Novartis (India)

<h3>Objective</h3> To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis. <h3>Methods</h3> We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes. <h3>Results</h3> At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, <i>p</i> = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (<i>p</i> &lt; 0.0001, both). Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all <i>p</i> &lt; 0.01). High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51–4.60]; <i>p</i> = 0.0006), relapses (rate ratio: 2.53 [1.67–3.83]; <i>p</i> &lt; 0.0001), brain volume loss (difference in means: −0.78% [−1.02 to −0.54]; <i>p</i> &lt; 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97–3.87]; <i>p</i> = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656–0.813] and IFN 0.789 [0.704–0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552–0.714] and IFN 0.794 [0.705–0.894]; <i>p</i> &lt; 0.001, both studies at all assessments). <h3>Conclusions</h3> Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.

Background In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. Methods We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapsefree survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. Results The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. Conclusions In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083. opens in new tab; EudraCT number, 2012-001266-15. opens in new tab.)

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1-year multicenter, multinational, randomized, partial double-blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total-hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N-terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β-C-telopeptide of type I collagen [β-CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA-based BMD (e.g., quantitative computed tomography and finite-element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849 ), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients &gt; 1 year after infusion; grade 3/4 infection rate did not increase &gt; 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.

BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. Self-administration by pre-filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience. OBJECTIVES: To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate-to-severe plaque psoriasis. MATERIALS AND METHODS: Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co-primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 (≥ 75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ). RESULTS: Co-primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high SIAQ-assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed. CONCLUSIONS: Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate-to-severe plaque psoriasis.

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

ABSTRACT While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly−Pivotal Fracture Trial (HORIZON−PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was −0.54% in Z9 vs. −1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: −0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. © 2015 American Society for Bone and Mineral Research.

BACKGROUND: KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum. METHODS: We conducted a phase 2, open-label study at three centers in Thailand to assess the antimalarial efficacy, safety, and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days, in two sequential cohorts of adults with uncomplicated P. vivax malaria (10 patients) or P. falciparum malaria (11). The primary end point was the parasite clearance time. RESULTS: The median parasite clearance time was 12 hours in each cohort (interquartile range, 8 to 16 hours in patients with P. vivax malaria and 10 to 16 hours in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 hours (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 hours (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 hour. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 hours (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen. CONCLUSIONS: KAE609, at dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01524341.).

Summary Objective To present the baseline data of the international TuberOus SC lerosis registry to increase disease Awareness ( TOSCA ) with emphasis on the characteristics of epilepsies associated with tuberous sclerosis complex ( TSC ). Methods Retrospective and prospective patients’ data on all aspects of TSC were collected from multiple countries worldwide. Epilepsy variables included seizure type, age at onset, type of treatment, and treatment outcomes and association with genotype, seizures control, and intellectual disability. As for noninterventional registries, the study protocol did not specify any particular clinical instruments, laboratory investigations, or intervention. Evaluations included those required for diagnosis and management following local best practice. Results Epilepsy was reported in 83.6% of patients (1852/2216) at baseline; 38.9% presented with infantile spasms and 67.5% with focal seizures. The mean age at diagnosis of infantile spasms was 0.4 year (median &lt;1 year; range &lt;1‐30 years) and at diagnosis of focal seizures was 2.7 years (median 1 year; range &lt;1‐66 years). A total of 1469 patients (79.3%) were diagnosed with epilepsy &lt;2 years. The rate of infantile spasms was higher in patients with a TSC 2 mutation than in patients with a TSC 1 mutation (47.3% vs 23%). ɣ ‐aminobutyric acid (GABA) ergic drugs were the most common treatment modality for both infantile spasms (78.7%) and focal seizures (65.5%). Infantile spasms and focal seizures were controlled in 76.3% and 58.2% of patients, respectively. Control of seizures was associated with lower rates of intellectual disability in both groups. Significance This registry reports the largest international cohort of patients with TSC . Findings confirmed the typical onset pattern of infantile spasms and other focal seizures in the first 2 years of life, and the high rates of infantile spasms in patients with TSC 2 mutation. Our results underscored the occurrence of focal seizures at all ages, including an onset that preceded emergence of infantile spasms. Seizure control was shown to be associated with lower rates of intellectual disability but did not preclude the presence of intellectual disability.

AIMS: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). METHODS AND RESULTS: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

INTRODUCTION: To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars). METHODS: databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded. RESULTS: Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases. The great majority of the publications did not report differences in immunogenicity, safety, or efficacy. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates. CONCLUSIONS: While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine.

