaugh said that from the clinician's perspective, the key questions about TNF-inhibitor treatment in AS are the risks vs benefits in terms of signs and symptoms.

Dr. Gensler agreed. "We really do have to base treatment decisions on signs and symptoms. I don't want clinicians to be lost in the fact that now we have a drug that prevents progression and assume that every AS patient should be on it."

Current guidelines call for first trying at least 2 NSAIDs (2 weeks each) over the course of 1 month before changing to TNF inhibitors, but they do not specify how to make the change.

"My opinion is not to drop the NSAID until the patient is in remission on the TNF inhibitor unless the patient is not tolerating the NSAID," Dr. Gensler said. "If you make too many changes at once and there is no response, you don't know whether it is because you dropped the NSAID or because the patient does not respond to the TNF inhibitor."

However, Pedro Machado, MD, who wrote an accompanying editorial, was unconvinced by the study data. Dr. Machado is currently a researcher in the Rheumatology Department at Leiden University Medical Center in the Netherlands and trained in the laboratory of Robert Landawé, MD, who coauthored the 3 studies that found no effect of TNF inhibitors on AS progression.

Dr. Machado questioned the researchers' use of mSASSS change of 1 unit/year or more for defining progression, a definition based on rate, rather than the definition of 2 mSASSS units during a 2-year period used in other studies. He did not address the issue of the shorter duration of treatment used in the earlier studies.

Lead author Nigil Haroon, MD, PhD, told Medscape Medical News that the rate of mSASSS progression had also come up during prepublication review. "The reviewers wanted data on a hard outcome, and they suggested number of syndesmophytes. The results were much stronger, with 75% reduced odds of progression when the dependent variable was syndesmophyte formation at follow-up," said Dr. Haroon, who is assistant professor of rheumatology at the University of Toronto, Ontario, Canada.

Dr. Machado suggested that the current study did not "take into account treatment and clinical changes between the two radiographic assessments," such that a hypothetical patient with no progression during the first 2 years while treated with NSAIDs but 3 mSASSS units of progression during the last 2 years while treated with a TNF inhibitor would have been classified as a nonprogressor. Dr. Gensler responded that treatment decisions are based on signs and symptoms, not progression. She also noted that the researchers took detailed medication intake histories every 6 months during the course of the study and found no significant differences in the univariate models. "This is probably because patients do not change their therapies much once in a maintenance phase, and very few patients stop the TNF inhibitor once they have started it," Dr. Gensler said.

Ultimately, Dr. Machado says that although it has been shown that TNF inhibitors do not accelerate progression, definitive evidence is still lacking to show the drugs have a protective effect. "The controversy continues and these intriguing questions will continue to challenge the spondyloarthritis scientific community," he concludes.

Dr. Gensler has been a consultant for Abbott USA and UCB. Dr. Haroon and one coauthor have disclosed receiving consultant/speaker honoraria from Abbott Immunology, Canada; Janssen Rheumatology, Canada; and Amgen/Pfizer/Wyeth Canada. Dr. Kavanaugh reports receiving grant and research support from Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Centocor-Janssen, Pfizer, Roche, and UCB. Dr. Machado has disclosed no relevant financial relationships.

Arthritis Rheum. Published online July 1, 2013. Article abstract, Editorial extract

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