Apremilast Reduces Number of Behçet’s-related Oral Ulcers
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Treatment with apremilast resulted in a greater reduction in the number of oral ulcers related to Behçet’s syndrome, compared with placebo, but is also associated with diarrhea, nausea and headache, according to data published in The New England Journal of Medicine.
“Apremilast, an orally available small-molecule phosphodiesterase 4 inhibitor, prevents degradation of cyclic adenosine monophosphate, thereby decreasing the production of proinflammatory cytokines and increasing the production of anti-inflammatory mediators,” Gülen Hatemi, MD, of Istanbul University–Cerrahpasa, and colleagues wrote. “This potential for regulating the downstream inflammatory signaling cascade has led to its use in patients with psoriasis and psoriatic arthritis.”
They added, “apremilast may have therapeutic effects in patients with Behçet’s syndrome by means of modulation of tumor necrosis factor [alpha], interleukin-2, interleukin-8, interleukin-12, interleukin-17, and interferon-[gamma] production, all of which are up-regulated proinflammatory mediators in Behçet’s syndrome.”
Following up on a phase 2 trial — in which apremilast (Otezla, Celgene) reduced the number of oral ulcers, as well as pain associated with them and disease activity — Hatemi and colleagues conducted a phase 3 study evaluating the efficacy and safety of the drug in a larger, more geographically diverse cohort of patients with Behçet’s syndrome, active oral ulcers and an insufficient response to at least one nonbiologic agent. The randomized, double-blind, placebo-controlled trial was conducted in 53 facilities across 10 countries in Asia, Europe and North America, including Israel, Lebanon and Turkey.
Of a total of 207 adult participants, 104 were randomly assigned to receive apremilast while the remaining 103 were selected for the placebo group. Those treated with apremilast were administered 30 mg twice daily for 12 weeks, followed by a 52-week extension phase. The primary endpoint was the area under the curve for the total number of oral ulcers during the 12-week placebo-controlled period. Lower values represented fewer ulcers. Among the 13 secondary endpoints were complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity and change from baseline in the Behçet’s Disease Quality of Life score.
According to the researchers, the area under the curve for the number of oral ulcers was 129.5 for those treated with apremilast, compared with 222.1 for participants in the placebo group (least-squares mean difference = –92.6; 95% CI, –130.6 to –54.6). Further, the change in Behçet’s Disease Quality of Life score from baseline was –4.3 among participants treated with apremilast, compared with –1.2 points in the placebo group (least-squares mean difference = –3.1; 95% CI, –4.9 to –1.3). However, adverse events reported in the apremilast group included diarrhea, nausea and headache.
“This trial showed the efficacy of apremilast as compared with placebo for the treatment of oral ulcers in patients with Behçet’s syndrome,” Hatemi and colleagues wrote. “Trials using an active comparator and longer follow-up are required in order to determine whether the effect of apremilast would be sustained beyond the 28 weeks of the active treatment duration of this trial and safe over long periods of administration.” – by Jason Laday
Disclosure: Hatemi reports funding support, as well as lecture and advisory board fees, from Celgene. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Linda Grinnell-Merrick, MS, NP-BC
Behcet’s Syndrome is a rare disease which causes significant pain, thus impacting the quality of life of patients afflicted with this disease. The medical community has been waiting for this study and the FDA approval of apremilast eagerly, so to finally have a treatment to offer our patients is very exciting.
This study shows significant improvement in resolution of oral ulcers, decrease pain and overall improvement in the quality of life in patient’s afflicted with Behcet’s.
Our rheumatology and dermatology colleagues are well aware of the potential adverse effects that some patients may experience with apremilast, and we are able to counsel and monitor patients through most of these adverse events. While we previously had few choices for treatment of Behcet’s, we are now able to offer an FDA-approved treatment that demonstrates improvement in the disease process.
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David A. McLain, MD, FACP, FACR
It is really satisfying to see a controlled trial being conducted in one of rheumatology’s orphan diseases and syndromes, such as Behçet’s. This placebo-controlled study with apremilast showed a significant reduction in the number of oral ulcers over a 12-week period (129.5 vs. 221.1)
Apremilast has been approved by the FDA for the treatment of moderate to severe plaque psoriasis, psoriatic arthritis and, as of July 2019, oral ulcers associated with Behçet’s disease. The proven efficacy of apremilast in Behçet’s is a welcome addition to our toolbox in treating this often difficult to treat disease. The researchers noted adverse events of diarrhea, nausea and headache in the apremilast group, and — in my experience — the gastrointestinal adverse drug reactions are a challenge with apremilast.
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