Early and sustained efficacy with apremilast monotherapy in biological-naïve patients with psoriatic arthritis: a phase IIIB, randomised controlled trial (ACTIVE)

Trial registration number NCT01925768[Abstract] Objective Evaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA. Methods Patients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52. Results Among 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (P<0.0001), HAQ-DI (P=0.023) and Gladman Enthesitis Index (P=0.001). Improvements were maintained with continued treatment through week 52. Over 52 weeks, apremilast’s safety profile was consistent with prior phase 3 studies in psoriasis and PsA. During weeks 0–24, the incidence of protocol-defined diarrhoea was 11.0% (apremilast) and 8.3% (placebo); serious adverse event rates were 2.8% (apremilast) and 4.6% (placebo). Conclusions In biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports

Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials.

OBJECTIVE: Psoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA. METHODS: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re-randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double-blind treatment continued to week 52; patients could continue apremilast during an open-label, long-term treatment phase. RESULTS: In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure-adjusted incidence rate [EAIR]/100 patient-years, 265.1) versus placebo (47.5%; EAIR/100 patient-years, 200.7) in the placebo-controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast-exposed patients were diarrhea (13.9%; EAIR/100 patient-years, 18.6), nausea (12.3%; EAIR/100 patient-years, 16.0), headache (9.4%; EAIR/100 patient-years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient-years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient-years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient-years, 1.8). Major adverse cardiac events (EAIR/100 patient-years, 0.5), malignancies (EAIR/100 patient-years, 0.9), and serious opportunistic infections (EAIR/100 patient-years, 0.0) were infrequent over the 3-year exposure period. Discontinuation rates due to AEs were low ( CONCLUSION: Apremilast demonstrated a favorable safety profile and was well tolerated up to 156 weeks

Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1–3 pooled analysis

Background The efficacy and safety of apremilast were assessed in patients with psoriatic arthritis (PsA) in three phase III clinical trials with similar designs (PALACE 1, 2, and 3). Methods Following a 24-week, randomized (1:1:1 to apremilast 30 mg twice daily, 20 mg twice daily, or placebo), double-blind phase and a 28-week blinded active treatment phase, patients could receive apremilast in open-label extension studies for an additional 4 years. Eligible adult patients had active PsA for ≥ 6 months and three or more swollen joints and three or more tender joints despite prior treatment with disease-modifying anti-rheumatic drugs. Results A total of 1493 randomized patients received one or more doses of study medication (placebo: n = 496; apremilast 30 mg twice daily: n = 497; apremilast 20 mg twice daily: n = 500). In patients continuing apremilast treatment, response was sustained without new safety issues. At week 260, 67.2% of remaining patients achieved an ACR20 response, and 44.4% and 27.4% achieved ACR50 and ACR70 responses, respectively. Among patients with baseline enthesitis and dactylitis, 62.4% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 80.9% achieved a dactylitis count of 0, respectively. In patients who had ≥ 3% baseline psoriasis body surface area involvement, 43.6% achieved ≥ 75% reduction from the baseline Psoriasis Area and Severity Index scores. The most commonly reported adverse events (AEs) were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis, with most diarrhea and nausea AEs occurring within the first 2 weeks of treatment and usually resolving within 4 weeks. Reported rates of depression during the study were low (≤ 1.8%). The majority of patients maintained their weight within 5% of baseline during the study. No new safety concerns or increases in the incidence or severity of AEs were observed over the long term. Conclusions Apremilast maintained clinical benefit and a favorable safety profile for up to 5 years among patients with PsA. Trial registration ClinicalTrials.gov NCT01172938, NCT01212757, NCT0121277

Cannabidiol improves memory and decreases IL-1β serum levels in rats with lipopolysaccharide-induced inflammation

