A Case Report of Systemic Sclerosis Complicated by Biventricular Heart Failure, Pulmonary Hypertension and Review of Literature

Background: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder whose aetiology is not fully understood. Skin fibrosis and visceral organs involvement are the hallmarks, and the heart could be disproportionately or subtly involved. Cardiovascular manifestations could include arrhythmias, pericarditis, myocardial fibrosis, pulmonary hypertension and congestive heart failure. Pulmonary involvement could cause lung fibrosis, arteriolar thickening, and pulmonary hypertension. The presence of these manifestations confers a poor prognosis. Case Report: The case report presents a 50-year-old male patient with generalized skin sclerosis, hypo and hyperpigmented skin lesions, dyspnoea at rest, displaced apical impulse, tachycardia and pan-systolic murmur at the apex radiating to the axilla. Echo cardiography features showed ejection fraction of 33.3% with dilated atrial and ventricular chambers. Conclusions: We present a case systemic sclerosis complicated by biventricular heart failure and pulmonary hypertension

Effect of Two Cowpea (Vigna unguiculata) Fodder Cultivars as Supplements on Voluntary Intake; Milk Yield and Manure Production of Bunaji Cows

The feeding value of fodder from two cowpea cultivars to a basal maize stover diet was investigated using fifteen lactating White Fulani (Zebu) cows. The two cultivars were IT-716 and 994-DP. Diet was constituted as 50g DM/kg live weight and each of the cultivars was supplemented at 50% of the daily dry matter requirement of individual animals. The experimental design was a complete randomize. The parameters measured included feed intake, milk yield and composition and manure production. In a separate trial, dry matter degradation of the fodder was assessed. There were no significant differences in dry matter intake of the supplements. However, the dry matter intake of stover in the control diet was higher than those on the supplemented groups. The milk yields ranged from 887 to 1378 ml/day. Milk yield differed among treatments. Supplementation did not affect (P 0.05) fat, protein, total solids and ash contents of the milk across the treatments. Manure productions were not significantly different among the treatments. Similarly, content of N, P and K in manure were comparable among the treatments except for N that was lower (P 0.05) in the control group. The dry matter degradation was influenced by the fodder cultivars. The feeding of dual-purpose forage legumes residues could enhance milk production in lactating Zebu cows. This may be further increased by exploring other ways of improving feed residue utilization in the dry season

Infections in Dupilumab Clinical Trials in Atopic Dermatitis : A Comprehensive Pooled Analysis

Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649

Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV1) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers. Methods: Patients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL−1, ≥300 eosinophils·µL−1, ≥25 ppb fractional exhaled nitric oxide (FeNO), and both ≥150 eosinophils·µL−1 and ≥25 ppb FeNO, at baseline. Results: Dupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements versus placebo after 52 weeks in pre-bronchodilator FEV1 (0.20 and 0.13 L, respectively, versus placebo) and post-bronchodilator FEV1 (0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s−1, respectively) and pre-bronchodilator FEV1/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p<0.001). Difference versus placebo in post-bronchodilator FEV1 slope of change (weeks 4–52) was significant (0.04 L·year−1; p<0.05). Greater improvements were achieved in patients with elevated baseline blood eosinophil and/or FeNO levels for most outcomes. Conclusions: Dupilumab improves lung function outcomes, including large and small airway measurements and fixed airway obstruction, in patients with uncontrolled, moderate-to-severe asthma; particularly in patients with elevated biomarkers of type 2 inflammation

Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.

BACKGROUND Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. METHODS In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. RESULTS We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. CONCLUSIONS In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743; SOLO 2 ClinicalTrials .gov number, NCT02277769.

Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study

BACKGROUND: Significant unmet need exists for long-term treatment of moderate to severe atopic dermatitis (AD). OBJECTIVE: To assess the long-term safety and efficacy of dupilumab in patients with AD. METHODS: This ongoing, multicenter, open-label extension study (NCT01949311) evaluated long-term dupilumab treatment in adults who had previously participated in phase 1 through 3 clinical trials of dupilumab for AD. This analysis examined patients given 300 mg dupilumab weekly for up to 76 weeks at data cutoff (April 2016). Safety was the primary outcome; efficacy was also evaluated. RESULTS: Of 1491 enrolled patients (1042.9 patient-years), 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials (420.4 adverse events/100 patient-years and 8.5 serious adverse events/100 patient-years), with no new safety signals; common adverse events included nasopharyngitis, conjunctivitis, and injection-site reactions. Sustained improvement was seen up to 76 weeks in all efficacy outcomes, including measures of skin inflammation, pruritus, and quality of life. LIMITATIONS: Lack of control arm, limited number of patients with 76 weeks or longer of treatment (median follow-up, 24 weeks), and patients not receiving the approved dose regimen of 300 mg every 2 weeks. CONCLUSION: The safety and efficacy profile from this study supports the role of dupilumab as continuous long-term treatment for patients with moderate to severe AD

Dupilumab in adolescents with uncontrolled moderate‐to‐severe atopic dermatitis : results from a phase IIa open‐label trial and subsequent phase III open‐label extension

Background Dupilumab (monoclonal antibody inhibiting IL‐4/IL‐13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate‐to‐severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16‐week, randomised, placebo‐controlled phase III trial in adolescents (NCT03054428). Objectives To characterize the pharmacokinetics of dupilumab, and long‐term safety and efficacy in adolescents. Methods This was a global, multicentre, phase IIa, open‐label, ascending‐dose, sequential cohort study with a phase III open‐label extension (OLE) in adolescents with moderate‐to‐severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg−1 or 4 mg kg−1) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8‐week safety follow‐up. Patients then enrolled in the OLE, continuing 2 mg kg−1 or 4 mg kg−1 dupilumab weekly. Primary end points were dupilumab concentration–time profile and incidence of treatment‐emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI). Results Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target‐mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L−1 and 161 ± 60 mg L−1 for 2 mg kg−1 and 4 mg kg−1, respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg−1], 47% [4 mg kg−1]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction −34% ± 20% (2 mg kg−1) and −51% ± 29% (4 mg kg−1)]. With continuing treatment, EASI scores improved further [week 52: −85% ± 12% (2 mg kg−1) and −84% ± 20% (4 mg kg−1)]. Conclusions In adolescents with moderate‐to‐severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52‐week safety and efficacy data support long‐term use of dupilumab in this patient population

Conjunctivitis in dupilumab clinical trials

Background Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-tosevere atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. Objectives To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. Methods We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). Results In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study