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Systematic Reviews, Meta-analyses and Guidelines

Cochrane


Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005112. Available at: www.thecochranelibrary.com

Summary:


Efficacy

Seven randomised controlled trials (RCTs) were identified that satisfied the inclusion criteria. Five studies (Rutgeerts 2005 ACT1; Rutgeerts 2005 ACT2; Jarnerot 2005; Probert 2003; Sands 2001) compared infliximab with placebo for the induction of remission of acute UC in patients who had failed to respond to conventional treatment using corticosteroids and immunosuppressants. Two studies (Probert 2003; Sands 2001) failed to show any benefit of infliximab but both had relatively small numbers of patients (n = 43 and 13 respectively). In patients with moderate-to-severe UC whose disease was refractory to conventional treatment using corticosteroids and/or immunosuppressive agents, infliximab (3 intravenous infusions at 0, 2, and 6 weeks) was more effective than placebo in inducing clinical remission (relative risk [RR] 3.22, 95% confidence interval [CI] 2.18 to 4.76); inducing endoscopic remission (RR 1.88, 95% CI 1.54 to 2.28); and in inducing clinical response (RR 1.99, 95% CI 1.65 to 2.41) at 8 weeks. The Jarnerot study showed that a single infusion of infliximab was also more effective than placebo in reducing the need for colectomy within 90 days after infusion (RR 0.44, 95% CI 0.22 to 0.87). However, this was a small study (n = 45) and it remains unclear whether colectomy can be prevented in the long term by infliximab. The studies by Armuzzi and Ochsenkuhn compared infliximab with corticosteroids. They both failed to show any significant difference between infliximab and corticosteroids but both had small numbers of patients.



Safety

Four studies (Jarnerot 2005; Ochsenkuhn 2004; Probert 2003; Sands 2001) reported no serious adverse events or infusion reactions with infliximab, although a few patients receiving infliximab developed pruritis, headache, upper respiratory or urinary tract infection and there was 1 case each of renal calculus, cellulitis, central venous catheter septicaemia and pneumothorax following catheter insertion. One patient treated with placebo (Probert 2003) developed life-threatening sepsis. Five of 7 patients receiving oral prednisolone (Ochsenkuhn 2004) developed Cushing-like symptoms, 2 developed facial acne and 1 developed dysphoria. In 2 studies, Rutgeerts 2005 ACT1 (follow up 54 weeks) and Rutgeerts 2005 ACT2 (follow up 30 weeks), the proportion of patients with adverse events was generally similar in the placebo and 2 infliximab groups. In Rutgeerts 2005 ACT1, one patient treated with infliximab developed tuberculosis (TB) and in Rutgeerts 2005 ACT2, one patient receiving infliximab developed histoplasmosis and died from acute respiratory distress syndrome. The incidence of infusion reactions in the 2 studies ranged from 8% to 12% and was similar in the placebo and infliximab groups. In both studies the occurrence of newly positive results for antinuclear antibodies and double-stranded anti-DNA antibodies occurred more frequently in the infliximab groups than the placebo groups. In Rutgeerts 2005 ACT1, 2 patients developed possible delayed hypersensitivity reactions (1 in placebo & 1 in infliximab group). In Rutgeerts 2005 ACT2, a possible delayed hypersensitivity reaction occurred in 1 patient treated with infliximab.



Implications for practice

Infliximab is effective in patients with moderate-to-severe UC whose disease is resistant to conventional therapy using corticosteroids and/or immunosuppressive agents. In such patients, infliximab was more effective than placebo for inducing clinical and endoscopic remission, clinical response and helping to avoid colectomy in the short term. In the 2 largest studies there was no statistically significant difference between a dose of 5 mg/kg and 10 mg/kg. The authors recommend an intravenous dose of 5 mg/kg. The schedule of therapy was not consistent between studies. In the 2 largest studies which demonstrated the largest effect, infliximab was given at 0, 2 and 6 weeks to induce remission, but in one study (Jarnerot 2005) a single infusion of infliximab was used as a 'rescue therapy' in patients with acute disease judged to have failed to respond to high dose corticosteroids. There is, therefore, insufficient evidence to provide recommendations on the ideal dosing schedule. The authors did not find any evidence to suggest that infliximab is more effective than high-dose corticosteroids in patients who are not steroid-refractory. Serious adverse events attributable to infliximab were not common in the included studies but physicians should be aware of and be prepared to deal with some of the uncommon adverse events such as anaphylactic reactions and infections. The authors found no evidence to support the use of other tumour necrosis factor alpha (TNFα) inhibitors in acute UC.



Implications for research

It is important for researchers to ensure adequate sample size by performing a priori power and sample size calculations. The more recent larger studies clearly demonstrated a benefit for infliximab in patients who had previously received corticosteroids and/or immunosuppressive agents. It is unclear from the results of included studies whether both corticosteroids and immunosuppressive agents should be used prior to infliximab therapy. The question of when it is appropriate to use infliximab in clinical practice should be addressed in future studies. The fact that infliximab is effective in UC does not necessarily mean that other TNFα inhibitors will also be effective, and these agents should be tested in randomised trials. Further long term studies are required to determine whether infliximab can prevent colectomy in the long term, and also to evaluate potential long term adverse events. Future studies should also include assessment of quality of life as an important outcome and such studies should be designed to ensure that there is adequate statistical power to detect any differences between groups with regard to this outcome. As in CD, there is an absence of proper RCTs on the effectiveness of infliximab in the paediatric population. Well designed clinical trials investigating the use of infliximab in childhood inflammatory bowel disease (IBD) are needed.


Alimentary Pharmacology & Therapeutics

Gisbert JP, Gonzalez-Lama Y, Mate J.



Systematic review: Infliximab therapy in ulcerative colitis. Alimentary Pharmacology & Therapeutics. Vol. 25(1)(pp 19-37), 2007.

Summary:


This was a systematic review and meta-analysis on the efficacy and tolerance of infliximab in UC. Methods: Selection of studies: evaluating efficacy of infliximab in UC. For the meta-analysis, randomised clinical trials comparing infliximab vs. placebo/steroids. Search strategy: electronic and manual. Study quality: independently assessed by 2 reviewers. Data synthesis: meta-analysis combining the odds ratios (OR). Results: Thirty-four studies (896 patients) evaluated infliximab therapy in UC, with heterogeneous results. Mean short-term (2.3 weeks) response and remission with infliximab was 68% (95% CI 65% - 71%) and 40% (36% - 44%). Mean long-term (8.9 months) response and remission was 53% (49% - 56%) and 39% (35% - 42%). Five RCTs compared infliximab with placebo, the meta-analysis showing an advantage (P < 0.001) of infliximab in all endpoints (short/long-term response/remission): ORs from 2.7 to 4.6, and number-needed-to-treat (NNT) from 3 to 5. Similar infliximab response was calculated independently of the indication (steroid refractory/non-steroid refractory) or the dose (5/10 mg/kg). Adverse effects were reported in 83% and 75% of the infliximab and placebo-treated patients (OR = 1.52; 95% CI 1.03-2.24; number-needed-to-harm (NNH) was 14). Conclusion: Infliximab is more effective than placebo, with an NNT from 3 to 5, for the treatment of moderate-to-severe UC, achieving clinical remission in 40% of the patients at approximately 9 months of follow-up. Further studies are necessary to confirm the long-term efficacy of infliximab in UC.

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