BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce 
inflammatory pain and swelling in inflammatory bowel disease (IBD) patients with 
rheumatological manifestations. While these drugs effectively reduce 
musculoskeletal pain and stiffness, long-term use is limited by gastrointestinal 
(GI) adverse effects (AEs) and disease exacerbation. As an alternative to 
NSAIDs, selective cyclooxygenase 2 (COX-2) inhibitors were developed to improve 
GI safety and tolerability. COX-2 inhibitors include drugs such as celecoxib, 
rofecoxib, valdecoxib, etoricoxib, and lumiracoxib. Rofecoxib and valdecoxib 
have been withdrawn from the market worldwide due to safety concerns (most 
importantly for cardiovascular adverse events) and lumiracoxib has been 
withdrawn in many countries due to liver toxicity. However, celecoxib and 
etoricoxib continue to be available for use in many countries. Several studies 
have examined whether COX-2 inhibitors can be safely used for the treatment of 
rheumatological manifestations of IBD with inconsistent results. Some 
investigators report acceptable safety profiles associated with these drugs 
while others found that COX-2 inhibitors are associated with high rates of 
disease exacerbation.
OBJECTIVES: The objective of this systematic review was to evaluate the 
tolerability and safety of COX-2 inhibitors used for the treatment of 
rheumatological manifestations of IBD.
SEARCH METHODS: We searched the following databases from inception to 19 
September 2013: PubMed, EMBASE, MEDLINE and CENTRAL. The search was not limited 
by language. Additional trials were identified by manually searching the 
reference lists of relevant papers and conference proceedings and through 
correspondence with experts and pharmaceutical companies.
SELECTION CRITERIA: Randomized controlled trials (RCTs) that compared COX-2 
inhibitors to placebo were considered for inclusion. Participants were adult 
patients with IBD presenting with rheumatological manifestations of at least two 
weeks duration.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial 
eligibility and extracted data. Methodological quality was assessed using the 
Cochrane risk of bias tool. The primary outcome measure was the proportion of 
patients with disease exacerbation as defined by the included studies. Secondary 
outcomes included GI adverse effects, renal toxicity, cardiovascular and 
thrombotic events. Data were analysed on an intention-to-treat basis where 
patients with missing final outcomes were assumed to have had an exacerbation of 
IBD. We calculated the risk ratio (RR) and corresponding 95% confidence interval 
(95% CI) for dichotomous outcomes. The overall quality of the evidence was 
assessed using the GRADE criteria.
MAIN RESULTS: There were no RCTs that assessed the tolerability or safety of the 
withdrawn COX-2 inhibitors rofecoxib, valdecoxib, or lumiracoxib. Two RCTs (n = 
381 IBD patients with rheumatological manifestations) were included in the 
review. One study (n = 159) compared etoricoxib (60 to 120 mg/day) to placebo in 
IBD patients with quiescent or active ulcerative colitis or Crohn's disease. The 
other study (n = 222) compared celecoxib (200 mg twice daily) to placebo in 
patients with quiescent ulcerative colitis. Both studies were judged to be at 
low risk of bias. The two included studies were not pooled for meta-analysis due 
to differences in patient populations and treatment duration. There was no 
statistically significant difference in exacerbation of IBD between etoricoxib 
and placebo. After 12 weeks of treatment the IBD exacerbation rate was 17% 
(14/82) in the etoricoxib group compared to 19% (15/77) in the placebo group (RR 
0.88, 95% CI 0.45 to 1.69). A GRADE analysis indicated that the overall quality 
of the evidence supporting this outcome was low due to very sparse data (29 
events). There was no statistically significant difference in exacerbation of 
ulcerative colitis between celecoxib and placebo. After two weeks of treatment 
4% (5/112) of celecoxib patients experienced an exacerbation of ulcerative 
colitis compared to 6% (7/110) of patients in the placebo group (RR 0.70, 95% CI 
0.23 to 2.14). A GRADE analysis indicated that the overall quality of the 
evidence supporting this outcome was low due to very sparse data (12 events). 
The study comparing etoricoxib to placebo documented but did not report on AEs. 
The proportion of patients who experienced AEs was similar in the celecoxib and 
placebo groups (21% and 17%, respectively, P > 0.20). No patients in either 
group died or experienced serious adverse events. Eleven percent of patients in 
the celecoxib and placebo groups experienced GI AEs (RR 0.97, 95% CI 0.46 to 
2.07). A GRADE analysis indicated that the overall quality of the evidence 
supporting this outcome was low due to very sparse data (24 events). GI AEs led 
to premature withdrawal from the study in 3% of patients in celecoxib and 
placebo groups respectively. GI AEs included increased stool frequency, rectal 
bleeding, and inflamed mucosa. No patients experienced any cardiovascular 
adverse events. Renal toxicity or thrombotic AEs were not reported.
AUTHORS' CONCLUSIONS: The results for disease exacerbation and AEs between the 
COX-2 inhibitors celecoxib and etoricoxib and placebo were uncertain. Thus no 
definitive conclusions regarding the tolerability and safety of the short term 
use of celecoxib and etoricoxib in patients with IBD can be drawn. The two 
included studies suggest that celecoxib and etoricoxib do not exacerbate IBD 
symptoms. However, it should be noted that both studies had relatively small 
sample sizes and short follow-up durations. Clinicians need to continue to weigh 
the risks and benefits of these drugs when treating patients IBD patients with 
rheumatological manifestations in order to avoid disease exacerbation and other 
adverse effects. Further RCTs are needed to determine the tolerability and 
safety of celecoxib and etoricoxib in these patients.