scholarly journals Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies

2011 ◽  
Vol 70 (10) ◽  
pp. 1713-1718 ◽  
Author(s):  
P Miossec ◽  
C L Verweij ◽  
L Klareskog ◽  
C Pitzalis ◽  
A Barton ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Options ◽  
Personalised Medicine ◽  
New Drugs ◽  
Regulatory Control ◽  
Critical Areas ◽  
Regulatory Bodies ◽  
Definition Of ◽  
Number Of Treatment ◽  
High Degree

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker–drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

scholarly journals Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS)

2021 ◽  
Vol 23 (11) ◽  
Author(s):  
Laura D’Erasmo ◽  
Simone Bini ◽  
Marcello Arca
Keyword(s):  
Familial Hypercholesterolemia ◽  
Treatment Options ◽  
New Drugs ◽  
Lipid Lowering ◽  
Homozygous Familial Hypercholesterolemia ◽  
Published Evidence ◽  
Novel Drugs ◽  
Life Threatening ◽  
History Of ◽  
Definition Of

Abstract Purpose of Review This review aims to summarize the most recent published literature concerning lomitapide and volanesorsen that are approved for the use in HoFH and FCS patients, respectively. Moreover, it will briefly revise the published evidence on novel, non-approved treatments that are under evaluation for the management of these rare forms of dyslipidemias Recent Findings The definition of rare dyslipidemias identifies a large number of severe disorders of lipid metabolism of genetic origin. Among them were homozygous familial hypercholesterolemia (HoFH) (OMIM #143890) and familial chylomicronemia syndrome (FCS) (OMIM #238600), which are characterized by a markedly impaired cholesterol- and triglyceride-containing lipoproteins metabolism. They are being particularly associated with poor health outcomes and quality of life. Considering the severity of these diseases, common lipid-lowering drugs are often ineffective or do not allow to achieve the recommended lipid targets to prevent the development of complications. Nowadays, several new drugs have been found to effectively treat HoFH and FCS with an acceptable safety profile. Summary Treating patients with HoFH and FCS remains very challenging. However, novel treatment options are emerging and might be considered in addition to conventional therapy for managing these diseases. These novel drugs will possibly change the natural history of these two rare and life-threatening diseases.

Adapting Probabilistic Methods To Conform to Regulatory Guidelines

2002 ◽  
Vol 5 (04) ◽  
pp. 302-310
Author(s):  
Herman G. Acuna ◽  
D.R. Harrell
Keyword(s):  
Probabilistic Analysis ◽  
Probabilistic Method ◽  
Securities And Exchange Commission ◽  
Probabilistic Methods ◽  
Regulatory Guidelines ◽  
Regulatory Bodies ◽  
Degree Of Confidence ◽  
Definition Of ◽  
High Degree ◽  
Hydrocarbon Reserves

