Upadacitinib monotherapy versus methotrexate monotherapy in patients with rheumatoid arthritis: efficacy and safety through 5 years in the SELECT-EARLY randomized controlled trial.

BACKGROUND: To evaluate the efficacy and safety of upadacitinib monotherapy versus methotrexate (MTX) monotherapy over 5 years among MTX-naïve patients with moderately to severely active rheumatoid arthritis (RA) in the long-term extension (LTE) of the phase 3 SELECT-EARLY trial. METHODS: Patients were randomized to receive upadacitinib 15 mg or 30 mg or MTX. Patients who did not achieve CDAI remission and had < 20% improvement in tender and swollen joint counts at week 26 received rescue therapy (addition of MTX in the upadacitinib group and addition of upadacitinib in the MTX group). Efficacy assessments were evaluated over 5 years and are reported as observed (AO) for patients who received continuous monotherapy with upadacitinib 15/30 mg or MTX and by randomized group applying non-responder imputation (NRI). Treatment-emergent adverse events (TEAEs) per 100 patient-years were summarized over 5 years. RESULTS: Of 945 patients randomized and treated, 775 (82%) completed week 48 and entered the LTE on study drug. Higher proportions of patients consistently achieved disease activity targets over 5 years with upadacitinib than MTX. In AO analyses, 53%/59% of patients attained CDAI remission with upadacitinib 15/30 mg versus 43% with MTX at week 260. NRI analyses showed better CDAI, DAS28(CRP), and ACR responses with upadacitinib relative to MTX at week 260 (all comparisons, nominal P < .001). Upadacitinib treatment also resulted in numerically greater inhibition of structural joint progression through week 260 compared to MTX. Most TEAEs, serious AEs, and AEs leading to discontinuation were numerically higher in patients receiving upadacitinib 30 mg. Rates of serious infections, herpes zoster, creatine phosphokinase elevation, nonmelanoma skin cancer, and neutropenia were numerically higher with upadacitinib than MTX. The observed safety profile of upadacitinib over 5 years was consistent with earlier trial results and integrated phase 3 safety analyses. CONCLUSIONS: Upadacitinib showed better clinical responses versus MTX in patients with RA throughout the 5-year trial. Higher rates of several AEs were observed with upadacitinib, especially in the 30 mg group, compared to MTX. When used as monotherapy in MTX-naïve patients, the approved upadacitinib 15 mg dose showed better long-term efficacy versus MTX and an overall favorable benefit-risk profile. TRIAL REGISTRATION: NCT02706873.

Efficacy and Safety of Secukinumab in US Patients with Psoriatic Arthritis: A Subgroup Analysis of the Phase 3 FUTURE Studies.

INTRODUCTION: The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2-5 studies in patients with psoriatic arthritis (PsA). METHODS: Data were pooled from US patients enrolled in the phase 3 FUTURE 2-5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons. RESULTS: Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m2 and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P < 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P < 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P < 0.05). CONCLUSIONS: In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300 mg than 150 mg.

Infant feeding practices and risk of preschool obesity in AlAin, UAE: A cross-sectional study.

Early childhood obesity is serious public health problem, and poses a risk of obesity in later life. The study aimed to investigate whether infant feeding affects risk of overweight and obesity in preschool children in the United Arab Emirates (UAE). A cross-sectional study was carried out. Data was collected in a kindergarten in Al Ain, UAE. One hundred and fifty parents and preschool children aged 2 to 6 years participated in the study. Univariate and multivariate linear regression were used to investigate associations. A longer duration of breastfeeding and later introduction of complementary foods were associated with a lower BMI z-score in preschool children. Each month of any breastfeeding was associated with a lower BMI z-score in the unadjusted model (ß = -0.03; 95% CI -0.05, -0.01; p = 0.01), and each month increase in the age of introducing complementary foods was associated with a lower BMI z-score in the unadjusted model (ß = -0.43; 95% CI: -0.60 to-0.027; p<0.001). These associations remained after adjustment for potential confounding factors (age, sex, maternal BMI, maternal education level, mother's age, social class, father's BMI) for duration of breastfeedinig (ß = -0.02; 95% CI: -0.05 to 0.00; p<0.001) and age of complementary feeding (ß = -0.39; 95% CI: -0.57 to-0.21; p<0.001). Poor infant feeding practices (shorter duration of breastfeedinig and early introduction of complementary foods) were found to be associated with higher BMI in preschool children. Promoting appropriate proper infant feeding practices in line with recommendations could be one strategy to help prevent childhood obesity in the UAE.