Aim: Memory improving and anti-inflammatory properties of cannabidiol (CBD) were investigated in an experimental model of lipopolysaccharide (LPS)-induced inflammation. Materials and methods: Male Wistar rats were randomly divided into 4 groups: control, LPS control, LPS + CBD 5 mg/kg bw, and LPS + CBD 10 mg/kg bw. Animals were treated with CBD 14 days before LPS administration and throughout the experiment. Step-through passive avoidance task, Y-maze, and novel object recognition test (NORT) were used to assess the memory functions. The following parameters were recorded: latency time, spontaneous alternations percentage (SA%) and recognition index (RI). IL-10, IL-6, TNF-α, and IL-1β serum levels were measured to evaluate the immunomodulatory properties of CBD. Results: LPS led to significant decrease of the recorded parameters in all memory tasks. This demonstrated the memory-impairing effect of LPS-induced inflammation. In the Y-maze and NORT tests, both doses of CBD increased SA% and RI, respectively. Significant difference was found in comparison with the LPS controls. Rats from the CBD treated groups showed increased latency in the step-through passive avoidance task. In the short-term memory test, both CBD doses significantly increased this parameter when compared with both control groups (p&amp;lt;0.05 and p&amp;lt;0.001, respectively), whereas in the long-term memory test, statistical significance was reached only in comparison with the LPS controls (p&amp;lt;0.01). CBD treatment failed to reduce TNF-α and IL-6 serum levels. The lower studied dose significantly decreased IL-10 and IL-1β concentrations compared to LPS controls (p&amp;lt;0.01 and p&amp;lt;0.05, respectively). Conclusions: CBD improved spatial working and recognition memory in rats with LPS-induced inflammation. Suppression of IL-1β production could be attributed to the observed effect

Subchronic toxicity of Sideritis scardica, Lamiaceae on male Wistar rats

Introduction: Sideritis scardica, Lamiaceae, is a plant with anti-inflammatory, antirheumatic, digestive, and antimicrobial properties that is widely used in folk medicine throughout the Balkan Peninsula. The name derives from the Greek word ‘sideros’, meaning iron, and it is believed that the plant was also used by soldiers to heal wounds caused by cutting weapons. Aim: The study aimed to assess the subchronic toxicity of a dry hydromethanolic extract from Sideritis scardica, Lamiaceae. Materials and methods: To investigate the subchronic toxicity, male Wistar rats were given orally a solution of dry hydromethanolic extract daily for 12-weeks at doses of 100, 200, and 400 mg/kg bw. Blood and blood serum were collected at the end of the experiment, and different organs were prepared for histopathological examination. Statistical analysis was performed with One-Way ANOVA test, using IBM SPSS 19.0. Results: All hematological and biochemical results remained within the normal reference ranges described for the species. The histological examination showed no abnormalities in the morphology of the examined organs (brain, stomach, liver, and kidney). Conclusions: The study contributes to a better understanding of the possible pharmacological effects, while documenting the absence of toxicity and safe use of the herb for future new indications

Apremilast monotherapy for long-term treatment of active psoriatic arthritis in DMARD-naïve patients

Objectives: apremilast monotherapy was evaluated up to 5 years in PALACE 4 (fourth PsA Long-term Assessment of Clinical Efficacy study) DMARD-naïve patients with PsA.Methods: patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg or apremilast 20 mg twice a day. Placebo patients were rerandomized to apremilast at week 16 or 24. Double-blind apremilast continued to week 52, with a 4-year open-label extension (≤260 weeks of exposure). Analyses through week 260 were based on observed data.Results: a total of 527 patients were treated. Among patients randomized to apremilast 30 mg at baseline, 45.5% completed week 260. At study end, 24.8% reported conventional synthetic DMARD or steroid use for any reason. At week 260, 65.8%/39.0%/20.3% of apremilast 30 mg patients achieved ACR20/ACR50/ACR70 responses, respectively. PsA sign and symptom improvements were sustained up to week 260 with continued treatment, including reductions in swollen (84.8%) and tender (76.4%) joint counts. Among apremilast 30 mg patients with baseline enthesitis or dactylitis, 71.2% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 95.1% achieved a dactylitis count of 0. Over 50% of patients achieved a HAQ Disability Index minimal clinically important difference (≥0.35). In patients with ≥3% baseline psoriasis-involved body surface area, 60.3% and 47.6% achieved ≥50% and ≥75% improvement in Psoriasis Area and Severity Index scores, respectively. Patients continuing apremilast 20 mg also demonstrated consistent, sustained improvements. The most common adverse events were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. No new safety concerns were observed long term.Conclusions: apremilast led to sustained PsA efficacy up to 260 weeks and was well tolerated

