Faculty Bibliography

BACKGROUND:The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited. METHODS:In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet's syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including 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 (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed. RESULTS:A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, -92.6; 95% confidence interval [CI], -130.6 to -54.6; P<0.001). The change from baseline in the Behçet's Disease Quality of Life score was -4.3 points in the apremilast group, as compared with -1.2 points in the placebo group (least-squares mean difference, -3.1 points; 95% CI, -4.9 to -1.3). Adverse events with apremilast included diarrhea, nausea, and headache. CONCLUSIONS:In patients with oral ulcers associated with Behçet's syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.).

Background: Behcet syndrome is a chronic, multisystem inflammatory disorder characterized by painful, recurrent oral ulcers (OU) that can impair quality of life (QoL). Apremilast (APR), an oral phosphodiesterase 4 inhibitor, demonstrated efficacy in the treatment of OU of Behcet's syndrome in a phase III, multicenter, randomized, double-blind, placebo (PBO)-controlled study (RELIEF).
Method(s): A total of 207 patients were randomized (1:1) to APR 30 mg BID or PBO BID for a 12-week PBO-controlled phase, followed by a 52-week active treatment extension. Eligible patients were >=18 years old, had active Behcet syndrome, with >=3 OU at randomization or >=2 OU at screening and randomization, and without active major organ involvement. The primary efficacy endpoint was area under the curve for the number of OU from baseline through 12 weeks (AUCWk0-12). Clinical improvement of OU was evaluated by assessments of OU pain (100 mm VAS) and measures of disease activity and QoL. Disease activity measures included the Behcet Disease Current Activity Index Form (BDCAF) and Behcet Syndrome Activity Score (BSAS). QoL assessments included the Behcet Disease QoL (BDQoL) and the 36-item Short-Form Health Survey version 2 (SF-36v2), consisting of Physical and Mental Component Summary (PCS and MCS) scores and Physical Functioning domain (PF) score. An ANCOVA model was used to analyze the primary endpoint and change from baseline in BDQoL score and SF-36v2 PCS, MCS, and PF scores.
Result(s): The primary efficacy endpoint of AUCWk0-12 for the number of OU was significantly lower in APR vs PBO patients (P <.0001). Significant improvements were observed with APR versus PBO in the mean change from baseline to Week 12 in BDQoL score (P =.0003), which was supported by significant improvements in the mean change from baseline to Week 12 in SF-36v2 PCS (P =.0204), MCS (P <.0001), and PF (P =.0060) scores in APR versus PBO patients. In all of the SF-36v2 subscale scores, a 10% to 25% greater proportion of patients receiving APR versus PBO experienced an improvement of at least 2.5 points (minimal clinically important difference) at Week 12.
Conclusion(s): APR demonstrated significant reductions in OU through Week 12 and clinically meaningful improvements in Behcet syndrome-related and overall health-related QoL, including physical and mental function.
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Background/Purpose : The Routine Assessment of Patient Index Data 3 (RAPID3) is an outcome measure of disease activity entirely derived from patient self-reported measures (Health Assessment Questionnaire-Disability Index [HAQ-DI] or multidimensional HAQ [MDHAQ], Pain visual analog scale [VAS], and Patient's Assessment of Disease Activity [PtGA] VAS). The Clinical Disease Activity in Psoriatic Arthritis (cDAPSA; 0-154) includes objective and subjective physician assessments (i.e., a composite of swollen and tender joints counts [SJC and TJC]), along with Patient's Assessment of Pain (PAP) and PtGA. In subjects receiving apremilast (APR), we examined trajectories for improvement in RAPID3 scores among subjects achieving RAPID3 near remission (REM) or low severity, cDAPSA among subjects achieving cDAPSA REM or low disease activity (LDA), and psoriatic arthritis (PsA) manifestations not measured by either outcome measure by Week 52. Methods : Pooled analyses of the phase III PALACE 1, 2, and 3 studies were performed for subjects assigned to receive APR 30 mg BID at baseline (BL). Subjects with available scores on RAPID3 and cDAPSA components at Week 52 were included and grouped according to RAPID3 categories at Week 52 (near REM: <3; low severity: >3 to <6; moderate severity: >6 to <12; and high severity: >12 to 30) and cDAPSA categories at Week 52 (REM: <4; LDA: >4 to <13; moderate disease activity: >13 to <27; high disease activity: >27). Mean RAPID3 and cDAPSA scores were assessed from BL through Week 52. Other measures of PsA disease activity were reported longitudinally by RAPID3 and cDAPSA categories at Week 52. Results : The RAPID3 and cDAPSA analysis included 376 and 375 APR subjects, respectively. Achievement of near REM or low severity (RAPID3) or REM or LDA (cDAPSA) by Week 52 with APR were associated with improvements over time in mean RAPID3 ( Figure 1 ) and cDAPSA ( Figure 2 ) trajectories. Subjects who achieved cDAPSA treatment targets were associated with no or mild articular and extra-articular manifestations at Week 52. Achieving RAPID3 treatment targets at Week 52 was associated with improvements in articular and extra-articular disease activity, although not all manifestations were controlled at Week 52 ( Table ). In both RAPID3 and cDAPSA analyses, similar improvements in SJC and TJC were observed for patients with REM or low severity (RAPID3) or REM or LDA (cDAPSA) at Week 52. In the RAPID3 analysis, mean TJC was higher than expected at Week 52, and achieving near REM RAPID3 scores was not associated with lower mean Psoriasis Area and Severity Index scores. Conclusion : Subjects who achieved RAPID3 and cDAPSA targets showed early improvements in disease activity by Week 16 and sustained improvements to Week 52 with continued treatment. Achievement of treatment targets was also associated with improvements in other domains not captured directly by RAPID3 or cDAPSA. Given that some patients may exhibit different disease outcomes from the population, a more comprehensive assessment may help better evaluate treatment targets.

Background/Purpose : Behcet's syndrome is a chronic, multi-system inflammatory disorder characterized by painful, recurrent oral ulcers (OU) that can impair quality of life (QoL). Apremilast (APR), an oral phosphodiesterase 4 inhibitor, demonstrated efficacy in the treatment of OU of Behcet's syndrome in a phase III, multicenter, randomized, double-blind, placebo (PBO)-controlled study (RELIEF). We report short-and long-term results from RELIEF for the efficacy of APR treatment on QoL and physical function for up to 64 weeks. Methods : A total of 207 patients were randomized (1:1) to APR 30 mg twice daily (APR 30 BID) or PBO twice daily for a 12-week PBO-controlled phase, followed by a 52-week active treatment extension. Eligible patients were >=18 years old, had active Behcet's syndrome, with >=3 OU at randomization or >=2 OU at screening and randomization ry endpoint and change from baseline in BDQoL score and SF-36v2 PCS, MCS and PF scores at Week 12. Data at Week 64 are as observed. Results : The primary efficacy endpoint of AUCWk0-12 for the number of OU was significantly lower in APR 30 BID vs PBO patients ( P < 0.0001); improvement in the number of OU and OU pain was sustained in patients continuing APR 30 BID treatment for up to 64 weeks and emerged in patients switched from PBO to APR 30 BID for Weeks 12 to 64. Significant improvements were observed with APR 30 BID vs PBO in mean change from baseline at Week 12 in BSAS ( P < 0.0001), BDCAF components ( P <=0.0335), and BDQoL score ( P =0.0003). The improvements in BSAS, BDCAF, and BDQoL outcomes were maintained in patients continuing APR 30 BID treatment for up to 64 weeks, and comparable effects were observed at Week 64 among patients who switched from PBO to APR 30 BID. Significant improvements were also observed in mean change from baseline at Week 12 in SF-36v2 PCS ( P =0.0204), MCS ( P < 0.0001), and PF ( P =0.0060) scores in APR 30 BID vs PBO patients. These effects in SF-36v2 scores were also maintained at Week 64 among patients initially randomized to APR 30 BID, and the improvements were generally similar among patients who switched from PBO to APR 30 BID (Table). Conclusion : Patients with active Behcet's syndrome treated with APR 30 BID vs PBO experienced significant reductions in OU and clinically meaningful improvements at Week 12 in disease activity and QoL. Improvements were sustained at Week 64 in patients continuing APR treatment

Background/Purpose : Oral ulcers, the hallmark lesion of Behcet's syndrome (BS) can be disabling and impair eating, drinking and speaking. Despite recent advances in systemic medications for the treatment of oral ulcers, some patients do not achieve complete remission. Topical agents may help such patients by decreasing the pain and duration of oral ulcers. Pentoxifylline (PTX) is a methylxanthine derivative that inhibits phosphodiesterase and is thought to have immunomodulatory effects in addition to improving blood flow which is its main reason for use in peripheral vascular disorders. The aim of this study is to assess the efficacy and safety of PTX gel for oral ulcers in patients with BS. We also aimed to explore the best tools for the assessment of treatment response to topical agents in randomized controlled trials (Clinicaltrial.gov ID: NCT 03888846). Methods : This was an open-label, randomized, parallel group study comparing PTX gel in addition to colchicine (PTX-COL) with colchicine alone (COL). Patients with BS who were treated with colchicine and not using any other systemic medications for BS, having at least one oral ulcer that appeared during the last 48 hours were included. PTX 5% gel with a dose of 1000 mg/day was applied in 4 divided doses per day for 14 days. Patients were contacted daily for 14 consecutive days. Photographs were taken every 24 -48 hours and graphical processing software was used to calculate the area of the index ulcer. Duration of the index ulcer, time to start of index ulcer shrinkage, time to 50% reduction in oral ulcer pain on a 10 mm visual analog scale (VAS), change from baseline in the area of the index ulcer over time, total number of oral ulcers and adverse events were evaluated. A total of 60 patients are planned to be recruited. We present here results of the interim analysis of the first 21 patients. Results : A total of 21 patients (ratio M:F 1:1.1, mean age:39.9 years), 11 in the PTX-COL group and 10 in the COL group have completed the study at the time of this analysis. One patient in the PTX-COL group withdrew from the study after day 1 and was not included in the current analysis. Mean duration of index ulcer, time to start of index ulcer shrinkage, time to 50% reduction in oral ulcer pain, and total number of oral ulcers during 14 days in each group were lower in the PTX-COL group as presented in the Table. Change from baseline in the area of index ulcer over time is shown in the Figure. There were no serious adverse events. Seven patients in the PTX-COL group reported transient discomfort and nausea while they kept the gel in their mouth, 1 patient withdrew from the study for this reason. Conclusion : The preliminary analysis of the first 21 patients of this open label, randomized trial showed that PTX gel may be a promising agent for decreasing the duration and pain of oral ulcers in patients with BS: However, caution is required when interpreting these results in a yet small number of patients. Duration of oral ulcers, time to start of ulcer shrinkage and 50% reduction in pain score seem to be relevant outcomes for studying topical agents in RCTs for oral ulcerations of BS. (Figure Presented)