Does human milk composition predict later risk of obesity? A systematic review.

BACKGROUND: Possible mechanisms behind the association of breastfeeding with a lower risk of later obesity are unknown but one possibility is the unique composition of human milk. Here, we systematically reviewed the evidence linking breast-milk macronutrient and hormonal composition with later obesity. METHODS: We searched 7 databases for studies that included infants predominantly breast-fed for the first 3 months and which analysed associations between a measure of breast-milk composition and later (> 6 months) measures of obesity or body composition. RESULTS: 47 publications were identified for full-text screening, of which 10 were eligible and only 3 found significant associations. Higher leptin concentration in breast milk at age 1 month was associated with lower infant BMI at 12, 18 and 24 months of age (1 study). Higher breast-milk adiponectin concentration at 6 weeks and 4 months were associated with adiposity at age 12 and 24 months (1 study). In 1 study, breast-milk carbohydrate content was positively associated, and fat content negatively associated, with adiposity at age 12 months. No significant associations were found between other hormones or macronutrients in human milk and later risk of obesity or body composition. CONCLUSIONS: The evidence linking breast-milk composition with later obesity was inconsistent and confined to single, individual studies. Our review highlights the methodological limitations of previous studies and the need for further research in this area.

Weight Gain in Early Infancy Impacts Appetite Regulation in the First Year of Life. A Prospective Study of Infants Living in Cyprus.

BACKGROUND: Eating behavior is associated with weight gain in infancy and childhood. Few studies found a bidirectional association between weight gain and eating behavior development in childhood, but there is little data on the association in early infancy, a period critical for the programming of obesity risk. OBJECTIVE: We investigated the bidirectional association between appetite traits and weight gain during the first year of life. METHODS: Participants were part of a cohort of 432 infants born in Cyprus. Appetite traits were measured using the Baby Eating Behavior Questionnaire or the Child Eating Behavior Questionnaire at age 2 to 4 wk, 6 mo, and 12 mo. Weight and length were collected at birth, 4 wk, 6 mo, and 12 mo. Multivariable linear regression was used to analyze associations between appetite traits at 2 to 4 wk and 6 mo and weight for age z-score change (WFAZC) between 4 wk and 6 mo and 6 and 12 mo. Associations were also analyzed in the opposite direction, between WFAZC from birth to 4 wk, 4 wk to 6 mo, and 6 mo to 12 mo and appetite traits at 4 wk, 6 mo, and 12 mo. RESULTS: Satiety responsiveness (SR) at 2 to 4 wk was associated with lower WFAZC from 4 wk to 6 mo (ß: -0.17; 95% CI: -0.30, -0.04) and SR at age 6 mo was associated with lower WFAZC from 6 to 12 mo (ß: -0.09; 95% CI: -0.17, -0.02). WFAZC from 4 wk to 6 mo was associated with higher enjoyment of food at 12 mo (ß: 0.11; 95% CI: 0.01, 0.20), higher food responsiveness at 12 mo (ß: 0.17; 95% CI: 0.04, 0.30), and lower SR at both 6 mo (ß: -0.11; 95% CI: -0.21, -0.01) and 12 mo (ß: -0.14; 95% CI: -0.24, -0.03). CONCLUSIONS: We found a bidirectional association between weight gain and appetite traits in infancy, suggesting that the effect of postnatal weight gain on obesity development is partly mediated by programming of appetite traits.

Catch-Up Growth in Infants and Young Children With Faltering Growth: Expert Opinion to Guide General Clinicians.