Summary Probabilistic methods have introduced inconsistent interpretations of how they should be applied while still complying with reserves certification guidelines. The objective of this paper is to present and discuss some pitfalls commonly encountered in the application of probabilistic methods to evaluate reserves. Several regulatory guidelines that should be followed during the generation of recoverable hydrocarbon distributions are discussed. An example also is given to understand the evolution of reserves categories as a function of probabilities. Most of the conflicting reserves interpretations can be attributed to the constraints of regulatory bodies [e.g., the U.S. Securities and Exchange Commission (SEC)] and the current SPE/World Petroleum Congresses (WPC) reserves definitions in which reserves categories are expressed in terms of the probabilities of being achieved. For example, proved reserves are defined as those hydrocarbon volumes with at least a 90% probability of being equaled or exceeded (P90). Unfortunately, these definitions alone fall short as guidance on how to derive the distributions from which these percentiles will be calculated. This may lead to distributions that do not comply with the remaining guidelines. While a P90 can be calculated from a noncomplying distribution, proved reserves may not be assigned at this percentile level. Introduction In 1997, new reserves definitions were drafted and introduced by SPE and WPC. For the first time, these reserves definitions included some language to address the increased interest in probabilistic analysis to estimate hydrocarbon reserves. Proved reserves were defined, in part, as those volumes of recoverable hydrocarbons with " . . . a high degree of confidence that the quantities will be recovered. If probabilistic methods are used, there should be at least a 90% probability that the quantities actually recovered will equal or exceed the estimate."1 The interpretation of this definition may be that satisfying the P90 criteria is sufficient to define proved reserves. We will discuss later in this paper why defining proved reserves as the P90 of any distribution is not always appropriate. Also, the definitions do not specify at what level the evaluator should apply the P90 test (i.e., is it at the field level or the total portfolio level?). These points are further clarified in the 2001 update of the SPE/WPC definitions.2 Probable reserves were then described in the SPE/WPC definitions as those recoverable hydrocarbon volumes that " . . . are more likely than not to be recoverable. In this context, when probabilistic methods are used, there should be at least a 50% probability that the quantities actually recovered will equal or exceed the sum of estimated proved plus probable reserves."1 Possible reserves were defined as those recoverable hydrocarbon volumes that " . . . are less likely to be recoverable than probable reserves. In this context, when probabilistic methods are used, there should be at least a 10% probability that the quantities actually recovered will equal or exceed the sum of estimated proved plus probable plus possible reserves."1 The SEC does not recognize probable and possible reserves. The SEC's guidelines for reporting proved reserves are set forth in its Regulation S-X, Rule 4-10 and subsequent clarifying bulletins. In Regulation S-X, Rule 4-10, there are no guidelines for the interpretation of probabilistic analysis. The regulation defines proved reserves as those recoverable hydrocarbon volumes with " . . . reasonable certainty to be recoverable in future years from known reservoirs . . ."3 Both the SPE/WPC and SEC proved reserves definitions have several other requirements that are usually applicable to deterministic methods that may conflict with probabilistic analysis if not properly incorporated. Evaluators of reserves should exercise caution when using probabilistic methods to ensure compliance with the reserves definitions adopted by the SEC and SPE/WPC. Caution is required because there are certain situations in which indiscriminate application of probabilistic methods may produce results that are inconsistent with the reserves definitions. For example, the SEC definition of proved reserves does not explicitly recognize the use of the probabilistic method and in no way allows for the probabilistic method to be used in such a manner as to violate any term of that definition. In this paper, we will first present a short definition of probabilistic analysis and the risks and benefits of using this technique. Next, we will address some significant shortcomings in the current reserves definitions and then present some examples on how some of these shortcomings can be addressed in the evaluation of reserves. Discussion of Probabilistic Analysis of Reserves The probabilistic analysis of reserves relies on the use of probabilistic techniques to estimate the uncertainty of the recoverable hydrocarbon volumes. In its purest sense, these probabilistic methods are used to collect and organize, evaluate, present, and summarize data. These methods provide the tools to analyze large amounts of representative data so that the significance of that data's variability and dependability can be measured and understood. Probabilistic analysis should be considered an important tool for internal analysis, allowing companies to understand and rank their hydrocarbon reserves and resources and the associated risks. This method provides the tools to identify the upside and the downside hydrocarbon potential to better organize the company's portfolio and to allocate capital and manpower resources more efficiently. However, it should be understood that the objectives of a hydrocarbon-property ranking study and an SPE/WPC or SEC reserves reporting evaluation might be different. For example, companies may have their own guidelines to group and analyze hydrocarbon assets to allocate company resources or for property acquisitions. These company guidelines may vary from project to project or from year to year (depending on pricing assumptions) and may be different from those guidelines provided in the SPE/ WPC and SEC definitions. It then becomes the primary challenge of the evaluator to reconcile both evaluations.

scholarly journals Possibilities for personalised medicine in rheumatoid arthritis: hype or hope

RMD Open ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. e001653
Author(s):  
Judith Heutz ◽  
Pascal Hendrik Pieter de Jong
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Options ◽  
Personalised Medicine ◽  
Treatment Strategies ◽  
Current Evidence ◽  
Current Management ◽  
The Past ◽  
New Treatment ◽  
Molecular Phenotypes ◽  
Management Recommendations

Knowledge of pathophysiology of rheumatoid arthritis (RA) has improved over the past decades, which resulted in new treatment options and strategies that led to better clinical outcomes. At the same time, we have come to understand that RA is a heterogeneous disease on a clinical as well as a pathophysiological level. Despite this heterogeneity, current management recommendations still adopt a ‘one-size-fits-all’ treatment approach, where ideally individualised treatment, or personalised medicine, is preferred. The first step towards personalised medicine in RA would be to designate different treatment strategies to distinct clinical or molecular phenotypes of patients. This viewpoint discusses current evidence and elaborates on future possibilities for personalised medicine in RA.

