Real-world effectiveness of apremilast in multirefractory mucosal involvement of Behçet’s disease

Relapsing oral and genital ulcers (OGUs) represent the stigmata of Behçet’s disease (BD) and may be very painful, affecting both quality of life and relationships. A wide number of topical and immunosuppressive drugs can be used to treat ulcers [1], but failures are commonly reported. The efficacy of the phosphodiesterase-4 inhibitor apremilast has been proven in OGUs of BD in two randomized clinical trials (RCT) [2, 3], whereas only two case reports are available until now [4, 5]. We aimed at evaluating the real-world effectiveness of apremilast in BD patients with OGUs refractory to conventional and/or biologic treatments. We retrospectively evaluated patients classified as BD, according to International Criteria for BD [6] and International Study Group [7] criteria, who underwent apremilast (30 mg twice daily) for multirefractory OGUs from November 2017 to January 2019. The number of OGUs was assessed at baseline and either at 3 and 6 months. Pain from ulcers and BD activity were evaluated via 100-mm visual-analogue scale (VAS) and BD Current Activity Form (BDCAF). We also recorded the number of oral and genital ulcer flares both in the 4 weeks prior to apremilast start and throughout the observation period (Table 1 and Supplementary Table 2). The occurrence of adverse events was also reported. Paired t-test or Wilcoxon matched-pair signed rank test were used for statistical analysis. The off-label use of apremilast was approved by the Hospital Ethics Committee in compliance with the Declaration of Helsinki. All patients provided a written informed consent. Thirteen patients (females 9/13) with disease duration (mean ± SD) of 154 ± 167 months were analysed (Table 1). At 3 months, (data from 12/13 patients) active OGUs were significantly less (p=0.02 for both) than baseline (Table 2). Three patients stopped the treatment due to diarrhoea. At 6 months, active oral ulcers and oral relapses were still lower than baseline (p=0.03 for both), whereas only a positive trend (p=0.07) for genital ulcers was seen (data from 8/13 patients) (Table 2). Ulcer VAS pain was 67 ± 16 at baseline, and a prompt amelioration was observed at 3 months (29 ± 32, p=0.002), and confirmed at 6 months (20 ± 19, p=0.005) (Table 2). Likewise, BDCAF dropped from 4.5 ± 2.9 of baseline to 3.2 ± 3.4 at 3 months (p=0.01), and was persistently low up to 6 months (2.3 ± 3.7, p=0.01) (Table 2). Serious adverse events were not observed. Our findings are consistent with a recent RCT on 111 BD patients [2], which showed the efficacy of apremilast in reducing both number and pain of oral ulcers [2]. Preliminary results from another study confirm the significant decrease of total number of oral ulcers and resolution of genital ulcers over 12 weeks in the apremilast group [3]. Similarly, in our study the mean number of oral relapses during therapy was significantly lower than that in the 4 weeks prior to apremilast. Interestingly, an appreciable reduction of VAS pain and BDCAF was already seen at 3 months and persisted up to 6 months. Of note, the overall beneficial effect of apremilast also on joint symptoms should be highlighted, as emerged by the BDCAF evaluations. Apremilast was safe and no serious adverse events were observed during the time span of our study. The main limitations of our study were the small sample size and the short-term follow-up. In addition, patients had been referred to our tertiary care centres since they were difficult-to-treat or refractory to therapy, configuring a possible selection bias. Nevertheless we provide evidence that apremilast may induce a meaningful and early benefit in BD patients with multirefractory OGUs also in real-life settings.