Tolerability of selective cyclooxygenase 2 (COX-2) inhibitors used for the treatment of rheumatological manifestations of inflammatory bowel disease

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammatory pain and swelling in inflammatory bowel disease (IBD) patients with rheumatological manifestations (e.g. arthritis). While these drugs effectively reduce musculoskeletal pain and stiffness, long-term use is limited by gastrointestinal (GI) side effects and disease exacerbation (i.e. an increase in the severity of a disease or its signs and symptoms). As an alternative to NSAIDs, selective cyclooxygenase 2 (COX-2) inhibitors were developed to improve tolerability (i.e. the degree to which the side effects of a drug can be tolerated by a patient). 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 Rofecoxib and valdecoxib have been withdrawn from the market worldwide due to safety concerns (most importantly an increased risk of heart attack or stroke) and lumiracoxib has been withdrawn in many countries due to liver toxicity. However, celecoxib and etoricoxib are available for use in many countries. The purpose of this systematic review was to examine the tolerability and safety of COX-2 inhibitors used for the treatment of rheumatological manifestations of IBD. Safety refers to whether the drug causes any harm and is typically assessed by the number and type of side effects caused by the drug.

This review does not include any studies that assessed the tolerability and safety of the withdrawn COX-2 inhibitors rofecoxib, valdecoxib, or lumiracoxib.This review identified two studies that included a total of 381 participants with IBD who were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.

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.

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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 strategy: 

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.

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