DMARD-free remission as novel treatment target in rheumatoid arthritis: A systematic literature review of achievability and sustainability.

OBJECTIVES: Although current treatment guidelines for rheumatoid arthritis (RA) suggest tapering disease-modifying anti-rheumatic drugs (DMARDs), it is unclear whether DMARD-free remission (DFR) is an achievable and sustainable outcome. Therefore, we systematically reviewed the literature to determine the prevalence and sustainability of DFR and evaluated potential predictors for DFR. METHODS: A systematic literature search was performed in March 2019 in multiple databases. All clinical trials and observational studies reporting on discontinuation of DMARDs in RA patients in remission were included. Our quality assessment included a general assessment and assessment of the description of DFR. Prevalence of DFR and its sustainability and flares during tapering and after DMARD stop were summarised. Also, potential predictors for achieving DFR were reviewed. RESULTS: From 631 articles, 51 were included, comprising 14 clinical trials and 5 observational studies. DFR definition differed, especially for the duration of DMARD-free state. Considering only high- and moderate-quality studies, DFR was achieved in 5.0%-24.3% and sustained DFR (duration>12 months) in 11.6%-19.4% (both relative to the number of patients eligible for tapering). Flares occurred frequently during DMARD tapering (41.8%-75.0%) and in the first year after achieving DFR (10.4%-11.8%), while late flares, >1 year after DMARD-stop, were infrequent (0.3%-3.5%). Many patient characteristics lacked association with DFR. Absence of autoantibodies and shared epitope alleles increased the chance of achieving DFR. CONCLUSIONS: DFR is achievable in RA and is sustainable in ~10%-20% of patients. DFR can become an important outcome measure for clinical trials and requires consistency in the definition. Considering the high rate of flares in the first year after DMARD stop, a DMARD-free follow-up of >12 months is advisable to evaluate sustainability.

The impact of a disease flare during tapering of DMARDs on the lives of rheumatoid arthritis patients.

OBJECTIVES: To determine the impact of a disease flare on patient reported outcome measures (PROMs) in rheumatoid arthritis (RA) patients, who are tapering treatment. METHODS: Data were used from the TARA trial; a multicenter, randomized controlled trial in which RA patients, with a well-controlled disease (DAS≤2.4 and SJC≤1) for at least 6 months, gradually tapered their DMARDs. PROMs of patients with a flare (DAS>2.4 and/or SJC>1) were compared every three months before and after a flare with their own norm values. Linear Mixed Models were used to investigate whether a disease flare influenced functional ability (HAQ-DI), fatigue (BRAF-MDQ), quality of life (EQ-5D and SF36), anxiety and depression (HADS), morning stiffness, general health (GH) and worker productivity, and if so, the duration was determined. For unemployment and sick leave we used descriptive statistics. RESULTS: A flare negatively influenced GH, morning stiffness, HAQ-DI, EQ-5D, BRAF-MDQ, and the SF36 physical component scale and this effect lasted >3 months. Except for the HAQ-DI, effect sizes exceeded the minimum clinically important differences (MCIDs). For the physical outcomes effects lasted >6 months. Worker productivity was not significantly affected by a flare. CONCLUSION: A disease flare influenced patients' lives, the largest effect was seen in the physical outcomes, and lasted 6 months. Although on a group level effect sizes for the separate PROMs were not always significant or larger than specific MCIDs, a disease flare can still be of great importance for individual patients.

Medical informatics and bioinformatics: a bibliometric study.

This paper reports on an analysis of the bioinformatics and medical informatics literature with the objective to identify upcoming trends that are shared among both research fields to derive benefits from potential collaborative initiatives for their future. Our results present the main characteristics of the two fields and show that these domains are still relatively separated.

Co-occurrence based meta-analysis of scientific texts: retrieving biological relationships between genes.

