No Increased Risk of Colitis Flares in Secukinumab Trials Save
No increased incidence of inflammatory bowel disease has been seen among patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis treated with secukinumab (Cosentyx) in the clinical trial programs for this interleukin (IL)-17A inhibitor, a researcher reported here.
For instance, during 12- to 16-week studies of secukinumab that included 2,877 patients, there was one case of Crohn's disease and one case of ulcerative colitis among patients with psoriasis compared with none among 793 patients receiving placebo, according to Stefan Schreiber, MD, who is the chair of gastroenterology at Christian-Albrechts University in Kiel, Germany.
Among 703 patients with psoriatic arthritis, there were no cases of either condition during those short-term studies, while among 300 patients receiving placebo there was one case of Crohn's disease, he reported at the annual European Congress of Rheumatology.
And among 394 patients with ankylosing spondylitis, there were two cases of Crohn's disease and one of ulcerative colitis and no cases among 196 placebo-treated patients.
There is an increased incidence of Crohn's disease among patients with these inflammatory skin and joint diseases. The risk has been estimated as about four-fold higher among psoriasis patients compared with the general population, and is even higher for psoriatic arthritis, being reported at an incidence of 0.05 per 100 patient-years. In addition, among patients receiving placebo in ankylosing spondylitis studies, the rate of Crohn's disease has been estimated at 0.7 cases per 100 patient-years.
Secukinumab is a monoclonal antibody that neutralizes IL-17A and has sustained efficacy in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis, he said.
"However, there are conflicting data regarding the role of IL-17 in gastrointestinal health. Inhibition of IL-17 may have dual effects, not only on inflammation but also potentially impairing barrier function. We have seen two trials in patients with Crohn's disease, one with secukinumab and another with an agent from Amgen, in which a considerable number of patients deteriorated on therapy with anti-IL-17, and one of the trials was stopped prematurely," Schreiber said.
"Other patients in these studies were improving with IL-17 blockade, but overall the risk-benefit ratio was considered unacceptable," he explained.
Therefore, to clarify the gastrointestinal risks among patients with rheumatic conditions, including those with a history of concomitant inflammatory bowel disease (though inactive), he analyzed data from ten phase II and III studies in moderate-to-severe psoriasis, two phase III studies in active psoriatic arthritis, and two phase III trials in active ankylosing spondylitis. (The current analysis and the included trials were sponsored by secukinumab's manufacturer, Novartis.)
Participants' mean age was about 45, and 20% to 50% were smokers, which is a strong risk factor for the development of Crohn's disease, and many also used nonsteroidal anti-inflammatory drugs (NSAIDs), which are known to prompt relapses of inflammatory bowel disease.
In longer term studies that continued for 52 to 112 weeks, rates of inflammatory bowel disease remained low.
Among 3,430 patients with psoriasis exposed to secukinumab, the exposure-adjusted incidence rate of Crohn's disease was 3 per 100 patient-years (95% CI 0.02-0.32). For the 974 patients with psoriatic arthritis treated with secukinumab, the adjusted incidence rate was 1 per 100 patient-years (95% CI 0-0.39), and for the 591 with ankylosing spondylitis, the incidence rate was 8 per 100 patient-years (95% CI 0.33-1.51), which included patients switched from placebo.
For ulcerative colitis, the incidence rates were 4 per 100 patient-years (95% CI 0.04-0.38) in the psoriasis studies, 2 per 100 patient-years (95% CI 0.02-0.50) in the psoriatic arthritis studies, and 3 per 100 (95% CI 0.06-0.84) in the ankylosing spondylitis studies.
Overall, a total of 12 patients in all the studies were reported as developing Crohn's disease. Six of these were exacerbations of preexisting disease and six were new onset. Among the exacerbations, some patients discontinued and some interrupted treatment, and among the new-onset cases some continued with treatment after the inflammatory bowel disease episode was controlled. "If you look at the outcome, there was no harm done to the patients, and there was no temporal pattern among the cases," Schreiber said.
All of these cases were among patients who had a history of Crohn's disease or symptoms suggestive of undiagnosed Crohn's disease, were smokers, or had used anti-tumor necrosis factor treatments or NSAIDs.
There also was a total of nine cases of ulcerative colitis, with four exacerbations and five new-onset. "Most of the patients recovered, and no harm was done," he said. Again, most cases were among patients with risk factors including a history of the inflammatory bowel disease, smoking, and NSAID use.
"There is no evidence of increased risk of new onset or exacerbations of Crohn's disease among patients with long-term secukinumab exposure, and the adjusted incidence rates were within the range of what is expected for psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab is a therapeutic option for patients with these conditions, even if they have concomitant stable inflammatory bowel disease, if it is properly managed," he concluded.
The study was sponsored by Novartis, maker of secukinumab.