Faltering growth (FG) is a problem regularly seen by clinicians in infants and young children (<2 years of age). It can occur due to non-disease-related and disease-related causes and is associated with a wide range of adverse outcomes, including shorter-term effects such as impaired immune responses and increased length of hospital stay, and longer-term consequences, including an impact on schooling and cognitive achievements, short stature, and socioeconomic outcomes. It is essential to detect FG, address underlying causes and support catch-up growth where this is indicated. However, anecdotal reports suggest misplaced fear of promoting accelerated (too rapid) growth may deter some clinicians from adequately addressing FG. An invited international group of experts in pediatric nutrition and growth reviewed the available evidence and guidelines on FG resulting from disease-related and non-disease-related effects on nutritional status in healthy term and small for gestational age infants and children up to the age of 2 years in low-, middle-, and high-income countries. Using a modified Delphi process, we developed practical consensus recommendations to provide clarity and practical recommendations for general clinicians on how FG should be defined in different young child populations at risk, how FG should be assessed and managed, and the role of catch-up growth after a period of FG. We also suggested areas where further research is needed to answer remaining questions on this important issue.

Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis.

OBJECTIVE: The study objective was to evaluate the safety, tolerability, pharmacodynamics, and preliminary efficacy of ATI-450 with methotrexate in patients with rheumatoid arthritis (RA). METHODS: A parallel-assignment, placebo-controlled, investigator-blinded/patient-blinded multicenter study evaluated patients with moderate-to-severe RA aged 18 to 70 years. Eligible patients were randomized (1:1) to ATI-450 50-mg oral tablets twice daily or placebo with a stable weekly dose of methotrexate for 12 weeks. The primary objective was to assess ATI-450 safety and tolerability. The secondary objectives were to assess the median percentage change from baseline high-sensitivity C-reactive protein (hs-CRP) levels, the mean change from baseline in Disease Activity Score in 28 joints based on CRP level (DAS28-CRP) and Rheumatoid Arthritis Magnetic Resonance Imaging Score hand-wrist assessments of synovitis or bone erosion at week 12, and the proportion of patients with American College of Rheumatology 20/50/70 (ACR 20/50/70) and with DAS28-CRP scores of less than 2.6. The exploratory outcomes were change from baseline in endogenous and ex vivo-stimulated cytokine levels. RESULTS: ATI-450 was well tolerated with no severe adverse events reported. ATI-450 reduced median hs-CRP levels by 42% or more at all posttreatment timepoints. In the ATI-450 group, a mean (median) decrease in DAS28-CRP score of 2.0 (2.1) was observed at week 12; proportions of patients with an ACR 20/50/70 response in the per-protocol population were 60%, 33%, and 20%, respectively, at week 12. Endogenous plasma levels of key inflammatory cytokines (tumor necrosis factor α, macrophage inflammatory protein 1ß, interleukin 6, interleukin 8) were reduced across the 12 treatment weeks. CONCLUSION: This is the first clinical study demonstrating that selective mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) pathway blockade leads to a sustained antiinflammatory effect. This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration.

Partial Hydrolyzed Protein as a Protein Source for Infant Feeding: Do or Don't?

Exclusive breastfeeding until the age of six months is the recommended feeding method for all infants. However, this is not possible for every infant. Therefore, a second choice of feeding, as close as possible to the gold standard, is needed. For historical reasons, this has been cow's-milk-based feeding. This paper discusses if this second-choice feeding method should contain intact protein or partially hydrolyzed proteins. The limited data available indicates that mother's milk is relatively rich in bioactive peptides. Whether partially hydrolyzed protein might be a protein source closer to human milk protein content than intact cow's milk needs further research. However, more research on protein and bioactive peptides in mother's milk should be a priority for future scientific development in this field. Results of such research will also provide an answer to the question of which option would be the best second choice for infant feeding if sufficient breast milk is not available.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Biology of human milk oligosaccharides: From basic science to clinical evidence.

Human milk oligosaccharides (HMOs) have been researched by scientists for over 100 years, driven by the substantial evidence for the nutritional and health benefits of mother's milk. Yet research has truly bloomed during the last decade, thanks to progress in biotechnology, which has allowed the production of large amounts of bona fide HMOs. The availability of HMOs has been particularly crucial for the renewed interest in HMO research because of the low abundance or even absence of HMOs in farmed animal milk. This interest is reflected in the increasing number of original research publications and reviews on HMOs. Here, we provide an overview and critical discussion on structure-function relations of HMOs that highlight why they are such interesting and important components of human milk. Clinical observations in breastfed infants backed by basic research from animal models provide guidance as to what physiological roles for HMOs are to be expected. From an evidence-based nutrition viewpoint, we discuss the current data supporting the clinical relevance of specific HMOs based on randomised placebo-controlled clinical intervention trials in formula-fed infants.

