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Background: Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6–17 years) with moderate‐to‐severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk–benefit profile in younger children remains a significant unmet need. Objectives: To determine the pharmacokinetics, safety and efficacy of single‐dose dupilumab in children with severe AD aged ≥6 months to <6 years. Methods: This open‐label, multicenter, phase 2, sequential, two‐age cohort, two‐dose level study (LIBERTY AD PRE‐SCHOOL; NCT03346434) included an initial cohort of older children aged ≥2 to <6 years, followed by a younger cohort aged ≥6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4‐week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low‐to‐medium potency topical corticosteroids was allowed. Results: Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose‐proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by −44.6% and −49.7% (older cohort) and −42.7% and −38.8% (younger cohort), and mean Peak Pruritus NRS scores by −22.9% and −44.7% (older cohort) and −11.1% and −18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children. Conclusions: Single‐dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non‐linear, consistent with previous studies in adults and adolescents. [ABSTRACT FROM AUTHOR]

Sleep disturbances are part of a symptom triad, along with itch and pain, that patients with atopic dermatitis (AD) report as being frequent and burdensome.1 The effects of dupilumab on sleep were evaluated in adults with chronic AD in five randomized, double-blind, placebo-controlled clinical trials ( I N i = 2632). 2a), sleep disturbances were reported to be less frequent among dupilumab-treated patients vs. placebo-treated patients; in particular, 58.6-63.4% of dupilumab-treated patients vs. 40.5% of placebo-treated patients reported no days of sleep disturbances. [Extracted from the article]

Summary: 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. What's already known about this topic? Adolescents with moderate‐to‐severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options.Dupilumab (monoclonal antibody against interleukin‐4 receptor α) is approved for the treatment of adolescents with moderate‐to‐severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union).A 16‐week, randomized, placebo‐controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long‐term safety and efficacy of dupilumab in adolescents with moderate‐to‐severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16‐week dupilumab phase III trial.The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16‐week phase III monotherapy trial. Linked Comment: Sibbald. Br J Dermatol 2020; 182:12–13. Plain language summary available online [ABSTRACT FROM AUTHOR]

No method with low morbidity presently exists for obtaining serial hepatic gene expression measurements in humans. While hepatic fine needle aspiration (FNA) has lower morbidity than core needle biopsy, applicability is limited due to blood contamination, which confounds quantification of gene expression changes. The aim of this study was to validate FNA for assessment of hepatic gene expression. Liver needle biopsies and FNA procedures were simultaneously performed on 17 patients with chronic hepatitis C virus infection with an additional FNA procedure 1 week later. Nine patients had mild/moderate fibrosis and eight advanced fibrosis. Gene expression profiling was performed using Affymetrix microarrays and TaqMan qPCR; pathway analysis was performed using Ingenuity. We developed a novel strategy that applies liver-enriched normalization genes to determine the percentage of liver in the FNA sample, which enables accurate gene expression measurements overcoming biases derived from blood contamination. We obtained almost identical gene expression results ( ρ = 0.99, P < 0.0001) comparing needle biopsy and FNA samples for 21 preselected genes. Gene expression results were also validated in dogs. These data suggest that liver FNA is a reliable method for serial hepatic tissue sampling with potential utility for a variety of preclinical and clinical applications. [ABSTRACT FROM AUTHOR]

Aims: Supraphysiologic glucocorticoid activity is well established to cause impaired glucose tolerance and insulin resistance, yet no study has evaluated dose-dependent effects of low-dose prednisone during short-term oral administration. Methods: The objective of this study was to quantify the effects of daily 10 or 25 mg prednisone administration for one week on insulin sensitivity by employing a two-step hyperinsulinemic euglycemic glucose clamp (Step 1: insulin infusion = 20 mU/m2/min; Step 2: insulin infusion = 80 mU/m2/min) in healthy, lean males. The amount of glucose infused at steady-state to maintain stable blood glucose [90 mg/dl (4.95 mmol/l)] was used to calculate several indices of insulin sensitivity. Results: During Step 1 of the clamp, whole body glucose disposal ( M) was reduced by 35% (p = 0.003) and M/ I was reduced by 29% (p = 0.025) for 25 mg prednisone compared to placebo. No appreciable effect of 10 mg prednisone was observed. During Step 2, M was reduced by 33% (p = 0.001) and 15% (p = 0.006) for 25 and 10 mg prednisone compared to placebo; and M/ I ratio was reduced by 31% (p < 0.001) and 13% (p = 0.026), respectively. The insulin sensitivity index, S i, calculated as the quotient of augmentation of M/I between Step 1 and 2, was reduced by 35.3% (p < 0.01) and 23.5% (p < 0.05) for 25 and 10 mg prednisone, respectively. Conclusion: Administration of relatively low pharmacological doses of prednisone for one week impaired insulin sensitivity in a dose-dependent manner in healthy males. These observed changes in insulin sensitivity are likely to be clinically relevant, especially in individuals predisposed to develop glucose intolerance. [ABSTRACT FROM AUTHOR]