Several studies have demonstrated clinical benefits of sustained cholinesterase inhibition with rivastigmine in Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Unlike donepezil and galantamine that selectively inhibit acetylcholinesterase (AChE; EC 3.1.1.7), rivastigmine is a unique cholinesterase inhibitor with both AChE and butyrylcholinesterase (BuChE; EC 3.1.1.8) inhibitory activity. Rivastigmine is also available as transdermal patch that has been approved by the US Food and Drug Administration for the treatment of mild, moderate, and severe AD as well as mild-to-moderate PDD. In this review, we explore the role of BuChE inhibition in addition to AChE inhibition with rivastigmine in the outcomes of cognition, global function, behavioral symptoms, and activities of daily living. Additionally, we review the evidence supporting the use of dual AChE-BuChE inhibitory activity of rivastigmine as a therapeutic strategy in the treatment of neurological disorders, with a focus on the role of rivastigmine in subcortical dementias such as vascular dementia (VaD) and PDD. Toward this objective, we performed a literature search in PubMed and Ovid with limits to articles published in the English language before June 2016. The available evidence from the literature suggests that the dual inhibition of AChE and BuChE may afford additional therapeutic potential of rivastigmine in subcortical dementias (subcortical VaD and PDD) with benefits on cognition and behavioral symptoms. Rivastigmine was found to specifically benefit executive dysfunction frequently observed in subcortical dementias; however, large randomized clinical studies are warranted to support these observations.

Abstract Purpose: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation–positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. Patients and Methods: Patients ages 1 to &amp;lt;18 years who had BRAF V600–mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. Results: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26–62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64–94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). Conclusions: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600–mutant pLGG.

Suzuki–Miyaura cross coupling reaction (SMCR) – A milestone in the synthesis of C–C coupled compounds.

Need for developing case definitionsand guidelines for data collection, analysis, and presentation for stillbirth as an adverse event following immunization during pregnancy.

With recent advances in sequencing technology, it is now feasible to measure DNA methylation at tens of millions of sites across the entire genome. In most applications, biologists are interested in detecting differentially methylated regions, composed of multiple sites with differing methylation levels among populations. However, current computational approaches for detecting such regions do not provide accurate statistical inference. A major challenge in reporting uncertainty is that a genome-wide scan is involved in detecting these regions, which needs to be accounted for. A further challenge is that sample sizes are limited due to the costs associated with the technology. We have developed a new approach that overcomes these challenges and assesses uncertainty for differentially methylated regions in a rigorous manner. Region-level statistics are obtained by fitting a generalized least squares regression model with a nested autoregressive correlated error structure for the effect of interest on transformed methylation proportions. We develop an inferential approach, based on a pooled null distribution, that can be implemented even when as few as two samples per population are available. Here, we demonstrate the advantages of our method using both experimental data and Monte Carlo simulation. We find that the new method improves the specificity and sensitivity of lists of regions and accurately controls the false discovery rate.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology, characterized by a clinical triad of high spiking fever, arthralgia (± arthritis), and evanescent skin rash. Management of AOSD poses several challenges, including difficulty in diagnosis and limited therapeutic options. In this review, we examined whether AOSD and systemic juvenile idiopathic arthritis (SJIA) represent a continuum of the same disease. We also explored the latest available evidence related to prevalence, clinical and laboratory manifestations, complications, diagnostic challenges, novel biomarkers, and treatment options in the era of biologics and identified the unmet needs of patients with AOSD. METHODS: A comprehensive systematic literature search was performed in the Embase and MEDLINE (via PubMed) literature databases. The search was limited to human studies published in English from inception up to March 2020. Additionally, abstracts presented at various conferences were screened and hand searches were performed. Publications were processed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 123 publications were identified through the literature search, majority of which were case series and retrospective observational studies. AOSD and SJIA are widely considered part of the same disease spectrum owing to similarities in their clinical and biological features. The clinical presentation of AOSD is highly variable, accompanied by a broad spectrum of disease manifestations. Recent evidence suggests that the AOSD disease course can be classified into two distinct categories: "systemic" and "articular." Furthermore, AOSD patients may experience various life-threatening complications, such as macrophage activation syndrome - reported in as high as 23% of AOSD patients and considered to be the most severe complication characterized by a high mortality rate. The ambiguity in presentation and lack of serologic markers make the diagnosis of AOSD difficult, often leading to a delay in diagnosis. Given these limitations, the Yamaguchi and Fautrel criteria are the most widely used diagnostic tools in clinical practice. It has been observed that a clinical diagnosis of AOSD is generally reached by exclusion while investigating a patient with fever of unknown origin. Recent advances have demonstrated a major role of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-18, and IL-37, and other biomarkers in the pathogenesis and management of AOSD. Owing to the rarity of the disease, there are very limited clinical trials evaluating management strategies for AOSD. The current AOSD treatment paradigm includes non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids initially, conventional synthetic disease-modifying anti-rheumatic drugs in steroid-refractory patients, and biologics in those resistant to conventional treatment. Only a few country-specific guidelines for the management of AOSD have been published, and a treat-to-target approach, as previously recommended for SJIA, is still lacking. Canakinumab is the only FDA-approved biologic for the treatment of AOSD. CONCLUSION: Emerging evidence supports that AOSD and SJIA represent a continuum of the same disease entity. Despite advancements in the understanding of AOSD, it continues to pose a substantial burden on patients and the healthcare systems, and substantial unmet needs exist across key domains such as the pathway to diagnosis, use of biomarkers in clinical practice, and standardized treatment strategies. Further research and collaboration is crucial for optimizing the diagnosis and management of AOSD patients.