Development and Evaluation of Fuzzy Criteria for the Diagnosis of Rheumatoid Arthritis

1996 ◽  
Vol 35 (04/05) ◽  
pp. 334-342 ◽  
Author(s):  
K.-P. Adlassnig ◽  
G. Kolarz ◽  
H. Leitich
Keyword(s):  
Rheumatoid Arthritis ◽  
Reference Model ◽  
American Rheumatism Association ◽  
Uniform Definition ◽  
Sensitivity Rate ◽  
Fuzzy Techniques ◽  
Definition Of ◽  
Different Levels ◽  
Specificity Rate

Abstract:In 1987, the American Rheumatism Association issued a set of criteria for the classification of rheumatoid arthritis (RA) to provide a uniform definition of RA patients. Fuzzy set theory and fuzzy logic were used to transform this set of criteria into a diagnostic tool that offers diagnoses at different levels of confidence: a definite level, which was consistent with the original criteria definition, as well as several possible and superdefinite levels. Two fuzzy models and a reference model which provided results at a definite level only were applied to 292 clinical cases from a hospital for rheumatic diseases. At the definite level, all models yielded a sensitivity rate of 72.6% and a specificity rate of 87.0%. Sensitivity and specificity rates at the possible levels ranged from 73.3% to 85.6% and from 83.6% to 87.0%. At the superdefinite levels, sensitivity rates ranged from 39.0% to 63.7% and specificity rates from 90.4% to 95.2%. Fuzzy techniques were helpful to add flexibility to preexisting diagnostic criteria in order to obtain diagnoses at the desired level of confidence.

In-block lateralization as a new technique for mobilization of the inferior alveolar nerve: a technique case series

2020 ◽  
Author(s):  
Marcos Augusto Tomazi ◽  
Alexandre da Silveira Gerzson ◽  
Angelo Menuci Neto ◽  
André Luciano Pasinato da Costa
Keyword(s):  
Treatment Options ◽  
Inferior Alveolar Nerve ◽  
Case Series ◽  
New Technique ◽  
Autogenous Bone ◽  
Minimal Risk ◽  
Short Implants ◽  
Bone Atrophy ◽  
A New Technique ◽  
Number Of Treatment

The edentulous atrophic posterior mandible is often a great challenge for implant rehabilitation. Although a number of treatment options have been proposed, including the use of short implants and surgical grafting techniques, in cases of severe bone atrophy, techniques for mobilization of the inferior alveolar nerve (IAN) have been shown to be efficient, with good results. Four female patients underwent IAN lateralization for prosthetic rehabilitation of the posterior mandible from 2013 to 2019, with 1 year to 5 years and 4 months of follow-up. This case series describes a new technique for mobilization of the IAN, named in-block lateralization, to facilitate access to the IAN and to reduce nerve manipulation. The implant is immediately installed (allowing nerve lateralization in unitary spaces) and the original mandibular anatomy is restored with autogenous bone from the original bed during the same surgical procedure. When well indicated and well performed, this new approach provides better and easier visualization of the IAN as well as safer manipulation aiming to achieve good results for implant stability and minimal risk of neurosensory disturbances, allowing rehabilitation even in unitary spaces.