Cannabidiol improves memory and decreases IL-1β serum levels in rats with lipopolysaccharide-induced inflammation

Aim: Memory improving and anti-inflammatory properties of cannabidiol (CBD) were investigated in an experimental model of lipopolysaccharide (LPS)-induced inflammation. Materials and methods: Male Wistar rats were randomly divided into 4 groups: control, LPS control, LPS + CBD 5 mg/kg bw, and LPS + CBD 10 mg/kg bw. Animals were treated with CBD 14 days before LPS administration and throughout the experiment. Step-through passive avoidance task, Y-maze, and novel object recognition test (NORT) were used to assess the memory functions. The following parameters were recorded: latency time, spontaneous alternations percentage (SA%) and recognition index (RI). IL-10, IL-6, TNF-α, and IL-1β serum levels were measured to evaluate the immunomodulatory properties of CBD. Results: LPS led to significant decrease of the recorded parameters in all memory tasks. This demonstrated the memory-impairing effect of LPS-induced inflammation. In the Y-maze and NORT tests, both doses of CBD increased SA% and RI, respectively. Significant difference was found in comparison with the LPS controls. Rats from the CBD treated groups showed increased latency in the step-through passive avoidance task. In the short-term memory test, both CBD doses significantly increased this parameter when compared with both control groups (p<0.05 and p<0.001, respectively), whereas in the long-term memory test, statistical significance was reached only in comparison with the LPS controls (p<0.01). CBD treatment failed to reduce TNF-α and IL-6 serum levels. The lower studied dose significantly decreased IL-10 and IL-1β concentrations compared to LPS controls (p<0.01 and p<0.05, respectively). Conclusions: CBD improved spatial working and recognition memory in rats with LPS-induced inflammation. Suppression of IL-1β production could be attributed to the observed effect

Apremilast monotherapy for long-term treatment of active psoriatic arthritis in DMARD-naive patients

Objectives: Apremilast monotherapy was evaluated up to 5 years in PALACE 4 DMARD-naive patients with PsA. Methods: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg or apremilast 20 mg twice daily. Placebo patients were rerandomized to apremilast at week 16 or 24. Double-blind apremilast continued to week 52, with a 4-year open-label extension (≤260 weeks of exposure). Analyses through week 260 were based on observed data. Results: 527 patients were treated. Among patients randomized to apremilast 30 mg at baseline, 45.5% completed week 260. At study end, 24.8% reported csDMARD or steroid use for any reason. At week 260, 65.8%/39.0%/20.3% of apremilast 30 mg patients achieved ACR20/ACR50/ACR70 responses, respectively. PsA sign/symptom improvements were sustained up to week 260 with continued treatment, including reductions in swollen (84.8%) and tender (76.4%) joint counts. Among apremilast 30 mg patients with baseline enthesitis or dactylitis, 71.2% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 95.1% achieved a dactylitis count of 0, respectively. Over 50% of patients achieved a HAQ-DI minimal clinically important difference (≥0.35). In patients with ≥3% baseline psoriasis-involved body surface area, 60.3% and 47.6% achieved ≥50% and ≥75% improvement in Psoriasis Area and Severity Index scores, respectively. Patients continuing apremilast 20 mg also demonstrated consistent, sustained improvements. The most common adverse events were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. No new safety concerns were observed long term. Conclusions: Apremilast led to sustained PsA efficacy up to 260 weeks and was well tolerated. Trial registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423

Deucravacitinib, a Tyrosine Kinase 2 Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial

Objective: To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE). Methods: Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI-4) response at week 32. Secondary outcomes assessed at week 48 included SRI-4, British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts. Results: At week 32, the percentage of patients achieving SRI-4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95% CI) 1.5, 5.1]; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 [95% CI 1.0, 3.4]; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 [95% CI 0.8, 2.9]; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI-50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported. Conclusion: Deucravacitinib treatment elicited higher response rates for SRI-4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE