乌鸦传媒

An update of a 2017 network meta-analysis found infliximab (Remicade) to be more effective than other biologics for biologic-naive patients with moderate to severely active ulcerative colitis (UC).

A total of 16 trials published through September 2019 ranked the tumor necrosis factor (TNF) antibody highest for the induction of clinical remission, for an odds ratio (OR) of 4.07 versus placebo (95% CI 2.67-6.21) and a surface under the cumulative ranking curve (SUCRA) of 0.95, reported Siddharth Singh, MD, MS, of the University of California San Diego, and colleagues.

Their analysis, published online in , also found infliximab best for endoscopic improvement (SUCRA 0.95, moderate confidence in estimates).

Patients previously exposed to anti-TNF therapy fared significantly better with the interleukin 12 and 13 blocker ustekinumab (Stelara) and the janus kinase inhibitor tofacitinib (Xeljanz), which were ranked highest for inducing clinical remission (SUCRA 0.87 for both), the researchers reported. Both agents were superior as second-line treatment to the anti-integrin α4β7 antibody vedolizumab (Entyvio), showing ORs as follows:

• OR vs ustekinumab: 5.99 (95% CI 2.67-6.21)

• OR vs tofacitinib: 6.18 (95% CI 1.00-8.00, moderate CE)

That finding represented an unexpected lowering of previous efficacy estimates for vedolizumab, Singh and co-authors noted. Ustekinumab and tofacitinib were also superior to the anti-TNF agent adalimumab (Humira).

With an estimated placebo rate of remission of 10% in included trials, the researchers estimated the following rates of remission induction by the agents assessed:

• Infliximab 31.1%

• Adalimumab 17.7%

• Golimumab (Simponi) 23.7%

• Vedolizumab 22.0%

• Tofacitinib 19.1%

• Ustekinumab 18.5%

Similarly, with an estimated placebo rate of endoscopic improvement of 30% in induction trials, the investigators made the following estimates of healing across the agents:

• Infliximab 58.7%

• Vedolizumab 51.9%

• Tofacitinib 46.5%

• Ustekinumab 44.4%

• Golimumab 42.7%

• Adalimumab 40.4%

In maintenance trials, vedolizumab was ranked safest, with the lowest risk of infections (SUCRA 0.81), followed by ustekinumab (SUCRA 0.63), the team reported, adding that none of the included trials assessed infliximab or golimumab as second-line agents.

With treatment options for moderate to severe UC expanding, how to position various agents as first-line and second-line therapy is a key knowledge gap, Ashwin Ananthakrishnan, MD, MPH, of Massachusetts General Hospital in Boston, who was not involved with the study, told 乌鸦传媒. "As we now have the luxury of multiple different mechanisms of action, it is increasingly important for us to understand the best positioning of these therapies and the right sequence in which to use them."

And although this network meta-analysis provides some important insights into this issue, "an important limitation in the field is that there are few head-to-head trials that are the gold standard to define comparative effectiveness," he said. "That is an important next step for the field to take."

Echoing that, Singh said: "Our findings provide indirect evidence on how these medications may be positioned in clinical practice in the management of moderate to severely active UC, as we await more head-to-head trials," he told 乌鸦传媒.

Singh and co-authors pointed out that compared with their the update included results from VARSITY, the first head-to-head trial of vedolizumab and adalimumab, and provides more robust results on comparative efficacy of second-line pharmacotherapy in patients with previous anti-TNF exposure.

The team emphasized that even though all the approved agents were shown to be effective, more direct comparisons are needed to "inform clinical decision-making with greater confidence and facilitate shared decision making for the management of moderate-severe UC."

"Pragmatic head-to-head trials in both biologic-naive and biologic exposed patients are warranted to optimally inform relative positioning of newly available agents in clinical practice," Singh and associates wrote.

Study limitations, the team said, included the ability to compare the agents only in induction trials and that due to the different trial designs for maintenance therapy, it was necessary to conduct two separate network meta-analyses, thereby limiting comparative assessments. Furthermore, most of the trials relied on local investigators for endoscopic reading of disease activity for recruitment and outcome assessment, whereas those involving tofacitinib and ustekinumab included blinded central readers, a difference that could have influenced absolute event rates of clinical remission and endoscopic improvement.

In addition, the efficacy outcome in some tofacitinib induction trials had more stringent outcome criteria, while inter-study differences in the timing of assessment meant that time-dependent variability in efficacy could not be analyzed in detail. Corticosteroid-free remission was inconsistently reported across trials, and no corticosteroid tapering was attempted in induction studies. Finally, the researchers said, the analysis was unable to compare the efficacy of biologic monotherapy against combination therapy with immunomodulators, and differences in study design of maintenance therapy and the lack of information on safety stratified by previous TNF antagonist exposure may have biased the safety-related results.

Comment