Efficacy and safety of apremilast in patients with moderate-to-severe genital psoriasis: Results from DISCREET, a phase 3 randomized, double-blind, placebo-controlled trial.

BACKGROUND: Genital psoriasis can be stigmatizing, is highly prevalent among patients with psoriasis, and has limited treatment options. Apremilast is a unique oral immunomodulating phosphodiesterase 4 inhibitor approved for psoriasis treatment. OBJECTIVE: To assess the efficacy and safety of apremilast 30 mg twice daily in patients with genital psoriasis. METHODS: DISCREET, a phase 3, placebo-controlled trial (NCT03777436), randomized patients with moderate-to-severe genital psoriasis (stratified by affected body surface area <10% or ≥10%) to apremilast or placebo for a 16-week period, followed by an apremilast extension period. Week 16 results are presented. RESULTS: Patients were randomized to apremilast (n = 143) or placebo (n = 146). At Week 16, 39.6% and 19.5% of apremilast and placebo patients, respectively, achieved a modified static Physician Global Assessment of Genitalia response (primary endpoint; score of 0/1, ≥2-point reduction); treatment difference was significant (20.1%, P = .0003). Improvements in genital signs and symptoms, skin involvement, and quality of life were observed. Common treatment-emergent adverse events were diarrhea, headache, nausea, and nasopharyngitis. LIMITATIONS: Lack of active-comparator. CONCLUSIONS: Apremilast demonstrated statistically and clinically meaningful genital Physician Global Assessment responses and improvement of signs, symptoms, severity, and quality of life in this first randomized, controlled study of an oral systemic treatment in patients with genital psoriasis.

Patient Knowledge, Risk Perception, and Barriers to Barrett's Esophagus Screening.

INTRODUCTION: Most patients with esophageal adenocarcinoma (EAC) do not have a previous diagnosis of Barrett's esophagus (BE), demonstrating a failure of current screening practices. An understanding of patient attitudes and barriers is essential to develop and implement interventions to improve BE screening adherence. METHODS: We conducted a Web-based survey of patients aged >50 years with chronic gastroesophageal reflux disease at 3 academic medical centers and 1 affiliated safety net health systems. Survey domains included patient characteristics, endoscopy history, familiarity with screening practices, perceived BE/EAC risk, and barriers to screening. RESULTS: We obtained a response rate of 22.6% (472/2,084) (74% men, mean age 67.9 years). Self-identified race and ethnicity of participants was 66.5% non-Hispanic White, 20.0% non-Hispanic Black, 13.4% other race, and 7.1% Hispanic. Screening for BE was recommended in only 13.2%, and only 5.3% reported previous screening. Respondents had notable gaps in knowledge about screening indications; only two-thirds correctly identified BE risk factors and only 19.5% believed BE screening was needed for gastroesophageal reflux disease. More than 1 in 5 respondents believed they would get BE (31.9%) or EAC (20.2%) but reported barriers to screening. Compared with White respondents, more Black respondents were concerned about getting BE/EAC and interested in screening but report higher barriers to screening. DISCUSSION: Patients at risk for BE, particularly racial and ethnic minorities, are worried about developing EAC but rarely undergo screening and have poor understanding of screening recommendations.

Trial of Apremilast for Oral Ulcers in Behçet's Syndrome.

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.).

Efficacy and safety of apremilast in patients with mild-to-moderate plaque psoriasis: Results of a phase 3, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Patients with mild-to-moderate psoriasis may have substantial quality-of-life impairment. OBJECTIVE: To evaluate apremilast 30 mg twice daily for mild-to-moderate psoriasis. METHODS: Phase 3, double-blind, placebo-controlled study in adults with mild-to-moderate psoriasis inadequately controlled or intolerant to ≥ 1 topical psoriasis therapy (NCT03721172). The primary endpoint was the achievement of static Physician Global Assessment score of 0 (clear) or 1 (almost clear) and ≥ 2-point reduction at week 16. RESULTS: Five hundred ninety-five patients were randomized (apremilast: 297; placebo: 298). The primary endpoint was met, with a significantly greater static Physician Global Assessment response rate observed at week 16 in the apremilast group compared with the placebo group (21.6% vs 4.1%; P < .0001). All secondary endpoints were met with the achievement of body surface area-75 (33.0% vs 7.4%), body surface area ≤ 3% (61.0% vs 22.9%), ≥ 4-point reduction in Whole Body Itch Numeric Rating Scale (43.2% vs 18.6%), Scalp Physician Global Assessment 0 or 1 and ≥ 2-point reduction (44.0% vs 16.6 %), and changes from baseline in body surface area, Psoriasis Area and Severity Index, and Dermatology Life Quality Index (all P < .0001). The most commonly reported adverse events (≥ 5%) with apremilast were diarrhea, headache, nausea, nasopharyngitis, and upper respiratory tract infection, consistent with prior studies. LIMITATIONS: The study lacked an active-comparator arm. CONCLUSION: Apremilast demonstrated efficacy in mild-to-moderate psoriasis and safety consistent with the established safety profile of apremilast.