The aim of the study presented here was to identify patients with multidrug resistant tuberculosis (MDRTB) in the Samara region of Russia and to analyze the susceptibility of their isolates to second-line drugs in order to develop an empirical, standard, second-line treatment regimen. Treatment of MDRTB can be individualized based on in vitro laboratory analysis or standardized. In the latter case there is still a need to ascertain local second-line drug-resistance patterns. Described here are the clinical characteristics of 251 MDRTB patients identified in the study and the second-line drug susceptibility of 69 MDRTB isolates obtained from them. Antimicrobial resistance to the following agents was detected in the isolates: rifabutin (88.2%), streptomycin (42.8%), amikacin (7.2%), doxycycline (7.4%), ciprofloxacin (4.3%), clofazimine (2.9%), cycloserine (7.4%), and prothionamide (1.5%). The results of the study indicate it is possible to develop a standard, effective, clinical treatment regimen using ethambutol, pyrazinamide, prothionamide, a fluoroquinolone and amikacin. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) and HIV rates continue to escalate in Russia, but true rates for drug resistance, especially multidrug resistant tuberculosis (MDR TB), are,unknown. A study was conducted with the aims of identifying first line drug resistance, both in the civilian and prison sectors, for new and previously treated cases; and risk factors for the development of drug resistance. Methods: A cross sectional survey was undertaken of 600 patients (309 civilians, 291 prisoners) with bacteriologically confirmed pulmonary TB over a 1 year period during 2001-2 in Samara Oblast, Russia. Results: The prevalence of isoniazid, rifampicin, streplornycin, ethambotol and `pyrazinamide resistance in new TB cases (civilian and prison patients) was 38.0%, 25.2%, 34.6%, 14.7%, and 7.2%, respectively. The prevalence of MDR TB was 22.7%, 19.8%, and 37.3% in all new cases, new civilian cases, and new prison cases, respectively, with an overall prevalence of 45.5% and 55.3% in previously treated cases. `Factors associated with resistance included previous TB treatment for more than 4 weeks, smoking (for `isoniazid resistance), the presence of cavitations on the chest radiograph, and imprisonment. H 1V.. was, not associated with resistance in all patients. The rates of resistance were significantly higher in prisoners, with rate ratios (RR) of 1.9 (95% Cl 1.1 to 3.2) for MDR TB, 1.9' (95% Cl .1 to 3.2) for rifampicin, and 1.6 (95% Cl 1.0 to 2.6) for isoniazid. Conclusions: Rates of first line drug resistance are high, particularly in prisoners and previously treated cases. TB control programmes should initially focus on standardised treatment to maxirnise cure, combined' with measures to reduce institutional TB spread (particularly in prisons) coupled with early diagnosis of MDR TB to reduce the spread and development of resistance. [ABSTRACT FROM AUTHOR]

