Abstract: There were no RCTs that assessed the tolerability or safety of the withdrawn COX-2 inhibitors rofecoxib, valdecoxib, or lumiracoxib.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. 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.

Plain-language summary: This review does not include any studies that assessed the tolerability and safety of the withdrawn COX-2 inhibitors rofecoxib, valdecoxib, or lumiracoxib.This review identified two studies that included a total of 381 participants with IBD who were experiencing rheumatological manifestations. One study (159 participants) compared etoricoxib (60 to 120 mg/day) to placebo (e.g. a sugar pill) in people with IBD (ulcerative colitis or Crohn's disease) who were in remission (i.e. no disease symptoms) or had active disease (i.e. had symptoms). The other study (222 participants) compared 2 weeks of treatment with celecoxib (200 mg twice daily) to placebo in people with ulcerative colitis who were in remission. The study that compared etoricoxib to placebo found no clear evidence of a difference in the proportion of patients who experienced exacerbation of IBD after 12 weeks of treatment. Although this study documented side effects experienced by the participants these side effects were not reported in the study manuscript. The study that compared celecoxib to placebo found no clear evidence of a difference in the proportion of patients who experienced exacerbation of ulcerative colitis after two weeks of treatment. The proportion of patients who experienced side effects was similar in the celecoxib and placebo groups (21% and 17%, respectively). No patients in either group died or experienced serious side effects. Eleven percent of patients in the celecoxib and placebo groups experienced GI side effects including increased stool frequency, rectal bleeding, and inflamed mucosa. No patients experienced any cardiovascular side effects (i.e. heart attack or stroke). Renal toxicity (i.e. the poisonous effect of a substance on the kidneys) or thrombotic side effects (i.e. the formation of a blood clot inside a blood vessel) were not reported. The results of the two included studies in this review suggest that celecoxib and etoricoxib do not exacerbate IBD symptoms. However, it should be noted that both studies assessed relatively small numbers of patients and were of short duration. Futhermore, the overall quality of the evidence from the studies was rated as low due to lack of precision of the results. No firm conclusions on the tolerability and safety of celecoxib and etoricoxib can be drawn from these studies. Further studies are needed to determine the tolerability and safety of celecoxib and etoricoxib in patients with rheumatological manifestations of inflammatory bowel disease.