Effects of Continuous vs On-Demand Diclofenac on Radiographic Progression of AS

Researchers at Charité University Medicine in Berlin, Germany, recently examined the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in preventing osteoproliferation in patients with ankylosing spondylitis (AS).¹ Data was analyzed from the phase 3 clinical trial entitled Effects of Non-Steroidal Anti-Inflammatory Drugs on RAdiographic Damage in Ankylosing Spondylitis (ENRADAS, ClinicalTrials.gov identifier NCT00715091) and recently published in Annals of the Rheumatic Diseases. 

In some patients with AS, syndesmophytes form in the spine and lead to vertebral fusion, resulting in restricted mobility and function. Though tumor-necrosis factor (TNF)-blockers can effectively manage signs and symptoms of AS, there is no effect of a 2–4 year course of TNF-blocker treatment on new bone formation. 

“Thus, next to an effective suppression of inflammation the prevention of structural damage, especially osteoproliferative changes in the spine, is an important treatment target,” wrote the study authors.

Previous findings suggest that NSAIDs, the first-line treatment for patients with axial spondyloarthritis (axSpA), may prevent radiographic progression in AS.² With the aim of confirming this effect, the investigators of the current study compared outcomes of patients who were randomized to either continuous treatment (150 mg/day) or on-demand treatment with diclofenac.

The sample included 167 adult patients who had back pain ≥4 on a scale of 0-10. Participants were excluded if they had a history of certain diseases such as chronic inflammatory bowel disease and cardiovascular disease, for example. Treatment with TNF-blockers was not allowed during the study period. Participants who were unable to tolerate diclofenac were permitted to switch to another NSAID of an equivalent dosage.

Radiographs of the cervical and lumbar spine were performed at baseline and at the end of the 2-year study period, and the primary outcome measure was radiographic progression as measured by changes in the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). 

Dose and frequency data pertaining to NSAID use were recorded at baseline and then every 12 weeks during the study, and the study nurse conducted a pill count at each visit and reconciled it with the patients’ diary of NSAID use. 

Of the 167 patients enrolled from 19 centers in Germany, 62 of those assigned to the continuous treatment condition and 60 of those assigned to the on-demand group completed the entire study. The results show a higher progression of the mSASSS in the continuous group compared to the on-demand group (P = .39): 1.28 (0.7 to 1.9) vs. 0.79 (0.2 to 1.4). 

When the analysis was restricted to patients with syndesmophytes or elevated levels of C-reactive protein at baseline–which are both established risk factors for radiographic progession–the scores were even higher: 1.68 (0.7 to 2.6) vs 0.96 (0.0 to 1.9) and 2.11 (1.1 to 3.1) vs 0.95 (0.0 to 1.9), respectively. No difference in adverse events was found between groups.

“The inhibitory effect of NSAIDs on bone formation has been linked to their capabilities to impair the production of prostaglandin E2, which, apart from its proinflammatory activity, enhances bone resorption by promoting osteoclast activity but which can also promote bone formation by stimulating proliferation and activity of osteoblasts… our data should stimulate future research addressing the question whether NSAIDs and Coxibs differ in their effect on new bone formation,” the researchers stated.

Summary and Clinical Applicability

Continuous treatment with NSAIDs offers no additional benefit vs on-demand treatment in preventing radiographic progression and new bone formation in patients with AS. 

Limitations and Disclosures

The authors note that although no differences in adverse effects were observed between the 2 groups, they cannot draw firm conclusions regarding potential side effects because of the sample size used and the lack of a non-NSAID control group.

Reference

1. Sieper J, Listing J, Poddubnyy D, et al. Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis. 2016; 75(8):1438-43. 
2. Lawrence R, Helmick C, Arnett F, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998; 41:778-799.

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