Apremilast in a Japanese subgroup with Behçet's syndrome: Results from a Phase 3, randomised, double-blind, placebo-controlled study.

OBJECTIVES: Apremilast efficacy and safety was assessed in a prespecified subgroup of Japanese patients with oral ulcers associated with Behçet's syndrome from a Phase 3 randomized, placebo-controlled, double-blind study of apremilast (RELIEF). METHODS: The primary end point was area under the curve for number of oral ulcers during the 12-week placebo-controlled phase (AUCWk0-12). Key secondary end points were change from baseline in oral ulcer pain, complete oral ulcer resolution, and measures of disease activity and quality of life (QoL). RESULTS: Thirty-nine Japanese patients were randomised (apremilast 30 mg BID: n = 19; placebo: n = 20). Improvements at Week 12 were observed for apremilast vs. placebo in AUCWk0-12 for the number of oral ulcers (115.9 vs. 253.3; nominal P = 0.0168); 57.9% vs. 25.0% achieved complete oral ulcer resolution, 47.4% vs. 0.0% achieved oral ulcer resolution by Week 6 and maintained oral ulcer-free status for ≥6 additional weeks; mean change from baseline in BSAS was -10.5 vs. 0.5. Favourable effects were observed for apremilast vs. placebo in other secondary end points, including QoL. Clinical benefits were sustained over 28 weeks of continued apremilast treatment. Adverse events were consistent with apremilast's known safety profile. CONCLUSIONS: Apremilast reduced the number of oral ulcers and overall disease activity in this Japanese subgroup with Behçet's syndrome.

Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical trial.

OBJECTIVES: This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks. METHODS: The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course. Oral ulcer number, complete and partial responses, pain and disease activity and quality of life (QoL) were also assessed throughout the study. RESULTS: A total of 207 participants were randomised and received at least one dose of study medication; 178 entered the extension phase and 143 completed Week 64. AUCWk0-12 was significantly lower with apremilast versus placebo (p<0.0001), and oral ulcers number, pain, complete/partial responses, disease activity and QoL with apremilast versus placebo showed improvements at Week 12, which were maintained through Week 64. The most common adverse events were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns were observed with longer-term apremilast exposure. CONCLUSIONS: In patients with oral ulcers associated with BS, apremilast was efficacious and benefits were sustained up to 64 weeks with continued treatment. Apremilast was well tolerated, and safety was consistent with its known safety profile.

Impact of apremilast on quality of life in Behçet's syndrome: analysis of the phase 3 RELIEF study.

