What is ulcerative colitis?
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, urgent bowel movements and bloody diarrhea. Treatment of UC focuses on induction of remission (treatment of symptoms of active disease) and prevention of clinical relapse (resumption of symptoms of active disease) in patients in remission (known as maintenance therapy). UC has a major impact on patients' health related quality of life (HRQL). HRQL refers to a person's physical functioning, social and emotional well-being, ability to work and freedom from disease symptoms. HRQL is significantly lower in patients with UC compared to the general population. Randomized controlled trials (RCTs) evaluating medical interventions for UC have traditionally used clinical disease activity indices which focus on subjective symptoms to define primary outcomes such as clinical remission or improvement. This focus on disease symptoms results in a failure to assess other important indicators of successful treatment such as HRQL.
What are biological interventions for ulcerative colitis?
Biologics are genetically engineered medications made from living organisms. They work by targeting specific cells in the gut that are involved in the inflammation process.
What did the researchers investigate?
The researchers assessed the impact of biologic medications (e.g. interferon-ß-1a, rituximab, infliximab, adalimumab, golimumab and vedolizumab) on HRQL in people with ulcerative colitis. The researchers extensively searched the medical literature up to September 9, 2015.
What did the researchers find?
The researchers identified nine RCTs that included a total of 4143 people with ulcerative colitis. One small study investigated rituximab, one study investigated interferon-ß-1a, one study investigated vedolizumab, and the remaining studies investigated tumor necrosis factor-alpha (TNF-α) antagonists including infliximab (two studies), adalimumab (three studies), and golimumab (one study). All of the studies compared the biologic medication to a placebo (a fake medicine) administered by intravenous infusion (an IV bag) or subcutaneous injection needle injection (a shot given into the fat layer between the skin and muscle). Eight of the studies were judged to of high quality and the study on rituximab was judged to be of poor quality due to a high drop out rate. The study that compared interferon-ß-1a to placebo found no clear evidence of a difference in the proportion of patients who experienced an improvement in HRQL at eight weeks. The study that compared rituximab to placebo found no clear evidence of a difference in HRQL at 12 weeks. Moderate quality evidence from the study comparing vedolizumab to placebo suggests that vedolizumab provides a clinically meaningful improvement in HRQL in UC patients receiving maintenance therapy. A clinically meaningful improvement would be a difference in HRQL that can be detected by the person with ulcerative colitis. Moderate quality evidence from the studies comparing adalimumab to placebo suggest that adalimumab may provide a benefit in terms of improved HRQL in people with UC receiving induction or maintenance therapy. However, the differences between adalimumab and placebo may not be clinically meaningful. High quality evidence from a study comparing golimumab to placebo suggests that golimumab patients had a better HRQL at six weeks than placebo patients. However, this difference in HRQL may not be clinically meaningful. High quality evidence suggests that infliximab provides a clinically meaningful improvement in HRQL in UC patients receiving induction therapy. High quality evidence shows that TNF-α antagonists (as a class of biologics) provide a clinically meaningful improvement in HRQL in UC patients receiving induction therapy. More research is needed to assess the long-term effect of biologic therapy on HRQL in people with UC. Future research should also focus on determining whether golimumab and adalimumab can provide UC patients with a clinically meaningful improvement in HRQL. Future research should involve direct head to head comparisons of biologics to determine which biologics provide the most benefit in terms of HRQL.
These results suggest that biologics have the potential to improve HRQL in UC patients. High quality evidence suggests that infliximab provides a clinically meaningful improvement in HRQL in UC patients receiving induction therapy. Moderate quality evidence suggests that vedolizumab provides a clinically meaningful improvement in HRQL in UC patients receiving maintenance therapy. These findings are important since there is a paucity of effective drugs for the treatment of UC that have the potential to both decrease disease activity and improve HRQL. More research is needed to assess the long-term effect of biologic therapy on HRQL in patients with UC. More research is needed to assess the impact of golimumab and adalimumab on HRQL in UC patients. Trials involving direct head to head comparisons of biologics would help determine which biologics provide optimum benefit for HRQL.
Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon that has a relapsing-remitting course. Health related quality of life (HRQL) is significantly lower in patients with UC than the general population due to the negative effects of the disease on physical, psychological and social well-being. Randomized controlled trials (RCTs) evaluating medical interventions for UC have traditionally used clinical disease activity indices that focus on symptoms to define primary outcomes such as clinical remission or improvement. However, this approach does not evaluate benefits that are highly relevant to patients such as HRQL
The primary objective was to assess the impact of biologic therapy on the HRQL of UC patients.
We searched PubMed, MEDLINE, EMBASE and CENTRAL from inception to September, 2015. Conference abstracts and reference lists were also searched.
RCTs that compared biologics to placebo in UC patients and reported on HRQL using the Inflammatory Bowel Disease Questionnaire (IBDQ), or the SF-36 or EQ-5D to measure HRQL were included.
Two authors independently screened studies for inclusion, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome was improvement in HRQL. For dichotomous outcomes we calculated the risk ratio (RR) and 95% confidence interval (CI). For continuous outcomes we calculated the mean difference (MD) and 95% CI. The overall quality of the evidence supporting the primary outcome was assessed using GRADE.
Nine RCTs (n = 4143) were included. Biologics included rituximab (one small study), interferon-ß-1a (one study), vedolizumab (one study), and the tumor necrosis factor-alpha (TNF-α) antagonists infliximab (two studies), adalimumab (three studies), and golimumab (one study). Risk of bias was low in eight studies. The rituximab study was judged to be at high risk of bias due to attrition bias. The studies comparing interferon-ß-1a and rituximab to placebo found no clear evidence of a difference in the proportion of patients who experienced an improvement in HRQL at 8 or 12 weeks respectively. The proportion of patients with a clinically meaningful improvement in HRQL at 6 or 52 weeks was significantly higher in vedolizumab patients compared to placebo. At 6 weeks 37% (83/225) of vedolizumab patients had an improvement in IBDQ score of at least 16 points from baseline compared to 23% (34/149) of placebo patients (RR 1.62, 95% CI 1.15 to 2.27; 1 study). At 52 weeks, 64% (157/247) of vedolizumab patients had an improvement in IBDQ score of at least 16 points from baseline compared to 38% (48/126) of placebo patients (RR 1.62, 95% CI 1.15 to 2.27; 1 study). A GRADE analysis indicated that the overall quality of the evidence supporting these outcomes was moderate due to sparse data (< 400 events). Patients who received maintenance vedolizumab every eight weeks had significantly higher mean SF-36 scores than placebo patients at 52 weeks (MD 3.40, 95% CI 1.56 to 5.24, 1 study 248 patients). This difference appears to be clinically meaningful as the lower boundary for a clinically meaningful change in SF-36 is three points. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (< 400 events). Adalimumab patients had significantly higher mean IBDQ scores than placebo patients at weeks 8 (MD 9.00, 95% CI 2.65 to 15.35; 1 study, 494 patients) and 52 (MD 8.00, 95% CI 0.68 to 15.32; 1 study, 494 patients). However, these differences may not be clinically meaningful as the lower boundary for a clinically meaningful change in IBDQ is 16 points. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (< 400 events). Golimumab patients who received a dose of 200/100 mg (MD 12.20, 95% CI 6.52 to 17.88; 504 patients) or 400/200 mg (MD 12.10, 95% CI 6.40 to 17.80; 508 patients) had significantly higher mean IBDQ scores than placebo patients at week 6. Although a GRADE analysis indicated that the overall quality of the evidence supporting these outcomes was high, the difference in IBDQ scores may not be clinically meaningful. Infliximab patients had significantly higher mean IBDQ scores at week 6 or 8 than placebo patients (MD 18,58, 95% CI 13.19 to 23.97; 2 studies, 529 patients). This difference in HRQL is clinically meaningful. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was high. The proportion of patients with a clinically meaningful improvement in HRQL at eight weeks was significantly higher in infliximab patients compared to placebo. Sixty-nine per cent (333/484) of infliximab patients had an improvement in IBDQ score of > 16 points from baseline compared to 50% of placebo patients (RR 1.39, 95% CI 1.21 to 1.60; 1 study). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was high. Similar results were found between infliximab and placebo when HRQL was measured using the SF-36 instrument. One small study (n = 43) found no difference in HRQL between infliximab and placebo when measured by the EQ-5D. Pooled analyses of TNF-α antagonists showed a benefit in HRQL favouring TNF-α over placebo.