Pulmonary Manifestations in Rheumatoid Arthritis, Psoriatic Arthritis and Peripheral Spondyloarthritis Prevalence, Diagnostic Approach and Treatment Options

2020 ◽  
Vol 16 ◽  
Author(s):  
Daniel Dejcman ◽  
Valentin Sebastian Schäfer ◽  
Dirk Skowasch ◽  
Carmen Pizarro ◽  
Andreas Krause ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Psoriatic Arthritis ◽  
Lung Disease ◽  
Current Knowledge ◽  
Treatment Options ◽  
Pulmonary Diseases ◽  
Chronic Obstructive ◽  
Pulmonary Manifestations ◽  
Major Cluster ◽  
Peripheral Spondyloarthritis

: Interstitial lung disease (ILD) is the most common form of pulmonary impairment in patients with rheumatoid arthritis (RA). However, patients with RA or other arthritic diseases such as psoriatic arthritis (PsA) or peripheral spondyloarthritis (pSpA) may develop several other pulmonary diseases such as chronic obstructive lung disease (COPD) with a higher risk than patients without arthritis. The article at hand aims at summarizing the current knowledge on the prevalence of pulmonary diseases in the above-mentioned forms of arthritis, the challenges for prevalence studies and detecting pulmonary diseases in patients with arthritis as well as possible treatment options. Dyspnea, cough or other pulmonary symptoms or findings in arthritis patients should prompt gradual diagnostic procedures considering pulmonary manifestations as a major cluster of differential diagnosis. Considering its poor prognosis and morbidity burden, RA-ILD needs to be ruled out. Treatment of manifestations often lacks solid evidencebased guidelines and referrals to specialized centers are often necessary.

scholarly journals Identification of effective spreaders in contact networks using dynamical influence

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruaridh A. Clark ◽  
Malcolm Macdonald
Keyword(s):  
Disease Transmission ◽  
Average Rate ◽  
Laplacian Matrix ◽  
Disease Spread ◽  
Eigenvector Centrality ◽  
Contact Networks ◽  
Human Contact ◽  
Spread Dynamics ◽  
Definition Of ◽  
High Degree

AbstractContact networks provide insights on disease spread due to the duration of close proximity interactions. For systems governed by consensus dynamics, network structure is key to optimising the spread of information. For disease spread over contact networks, the structure would be expected to be similarly influential. However, metrics that are essentially agnostic to the network’s structure, such as weighted degree (strength) centrality and its variants, perform near-optimally in selecting effective spreaders. These degree-based metrics outperform eigenvector centrality, despite disease spread over a network being a random walk process. This paper improves eigenvector-based spreader selection by introducing the non-linear relationship between contact time and the probability of disease transmission into the assessment of network dynamics. This approximation of disease spread dynamics is achieved by altering the Laplacian matrix, which in turn highlights why nodes with a high degree are such influential disease spreaders. From this approach, a trichotomy emerges on the definition of an effective spreader where, for susceptible-infected simulations, eigenvector-based selections can either optimise the initial rate of infection, the average rate of infection, or produce the fastest time to full infection of the network. Simulated and real-world human contact networks are examined, with insights also drawn on the effective adaptation of ant colony contact networks to reduce pathogen spread and protect the queen ant.

scholarly journals Genomic Tackling of Human Satellite DNA: Breaking Barriers through Time

2021 ◽  
Vol 22 (9) ◽  
pp. 4707
Author(s):  
Mariana Lopes ◽  
Sandra Louzada ◽  
Margarida Gama-Carvalho ◽  
Raquel Chaves
Keyword(s):  
Human Genome ◽  
Satellite Dna ◽  
Repetitive Sequences ◽  
Nucleotide Composition ◽  
Genomic Component ◽  
Genomic Studies ◽  
Human Genomic ◽  
Definition Of ◽  
High Degree

(Peri)centromeric repetitive sequences and, more specifically, satellite DNA (satDNA) sequences, constitute a major human genomic component. SatDNA sequences can vary on a large number of features, including nucleotide composition, complexity, and abundance. Several satDNA families have been identified and characterized in the human genome through time, albeit at different speeds. Human satDNA families present a high degree of sub-variability, leading to the definition of various subfamilies with different organization and clustered localization. Evolution of satDNA analysis has enabled the progressive characterization of satDNA features. Despite recent advances in the sequencing of centromeric arrays, comprehensive genomic studies to assess their variability are still required to provide accurate and proportional representation of satDNA (peri)centromeric/acrocentric short arm sequences. Approaches combining multiple techniques have been successfully applied and seem to be the path to follow for generating integrated knowledge in the promising field of human satDNA biology.