Secukinumab provides sustained improvement in nail psoriasis, signs and symptoms of psoriatic arthritis and low rate of radiographic progression in patients with concomitant nail involvement: 2-year results from the Phase III FUTURE 5 study.

OBJECTIVES: To evaluate the impact of secukinumab on nail psoriasis and other psoriatic disease manifestations in patients with psoriatic arthritis (PsA) with concomitant nail psoriasis from the FUTURE 5 study. METHODS: Eligible patients were randomly allocated to receive subcutaneous secukinumab (300 mg load [300 mg], 150 mg load [150 mg], and 150 mg [no load]) or placebo weekly and then every 4 weeks starting Week 4. Key assessments through Week 104 in this post hoc analysis included modified Nail Psoriasis Severity (mNAPSI), Psoriasis Area and Severity Index (PASI 90), resolution of dactylitis and enthesitis, Dermatology Life Quality Index (DLQI) and radiographic progression (assessed by vdH-mTSS). RESULTS: At baseline, 66.6% patients (663/996) had concomitant nail psoriasis. Baseline characteristics were balanced in the nail subset and comparable with the overall population. Secukinumab reduced mNAPSI score at Week 16 versus placebo: -8.71 (300 mg), -8.95 (150 mg), -7.55 (150 mg no load) versus -2.34 (placebo); all p<0.0001. Mean change from baseline in DLQI at Week 16 was -8.5 (300 mg), -7.4 (150 mg), -7.3 (150 mg no load) versus -2.4 (placebo); all p<0.0001. Overall, the improvements reported at Week 16 sustained through Week 104. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS≤0.5) at Week 104 was 91.9% (300 mg) 78.9% (150 mg), and 82.4% (150 mg no load). CONCLUSIONS: Secukinumab provided sustained improvements in nail disease, signs and symptoms of PsA, and a low rate of radiographic progression through 2 years in patients with concomitant nail psoriasis.

Health status of tribes of Uttar Pradesh with special reference to health-seeking behaviour of uncharted Tharu tribe: A mapping review.

Background & objectives: The tribal population in India is considered as one of the vulnerable groups with respect to their achievements in health and other developmental issues. In this context, this mapping review attempted to understand the health profile of the Tharu tribal community residing in the northern State of Uttar Pradesh, India through literature mining. Tharu tribe is one of the indigenous groups living in the Terai plain on the Indo-Nepal border. In 1967, this tribe was documented as a Scheduled Tribe by the Government of India. The present review aimed to map the health-seeking behaviour of the Tharu population and review other factors pertaining to their health such as socioeconomic, developmental, employment, education, etc. Methods: Online data search was carried out on PubMed and Google Scholar using search terms 'Tharu' AND 'India'. In addition, official reports avaibale in public domain and grey literature was also searched. Results: Twenty seven studies including reviews, articles, books/book chapters were evaluated along with 13 reports (including reports from government organizations and grey literature) were retrieved and analyzed. Of the 27 published reports, 16 were found relevant to Tharu tribe in India. A total of 29 (16 articles + 13 reports ) were included in this review. Interpretation & Conclusions: This mapping review highights the health seeking behaviour of the Tharu tribe in India that can help inform future interventions to improve the health status of the Tharu tribe as well as other aspects of their development.

Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial.