OBJECTIVE: To assess apremilast's impact on patient quality of life (QoL) in active Behçet's syndrome and correlations between improvement in patients' QoL and efficacy measures in the phase 3 RELIEF study. METHODS: QoL measures included Behçet's Disease QoL (BDQoL), 36-Item Short-Form Health Survey V.2 (SF-36v2) Physical/Mental Component Summary (PCS/MCS) and eight subscale scores, focusing on Physical Functioning (PF). Pearson's correlation coefficients assessed relationships between efficacy endpoints (oral ulcer count, oral ulcer pain, Behçet's Syndrome Activity Scale (BSAS), Behçet's Disease Current Activity Form (BDCAF)) and QoL endpoints for apremilast at Week 12. RESULTS: Apremilast (n=104) demonstrated significantly greater improvements versus placebo (n=103) in SF-36v2 PCS (3.1 vs 0.9), MCS (4.6 vs ─0.7) and PF (2.9 vs 0.14), respectively (all p<0.05). Mild correlations were observed in improvements of SF-36v2 measures (PCS, MCS, PF) with oral ulcer count (r=-0.11, PCS), and change in oral ulcer pain from baseline (r=-0.28, PCS; r=-0.10, PF) and BSAS (r=-0.38, PCS; r=-0.20, PF; r=-0.16, MCS). Correlations among BDCAF and SF-36v2 components and BDQoL were variable. BDQoL showed mild/moderate correlations with SF-36v2 components (r=-0.18, PCS; r=-0.13, PF; r=-0.45, MCS). CONCLUSIONS: Apremilast was associated with significant improvements in QoL measures of SF-36v2 PCS, MCS and PF and BDQoL in patients with Behçet's syndrome. Correlations of improvement among QoL endpoints support the beneficial clinical effects of apremilast in Behçet's syndrome. TRIAL REGISTRATION NUMBER: NCT02307513.

A Pilot Study of the Short Term Effectiveness and Safety of Amniotic Fluid in Severe Dry Eye Disease.

The aim of this study was to evaluate if amniotic fluid (AF) mixed with artificial tears or soaked with a soft contact lens (SCL) as a treatment for severe dry eye disease (DED) would improve its signs or symptoms. In this retrospective pilot study 22 consecutive eyes of 11 patients with level 3 DED classified by DEWS 1 (Dry Eye WorkShop 1 2007), were included in the study between June 1 and September 30 in 2017. The study was conducted before DEWS II (Dry Eye WorkShop II 2017), which was published in October 2017. Therefore, DEWS II was not adopted for this study. Soft Contact Lens Acuvue Oasys of Plano with 8.8 base curve and 14 mm diameters by Johnson and Johnson were used to soak in FloGraft, which is an AF, for 30 minutes before placing in 12 eyes in Group 1. The contact lenses were placed in the left eye for 1 week. In Group 2, 10 eyes used 6 mL of artificial tears mixed with 0.25 mL of AF, which were applied to the eye four times a day for 1 week. No other eye medications were used. The eyes that were included had diffuse punctate staining and fast tear breaking times of <5 seconds with severe ocular symptoms (DEWS 1 level 3-4). Photos of fluorescein stain corneas before the treatment and 1 week after the treatment were used to compare the distribution of punctate staining as the objective outcomes for signs. Several questions adopted from the Ocular Surface disease Index (OSDI) about subjective symptoms before and after the treatment were asked, and documented on the chart. Improvement either in symptoms or signs or both of DED after 1 week at follow-up examination was recorded. Group 1, with SCL 46% had improvement after 1 week and Group 2, with artificial tears 50% had improvement after 1 week. Improvement means either symptom relief or comparatively decreased distribution of punctate staining on the cornea or both. No cases had inflammation, infection, irritation or blurred vision. We concluded that FloGraft as an AF can safely improve the symptoms or the signs of severe DED either as a mix with artificial tears or soaked with SCL by about 50% in this case series without evidence of irritation, inflammation or blurred vision in the short term.

A Phase 2 Randomized Trial of Apremilast in Patients with Atopic Dermatitis.

A phase 2, double-blind, placebo-controlled trial evaluated apremilast efficacy, safety, and pharmacodynamics in adults with moderate to severe atopic dermatitis. Patients were randomly assigned to receive placebo, apremilast 30 mg twice daily (APR30), or apremilast 40 mg twice daily (APR40) for 12 weeks. During weeks 12-24, all patients received APR30 or APR40. A biopsy substudy evaluated atopic dermatitis-related biomarkers. Among 185 randomly assigned intent-to-treat patients at week 12, a dose-response relationship was observed; APR40 (n = 63), but not APR30 (n = 58), led to statistically significant improvements (vs. placebo, n = 64) in Eczema Area and Severity Index (mean [standard deviation] percent change from baseline = -31.6% [44.6] vs. -11.0% [71.2], P < 0.04; primary endpoint). mRNA expression of T helper type 17/T helper type 22-related markers (IL-17A, IL-22, and S100A7/A8; P < 0.05) showed the highest reductions with APR40, with minimal changes in other immune axes. Safety with APR30 was largely consistent with apremilast's known profile (common adverse events: nausea, diarrhea, headache, and nasopharyngitis). With APR40, adverse events were more frequent, and cellulitis occurred (n = 6). An independent safety monitoring committee discontinued the APR40 dosage. APR40 showed modest efficacy and decreased atopic dermatitis-related biomarkers in moderate to severe atopic dermatitis patients. Adverse events, including cellulitis, were more frequent with APR40, which was discontinued during the trial. Clinical Trial Registration Number: NCT02087943 (clinicaltrials.gov).

