2Rutgers Post-Doctoral Fellow at Pfizer, New York, NY, USA.
3Pfizer Ltd, Walton Oaks, UK
Keywords: Ankylosing spondylitis; Celecoxib; Disease modification
This publication outlines the key role of inflammation in ankylosing spondylitis and reviews the available data on the safety and efficacy of the COX-2 selective inhibitor celecoxib, one of the more extensively studied NSAID treatments for ankylosing spondylitis. Finally, the potential disease modifying properties of celecoxib are discussed.
The American College of Rheumatology (ACR) guidelines [4] are similar, also strongly recommending ongoing treatment with NSAIDs and physical therapy. In the ACR guidelines, anti- TNF therapy is strongly recommended in patients who do not respond to NSAIDs as is surgery for more severe patients, while the guidelines strongly recommended against the use of systemic glucocorticoids [4].
Overall, celecoxib was well tolerated in these trials and was typically associated with numerically fewer gastrointestinal adverse events than the non-selective NSAID comparators [7-11], consistent with the established superior gastrointestinal safety of COX-2 selective inhibitors [12]. There was also no notable difference in cardiovascular adverse events in the trials, although the trials were of limited duration and in relatively young patients (Table 1) [13]. Being significantly younger and with fewer comorbidities than the majority of other patients treated with celecoxib, ankylosing spondylitis patients would likely be at lower risk of gastrointestinal and cardiovascular complications [13]. Nevertheless, currently available data from patients with osteoarthritis and rheumatoid arthritis supports the view that celecoxib is not associated with an increased cardiovascular risk when compared with non-selective NSAIDs such as ibuprofen and naproxen [14, 15].
An alternative COX-2 selective inhibitor, etoricoxib, has also been examined in a 52 week randomized, controlled trial [16]. This trial included a 6 week placebo controlled period and a 46- week active-comparator controlled period in which etoricoxib at 90 or 120 mg once daily was compared with placebo and naproxen at 500 mg twice daily [16]. At 6 weeks, mean change in pain score was -12.6 with placebo compared with -33.7 with naproxen, and -41.5 and -41.6 with etoricoxib 90 mg and 120 mg, respectively and this improvement was maintained over the 1 year active-comparator phase [16]. The recommended dose of etoricoxib was initially limited to 90 mg/day by health authorities, however recent regulatory activity has led to a reduction in the initial dose of etoricoxib recommended for ankylosing spondylitis in some countries [17]. A starting dose of 60 mg/day is now recommended, with the caveat that some patients may benefit from increasing the dose to 90 mg/day. The labeling further recommends a potential return to 60 mg/day in patients once they are clinically stabilized [18].
Other acute phase reactants have also been implicated in this process with continuous NSAID treatment leading to a more pronounced slowing of radiographic progression in patients with elevated erythrocyte sedimentation rate (ESR), high Ankylosing spondylitis disease activity score (ASDAS)-CRP, or high ASDAS
Study |
Patients (N) |
Mean age, range (years) |
Duration (weeks) |
Celecoxib |
Comparator(s) |
||||
Dose |
N |
Mean change in pain intensity |
Dose |
n |
Mean change in pain intensity |
||||
Dougados, 2001 [8] |
246 |
38-40 |
6 |
Celecoxib 100 mg qd |
80 |
-27 |
Ketoprofen 100 mg qd |
90 |
-21 |
Placebo |
76 |
-13 |
|||||||
|
|
|
|||||||
Barkhuizen, 2006 [7] |
611 |
44-45 |
12 |
Celecoxib 200 mg qd |
137 |
-30.0 |
Naproxen 500 mg bid |
157 |
-36.3 |
Celecoxib 400 mg qd |
161 |
-30.4 |
Placebo |
156 |
-9.9 |
||||
Sieper, 2008 [10] |
458 |
45 |
12 |
Celecoxib 200 mg qd |
153 |
-29.1 |
Diclofenac 75 mg bid |
155 |
-32.7 |
Celecoxib 200 mg bid |
150 |
-31.7 |
|
|
|
||||
Huang, 2014 [9] |
219 |
29 |
6 |
Celecoxib 200 mg qd |
111 |
-23.8 |
Diclofenac 75 mg qd |
108 |
-27.1 |
Walker, 2016 [11] |
330 |
44 |
12 |
Celecoxib 200 mg qd |
107 |
-25.8 |
Diclofenac 50 mg tid |
115 |
28.2 |
Celecoxib 400 mg qd |
108 |
-30.6 |
|
|
|
Inhibition of new bone formation with NSAIDs may be associated with the Wnt signaling pathway which plays an important regulatory role in cartilage cell regeneration and fracture repair processes and interacts with the signally pathway of prostaglandins [24]. A recent genome-wide association analysis showed that the prostaglandin E receptor 4 gene (PTGER4) was associated with susceptibility to, and severity of, ankylosing spondylitis [25] and NSAIDs, in particular COX-2 selective inhibitors, could influence this process.
Syndesmophytes and elevated inflammation levels at baseline are risk factors for radiographic progression in ankylosing spondylitis, and these patients have been shown to benefit more when using NSAIDs continuously [20,22]. This suggests that, in terms of retarding radiographic progression and new bone formation, NSAIDs have the greatest benefit in those patients at higher risk.
stock options with Pfizer. Jian Zhu reports no conflicts of interest. Medical writing support was provided by Joshua Fink PhD, of Engage Scientific Solutions, and funded by Pfizer.
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