BACKGROUND: ABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile. METHODS: We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America. We enrolled patients who were 18 years or older with rheumatoid arthritis and inadequate response or intolerance to biological disease-modifying antirheumatic drugs. Eligible patients were randomly assigned (3:2:2:2:2:1) via interactive response technology to receive daily, orally administered ABBV-599 (ie, upadacitinib 15 mg plus elsubrutinib 60 mg), elsubrutinib 60 mg, elsubrutinib 20 mg, elsubrutinib 5 mg, upadacitinib 15 mg, or placebo. Randomisation was stratified by the number of previous biological disease-modifying antirheumatic drugs. The investigator, study site personnel, and patients were masked throughout the study. The primary endpoint was change from baseline in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 for all patients who received a study drug. Pharmacokinetics and safety were also assessed. This study is registered with ClinicalTrials.gov, number NCT03682705. FINDINGS: Between Oct 8, 2018, and March 26, 2020, 242 patients were randomly assigned to receive ABBV-599 (n=62), elsubrutinib 60 mg (n=41), elsubrutinib 20 mg (n=39), elsubrutinib 5 mg (n=41), upadacitinib 15 mg (n=40), or placebo (n=19). Of the 242 patients, 204 (84%) were female, 38 (16%) were male, and 220 (91%) were White; the mean age at baseline was 58·0 years (SD 11·3). Compared with placebo, the least squares mean changes from baseline in DAS28-CRP were -1·44 (90% CI -2·03 to -0·85; p<0·0001) for ABBV-599, -0·40 (-1·03 to 0·23; p=0·29) for elsubrutinib 60 mg, -0·20 (-0·85 to 0·44; p=0·61) for elsubrutinib 20 mg, -0·21 (-0·84 to 0·41; p=0·57) for elsubrutinib 5 mg, and -1·75 (-2·38 to -1·13; p<0·0001) for upadacitinib. No significant improvements in efficacy measures for elsubrutinib alone (any dose) versus placebo were detected, despite adequate plasma exposure and target engagement. Treatment-emergent adverse events were observed in 113 (47%) of 242 patients, with similar proportions for all groups. INTERPRETATION: Significant improvements in disease activity metrics of rheumatoid arthritis with ABBV-599 were driven by the JAK inhibitor upadacitinib with no discernible effect by the BTK inhibitor elsubrutinib. FUNDING: AbbVie.

Secukinumab provides sustained improvement in signs and symptoms and low radiographic progression in patients with psoriatic arthritis: 2-year (end-of-study) results from the FUTURE 5 study.

OBJECTIVE: Secukinumab provided sustained efficacy, low radiographic progression and consistent safety over 52 weeks in patients with psoriatic arthritis (PsA) in the FUTURE 5 study. Here, we report 2-year (end-of-study) results from this study. METHODS: Adults with active PsA were randomised 2:2:2:3 to receive subcutaneous secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load or placebo at baseline; weeks 1, 2, 3 and 4; and every 4 weeks thereafter. Secukinumab could be escalated from 150 mg to 300 mg starting at week 52, if active signs of disease were observed based on physician's assessment. Assessments at week 104 (2 years) included clinical end points and radiographic damage (mean change in van der Heijde-modified total Sharp score (vdH-mTSS)). Safety analysis included all patients who received ≥1 dose of study medication. RESULTS: Of the 996 patients randomised, 783 patients (78.6%) completed 2 years of treatment. Improvement in clinical end points was sustained through 2 years. The vdH-mTSS (mean change (SD)) was 0.10 (1.74; 300 mg), 0.52 (2.66; 150 mg) and 0.41 (2.20; 150 mg no load) at 2 years. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ≤0.5) at 2 years was 89.5% (300 mg), 82.3% (150 mg) and 81.1% (150 mg no load). CONCLUSION: Secukinumab with and without loading regimen provided sustained clinical efficacy and low radiographic progression through 2 years in patients with PsA. No new safety findings were reported. TRIAL REGISTRATION NUMBER: NCT02404350.

Obesity in Toddlers and Young Children: Causes and Consequences.

The rapid rise in obesity in toddlers and young children (aged 0-5 years) is a major concern for public health globally. Understanding risk factors for obesity in the early years is therefore fundamental to help guide parents, educators, and health care professionals caring for young children and to develop preventative strategies. Most research has focused on biological risk factors, which can be broadly categorized as genetic predisposition, poor diet (and the behaviors that influence excessive food intake), insufficient physical activity, and the role of developmental factors in early life that influence long-term health. The latter includes establishment of dietary habits and dietary patterns in young (preschool) children and the effect of a high protein intake on the increasing risk of later obesity. Other risk factors particularly relevant to young children include inadequate sleep, high consumption of sugar-sweetened drinks, and large food portions. Understanding the causes of obesity in preschool children is particularly important in view of long-term detrimental consequences of obesity in this age group on the risk of obesity and cardiometabolic disease in adults. The present chapter reviews causes of obesity in preschool children and its consequences for long-term health, focusing particularly on modifiable nutritional risk factors.