scholarly journals OP0220 ASSESSING THE EFFECT OF INCREASED BODY MASS INDEX ON RESPONSE TO TNF INHIBITORS IN ESTABLISHED RHEUMATOID ARTHRITIS: RESULTS FROM THE METEOR DATABASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 137.1-137
Author(s):  
M. Dey ◽  
S. S. Zhao ◽  
R. J. Moots ◽  
R. B. M. Landewé ◽  
N. Goodson
Keyword(s):  
Rheumatoid Arthritis ◽  
Body Mass Index ◽  
Body Mass ◽  
Personalised Medicine ◽  
Normal Weight ◽  
Sensitivity Analyses ◽  
Established Rheumatoid Arthritis ◽  
Eular Response ◽  
Significant Difference ◽  
Das28 Remission

Background:Rheumatoid arthritis (RA) is associated with increased body mass index (BMI)- 60% of patients are either overweight or obese. Obesity in RA has been shown to predict reduced response to biologic therapy including tumour-necrosis-factor inhibitors (TNFi) [1]. However, it is not clear whether increased BMI influences response to all TNFi drugs in RA.Objectives:1.To explore whether BMI is associated with response to TNFi in patients with established rheumatoid arthritis (estRA), including those newly-starting on these drugs.Methods:Participants with estRA (>1year since diagnosis) taking biologic medications, registered on METEOR (international database of RA patients), 2008-2013, were included. EULAR response, DAS28 remission (including components), and treatment regimens were recorded at baseline, 6, and 12 months. WHO definitions of overweight (BMI≥ 25) and obese (BMI≥30) were explored as predictors of TNFi response (good EULAR response and DAS28 remission) using normal BMI as comparator. Logistic and linear regression models (controlling for age, gender, smoking, and baseline outcomes) and sensitivity analyses were performed. Subgroup analyses were performed for grouped TNFi and individual TNFi (infliximab, IFX; adalimumab, ADA; etanercept, ETN).Results:247 patients with estRA were taking a biologic at 6 months, and 231 patients were taking a biologic at 12 months. Obese patients taking any biologic were significantly less likely to achieve DAS28 remission (OR 0.33 [95%CI 0.12-0.80]) or good EULAR response (OR 0.37 [95%CI 0.16-0.81]) after 6 months, compared to those of normal BMI; this was also demonstrated in those co-prescribed methotrexate (DAS28 remission: OR 0.23 [95%CI 0.07-0.62]; good EULAR response: OR 0.39 [95%CI 0.15-0.92]). These associations did not remain statistically significant at the 12 months assessment.Regarding specific anti-TNF therapies, RA patients treated with monoclonal antibody (-mab) TNFis (IFX/ADA/ GOL) were significantly less likely to achieve good EULAR response at 6 months if they were obese RA (n=38), compared to those of normal weight (n=44) (OR 0.17 [95%CI 0.03-0.59]). A similar non-significant difference was demonstrated for DAS28 remission, and 12-month remission. Specifically, obese individuals were significantly less likely to achieve good EULAR response at 6 months with IFX (OR 0.09 [95%CI 0.00-0.61]; n=20), and significantly less likely to achieve DAS28 remission at 6 months when newly-starting ADA (OR 0.14 [95%CI 0.01-0.96]; n=17), compared to those of normal weight. There were no significant differences in remission outcomes between individuals of different BMI taking ETN. A small number of individuals stopped taking their respective biologic after 6months; reason for cessation was not recorded.Similar outcomes were seen in patients already established on anti-TNF therapy, with overweight and obese individuals less likely overall to be in DAS28 remission at all time points.Conclusion:In established RA, obesity is associated with reduced treatment response to -mab TNFi. No association between increased BMI and response to ETA was observed. Using BMI to direct biologic drug choice could prove to be a simple and cost-effective personalised-medicine approach to prescribing.References:[1]Schäfer M, Meißner Y, Kekow J, Berger S, Remstedt S, Manger B, et al. Obesity reduces the real-world effectiveness of cytokine-targeted but not cell-targeted disease-modifying agents in rheumatoid arthritis. Rheumatology. 2019 Nov 20.Disclosure of Interests:Mrinalini Dey: None declared, Sizheng Steven Zhao: None declared, Robert J Moots: None declared, Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Nicola Goodson: None declared

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