Comparing the intraoperative complication rate of femtosecond laser-assisted cataract surgery to traditional phacoemulsification.

AIM: To compare the complication rate of femtosecond laser-assisted cataract surgery (FLACS) and traditional phacoemulsification for the first 18mo of FLACS use at a private surgical center in Hawaii. METHODS: A retrospective chart review was conducted from January 2012 to June 2013. The first 273 consecutive eyes receiving FLACS and 553 eyes receiving traditional phacoemulsification were examined. All surgeries were performed at a single surgical center in Hawaii. The presence of intraoperative complications was used as the main outcome measure. Approval was obtained from the institutional review board of the University of Hawaii. RESULTS: The overall complication rate for FLACS was 1.8%, while that of the traditional procedure was 5.8% (P<0.05). A majority of the surgeons (80%) had a lower complication rate while using FLACS. CONCLUSION: FLACS is comparable in safety, if not safer, than traditional cataract surgery when performed by qualified cataract surgeons on carefully selected patients.

Comparing the utility of the non-mydriatic fundus camera to the direct ophthalmoscope for medical education.

Visualization of the fundus is an important component of any ophthalmologic exam. Students are taught to visualize the fundus using a direct handheld ophthalmoscope. However, this device has many limitations, which may be a detriment to medical education and patient care. The invention of the non-mydriatic automatic fundus camera could significantly improve medical education. Our study examined the ability of a group of 5 medical students to visualize pathology and form a diagnosis with a traditional handheld ophthalmoscope and an automatic fundus camera. With the direct ophthalmoscope, none of the students were able to visualize the macula, a crucial aspect of the ophthalmologic exam. With the automatic fundus camera, all students were able to visualize the fundus. The latter modality also increased the proportion of students that was able to correctly diagnose the patients with diabetic retinopathy, 100% vs 40%. On average, students were also more confident in their ability to visualize basic retinal anatomy with the automatic fundus camera, 9.6/10 vs 6.4/10. Thus, incorporating the non-mydriatic automatic fundus camera into medical education, alongside the handheld ophthalmoscope, has the potential to improve both learning outcomes and patient care.

Oral diazepam versus intravenous midazolam for conscious sedation during cataract surgery performed using topical anesthesia.

PURPOSE: To compare the intraoperative pain, anxiety, undesired movement, and cooperation between patients receiving oral diazepam or intravenous (IV) midazolam for conscious sedation during cataract surgery under topical anesthesia. SETTING: Ambulatory surgical center, Honolulu, Hawaii, USA. DESIGN: Prospective randomized controlled trial. METHODS: Patients having first-time cataract extraction with topical anesthesia were randomized to receive sedation with oral diazepam 30 minutes before surgery or IV midazolam immediately preceding surgery. The outcomes of intraoperative pain, anxiety, undesired movement, and poor cooperation were observed by the surgeon and recorded during surgery. RESULTS: One hundred fifty-six cataract surgeries were included, 83 in the IV midazolam group and 73 in the oral diazepam group. Twenty-four patients (29%) in the IV group and 7 patients (10%) in the oral group showed undesired movement (P < .02). Seven patients (8%) in the IV group and 2 patients (3%) in the oral group showed poor cooperation (P > .05). Fifteen patients (18%) in the IV group and 9 patients (12%) in the oral group had anxiety (P > .05). Three patients (4%) in the IV group and 3 patients (4%) in the oral group experienced pain (P > .05). CONCLUSIONS: Fewer patients receiving oral diazepam 30 minutes before cataract surgery than patients receiving IV midazolam immediately preceding surgery showed undesired movement during surgery. There was no statistically significant difference in the number of patients showing poor cooperation or experiencing pain or anxiety between the 2 groups. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Apremilast in Patients With Active Rheumatoid Arthritis: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study.