BACKGROUND: Most evidence for TSC-associated neuropsychiatric disorders (TAND) to date have come from small studies and case reports, and very little is known about TAND in adults. We explored baseline TAND data from the large-scale international TOSCA natural history study to compare childhood and adult patterns, describe age-based patterns, and explore genotype-TAND correlations. RESULTS: The study enrolled 2216 eligible participants with TSC from 170 sites across 31 countries at the data cut-off for the third interim analysis (data cut-off date: September 30, 2015). The most common behavioural problems (reported in > 10% of participants) were overactivity, sleep difficulties, impulsivity, anxiety, mood swings, severe aggression, depressed mood, self-injury, and obsessions. Psychiatric disorders included autism spectrum disorder (ASD, 21.1%), attention deficit hyperactivity disorder (ADHD, 19.1%), anxiety disorder (9.7%), and depressive disorder (6.1%). Intelligence quotient (IQ) scores were available for 885 participants. Of these, 44.4% had normal IQ, while mild, moderate, severe, and profound degrees of intellectual disability (ID) were observed in 28.1, 15.1, 9.3, and 3.1%, respectively. Academic difficulties were identified in 58.6% of participants, and neuropsychological deficits (performance <5th percentile) in 55.7%. Significantly higher rates of overactivity and impulsivity were observed in children and higher rates of anxiety, depressed mood, mood swings, obsessions, psychosis and hallucinations were observed in adults. Genotype-TAND correlations showed a higher frequency of self-injury, ASD, academic difficulties and neuropsychological deficits in TSC2. Those with no mutations identified (NMI) showed a mixed pattern of TAND manifestations. Children and those with TSC2 had significantly higher rates of intellectual disability, suggesting that age and genotype comparisons should be interpreted with caution. CONCLUSIONS: These results emphasize the magnitude of TAND in TSC and the importance of evaluating for neuropsychiatric comorbidity in all children and adults with TSC, across TSC1 and TSC2 genotypes, as well as in those with no mutations identified. However, the high rates of unreported or missing TAND data in this study underline the fact that, even in expert centres, TAND remains underdiagnosed and potentially undertreated.

OBJECTIVES: MAXIMISE (Managing AXIal Manifestations in psorIatic arthritis with SEcukinumab) trial was designed to evaluate the efficacy of secukinumab in the management of axial manifestations of psoriatic arthritis (PsA). METHODS: This phase 3b, double-blind, placebo-controlled, multi-centre 52-week trial included patients (≥18 years) diagnosed with PsA and classified by ClASsification criteria for Psoriatic Arthritis (CASPAR) criteria, with spinal pain Visual Analogue Score ≥40/100 and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥4 despite use of at least two non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomised (1:1:1) to secukinumab 300 mg, secukinumab 150 mg or placebo weekly for 4 weeks and every 4 weeks thereafter. At week 12, placebo patients were re-randomised to secukinumab 300/150 mg. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society) response with secukinumab 300 mg at week 12. RESULTS: Patients were randomly assigned; 167 to secukinumab 300 mg, 165 to secukinumab 150 mg and 166 to placebo. Secukinumab 300 mg and 150 mg significantly improved ASAS20 response versus placebo at week 12 (63% and 66% vs 31% placebo). The OR (95% CI) comparing secukinumab 300 mg and 150 mg versus placebo, using a logistic regression model after multiple imputation, was 3.8 (2.4 and 6.1) and 4.4 (2.7 and 7.0; p<0.0001). CONCLUSIONS: Secukinumab 300 mg and 150 mg provided significant improvement in signs and symptoms of axial disease compared with placebo in patients with PsA and axial manifestations with inadequate response to NSAIDs. TRIAL REGISTRATION NUMBER: NCT02721966.

Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001). Conclusions and Relevance: This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise. Trial Registration: ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25.