Background: A description is given of a major outbreak of isoniazid monoresistant tuberculosis (TB) chiefly in north London, including prisons. The earliest case was diagnosed in 1995 with most cases appearing after 1999.Methods: Confirmation of a local cluster of cases was confirmed by restriction fragment length polymorphism (RFLP IS6110) typing or "rapid epidemiological typing" (RAPET). Further cases were found by retrospective analysis of existing databases, prospective screening of new isolates, and targeted epidemiological case detection including questionnaire analysis.Results: By the end of 2001, 70 confirmed cases in London had been linked with a further 13 clinical cases in contacts and nine epidemiologically linked cases outside London. The epidemic curve suggests that the peak of the outbreak has not yet been reached. Cases in the outbreak largely belong to a social group of young adults of mixed ethnic backgrounds including several individuals from professional/business backgrounds. Compared with other cases of TB reported to the enhanced surveillance scheme in London during 1999-2001, the cases are more likely to be of white (26/70 (37%) v 1308/7666 (17%)) or black Caribbean ethnicity (17/70 (24%) v 312/7666 (4%)), born in the UK (41/70 (59%) v 1335/7666 (17%)), and male (52/70 (74%) v 4195/7666 (55%)). Drug misuse and/or prison detention are factors common to many cases.Conclusions: The investigation of the outbreak revealed significant problems on an individual patient and population based level including difficulties with contact tracing, compliance, and the risk of developing multidrug resistance. This incident has demonstrated the value of molecular strain typing in investigating an extensive outbreak of TB. This is the first documented outbreak involving a UK prison. [ABSTRACT FROM AUTHOR]

Summary: 特应性皮炎 (AD) 也称为湿疹, 其表现为皮肤发红、渗液和干燥并可能发生开裂和感染。剧烈瘙痒可能非常麻烦, 而且可能导致睡眠障碍, 是 AD 患者的主要主诉。 AD 通常从儿童开始, 而且影响全世界 1/4 的青少年。对于青少年, AD 皮肤的瘙痒和外观可显著降低生活质量,但适合长期使用的中度至重度 AD 有效治疗选择很少。 Dupilumab 是一种新的药物, 其可阻断导致过敏症状(如 AD)的关键分子。研究显示, 该药物对治疗成人中度至重度 AD 是有效的, 而且长期使用相对安全。 这项研究在 40 例年龄 12 至 17 岁的接受 dupilumab 治疗最长一年的患者中进行, 涉及欧洲和加拿大多个中心。研究人员希望了解 dupilumab 是否对治疗 AD 有效以及这类患者长期使用是否安全 。他们还希望了解 dupilumab 在此年龄段 AD 患者中的身体处理方式。 他们发现, dupilumab 治疗在这些年轻患者中显著改善了皮肤和 AD 症状(包括瘙痒), 而且不会造成任何意外的副作用。他们还发现 dupilumab 在这些年轻患者中的处理方式与成人相同。在整个一年治疗期内维持了改善。 研究结果支持使用 dupilumab 持续治疗中度至重度 AD 青少年患者。 This summary relates to the study: dupilumab 用于未控制的中度至重度特应性皮炎青少年患者中:IIA 期开放标签试验和随后的 III 期开放标签扩展研究结果 Linked Article: Cork et al. Br J Dermatol 2020; 182:85–96 [ABSTRACT FROM AUTHOR]

Summary: Atopic dermatitis (AD), also known as eczema, is characterized by red, oozy, and dry skin that can become cracked and infected. Intense itching, which can be very troublesome and can cause sleep disturbance, is the main complaint of patients with AD. AD often begins in childhood and affects 1 in 4 teenagers worldwide. For teenagers, the itchiness and appearance of AD skin can significantly reduce quality of life, but there are few effective treatment options for moderate‐to‐severe AD that are suitable for long‐term use. Dupilumab is a new drug that blocks key molecules that cause allergic conditions, such as AD. It has been shown to be effective in treating moderate‐to‐severe AD in adults and to be relatively safe for long‐term use. This study was conducted in multiple centres across Europe and Canada in 40 patients aged 12 to 17 who received treatment with dupilumab for up to a year. The researchers wanted to know whether dupilumab is effective and safe for treating AD with long‐term use in these patients. They also wanted to know how dupilumab is processed by the body in patients with AD in this age group. They found that treatment with dupilumab substantially improves the skin and symptoms of AD, including itching, in these younger patients, without causing any unexpected side effects. They also found that dupilumab is processed the same way in these younger patients as in adults. The improvements were maintained throughout the one year of treatment. The study results support the use of dupilumab in the continuous treatment of adolescents with moderate‐to‐severe AD. This summary relates to the study: 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 Linked Article: Cork et al. Br J Dermatol 2020; 182:85–96 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses about an outbreak of isoniazid monoresistant tuberculosis in the previous issue.

Presents a letter to the editor about the factors involved in the development of drug resistance during treatment of tuberculosis.