OBJECTIVE: To study the efficacy/safety of apremilast, an oral phosphodiesterase 4 inhibitor, compared with placebo in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX). METHODS: Patients were randomized 1:1:1 to receive placebo, apremilast 20 mg twice a day, or apremilast 30 mg twice a day. Patients whose swollen and tender joint counts had not improved by ≥20% were considered nonresponders at week 16 and were required to enter the protocol-defined early escape. At week 24, patients were transitioned in a blinded manner to receive apremilast 20 mg twice a day if they were initially randomized to receive placebo. Patients who were not initially randomized to receive placebo continued to receive their target apremilast dose. Patients were required to take a stable dose of MTX (7.5-25 mg/week) throughout the study. Magnetic resonance imaging (MRI) was performed in a subset of patients. RESULTS: A total of 237 patients who were receiving MTX therapy were randomized and received ≥1 dose of study medication. At week 16, similar proportions of patients receiving placebo (35%), apremilast 20 mg twice a day (28%), and apremilast 30 mg twice a day (34%) met the American College of Rheumatology criteria for 20% improvement in disease activity (the primary efficacy end point). In the MRI substudy, mean change from baseline in total joint damage scores according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system was generally similar with either apremilast dose at week 16. At week 52, no trends were noted for clinical end points by treatment group. Both apremilast doses were generally well tolerated. CONCLUSION: Apremilast efficacy was not demonstrated in patients who had active RA despite stable MTX therapy.

Observation of reward delivery to a conspecific modulates dopamine release in ventral striatum.

Dopamine (DA) neurons increase and decrease firing for rewards that are better and worse than expected, respectively. These correlates have been observed at the level of single-unit firing and in measurements of phasic DA release in ventral striatum (VS). Here, we ask whether DA release is modulated by delivery of reward, not to oneself, but to a conspecific. It is unknown what, if anything, DA release encodes during social situations in which one animal witnesses another animal receive reward. It might be predicted that DA release will increase, suggesting that watching a conspecific receive reward is a favorable outcome. Conversely, DA release may be entirely dependent on personal experience, or perhaps observation of receipt of reward might be experienced as a negative outcome because another individual, rather than oneself, receives the reward. Our data show that animals display a mixture of affective states during observation of conspecific reward, first exhibiting increases in appetitive calls (50 kHz), then exhibiting increases in aversive calls (22 kHz). Like ultrasonic vocalizations (USVs), DA signals were modulated by delivery of reward to the conspecific. We show stronger DA release during observation of the conspecific receiving reward relative to observation of reward delivered to an empty box, but only on the first trial. During the following trials, this relationship reversed: DA release was reduced during observation of the conspecific receiving reward. These findings suggest that positive and negative states associated with conspecific reward delivery modulate DA signals related to learning in social situations.

Comparison of CDE data in phacoemulsification between an open hospital-based ambulatory surgical center and a free-standing ambulatory surgical center.

Mean CDE (cumulative dissipated energy) values were compared for an open hospital- based surgical center and a free-standing surgical center. The same model of phacoemulsifier (Alcon Infiniti Ozil) was used. Mean CDE values showed that surgeons (individual private practice) at the free-standing surgical center were more efficient than surgeons (individual private practice) at the open hospital-based surgical center (mean CDE at the hospital-based surgical center 18.96 seconds [SD = 12.51]; mean CDE at the free-standing surgical center 13.2 seconds [SD = 9.5]). CDE can be used to monitor the efficiency of a cataract surgeon and surgical center in phacoemulsification. The CDE value may be used by institutions as one of the indicators for quality control and audit in phacoemulsification.

A retrospective randomized study to compare the energy delivered using CDE with different techniques and OZil settings by different surgeons in phacoemulsification.

Cumulative dissipated energy (CDE) was used with Infiniti((R)) Vision System (Alcon Labs) as an energy delivery guide to compare four different phaco techniques and phaco settings. The supracapsular phaco technique and burst mode is known for efficiency and surgery is faster compared with the old phaco unit. In this study, we found that supracapsular phaco with burst mode had the least CDE in both cataract and nuclear sclerosis cataract with the new Infiniti((R)) unit. We suggest that CDE can be used as one of the references to modify technique and setting to improve outcome for surgeons, especially for new surgeons.