title: Tolerability of selective cyclooxygenase 2 inhibitors used for the treatment of rheumatological manifestations of inflammatory bowel disease.
abstract: 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 Rofecoxib and valdecoxib have been withdrawn from the market worldwide due to safety concerns (most importantly for cardiovascular adverse events) and lumiracoxib has been withdrawn in many countries due to liver toxicity.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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Department of Gastroenterology, Hai Nan Provincial People's Hospital, 19 Xiu Hua Road, Xiu Ying District, Hai Kou City, Han Nan Province, China, 570311.
authors.forename: Xin-Pu
authors.initials: XP
authors.lastname: Miao
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Ren-Wei
authors.initials: RW
authors.lastname: Hu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Li
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D000068579:Celecoxib; D003093:Colitis, Ulcerative / Q000150:complications / Q000188:drug therapy*; D003424:Crohn Disease / Q000150:complications / Q000188:drug therapy*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D004008:Diclofenac / Q000009:adverse effects / Q000031:analogs & derivatives; D000077613:Etoricoxib; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects; D007783:Lactones / Q000009:adverse effects; D011720:Pyrazoles / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D056737:Safety-Based Drug Withdrawals; D013449:Sulfonamides / Q000009:adverse effects*; D013450:Sulfones / Q000009:adverse effects*; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; D000077613:Etoricoxib; D007555:Isoxazoles; D007783:Lactones; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; C406224:valdecoxib; D000096926:Benzenesulfonamides; C473384:lumiracoxib