MOTIVATION: The advent of high-throughput experiments in molecular biology creates a need for methods to efficiently extract and use information for large numbers of genes. Recently, the associative concept space (ACS) has been developed for the representation of information extracted from biomedical literature. The ACS is a Euclidean space in which thesaurus concepts are positioned and the distances between concepts indicates their relatedness. The ACS uses co-occurrence of concepts as a source of information. In this paper we evaluate how well the system can retrieve functionally related genes and we compare its performance with a simple gene co-occurrence method. RESULTS: To assess the performance of the ACS we composed a test set of five groups of functionally related genes. With the ACS good scores were obtained for four of the five groups. When compared to the gene co-occurrence method, the ACS is capable of revealing more functional biological relations and can achieve results with less literature available per gene. Hierarchical clustering was performed on the ACS output, as a potential aid to users, and was found to provide useful clusters. Our results suggest that the algorithm can be of value for researchers studying large numbers of genes. AVAILABILITY: The ACS program is available upon request from the authors.

Distribution of information in biomedical abstracts and full-text publications.

MOTIVATION: Full-text documents potentially hold more information than their abstracts, but require more resources for processing. We investigated the added value of full text over abstracts in terms of information content and occurrences of gene symbol--gene name combinations that can resolve gene-symbol ambiguity. RESULTS: We analyzed a set of 3902 biomedical full-text articles. Different keyword measures indicate that information density is highest in abstracts, but that the information coverage in full texts is much greater than in abstracts. Analysis of five different standard sections of articles shows that the highest information coverage is located in the results section. Still, 30-40% of the information mentioned in each section is unique to that section. Only 30% of the gene symbols in the abstract are accompanied by their corresponding names, and a further 8% of the gene names are found in the full text. In the full text, only 18% of the gene symbols are accompanied by their gene names.

Extensions to the HISA standard--the SynEx computing environment.

OBJECTIVES: This paper reports on the integration work required to support the delivery of healthcare. Specifically, four elements are included being: the DHE (a standards based distributed healthcare environment), Synapses which is a patient record server, XML as a technology to deliver records, and finally two client applications that facilitate structured data entry (SDE) and the remote booking of specialist services. METHODS: A general motivation for the work is presented and augmented on hand of a clinical scenario. Additionally, the adoption of a middleware approach is reviewed. The role of computerised patient records is described followed by an account of a federated record server. The approach favoured by standards bodies in utilising XML is covered and the tailoring to suit the needs of the integration is explained. The main practical challenges in achieving integration are presented, one of these being the mapping between the DHE data model and the Synapses server record architecture. RESULTS: The described environment has been demonstrated to provide the functionality that is required and in addition it has been shown that the engineering challenges can be met in a controlled and orderly manner. CONCLUSIONS: The role of the DHE middleware component acting as an 'anchor' has been shown to be a valid one onto which other specialised components can be added to provide a richer service environment. Additionally, it has been demonstrated that XML is a good candidate technology that facilitates connectivity to client applications over an extranet. The demands inherent in both the clinical scenario and the computerised patient record can be met by the computing environment described in the paper.

Facilitating networks of information.

In this paper we describe an approach to respond to a request for information with the identification and location of the appropriate person as a source of information for answering the question. The expertise of a person is characterized using a weighted profile that has been derived from a series of documents describing the expert's activities. Having these profiles, requests for information can be matched with these profiles. The best matches correspond with the people that are experts for providing information on the request.

UMLS-based access to CPR data. Unified Medical Language Systems.

This paper describes the results of a project that explores the use the Unified Medical Language System (UMLS) for knowledge-driven tasks, such as browsing a computer-based patient record (CPR). The project consisted of a number of steps: the mapping between CPR terms and UMLS concepts, the development of an algorithm that explores the CPR data using this mapping and the implementation of a first prototype browser that visualizes 'found' data. A second task addressed in this project has been the direct access to online medical literature (MEDLINE) using the UMLS concepts found in the CPR data. In this project, we used a preliminary version of the Open Records for Patient Care (ORCA) CPR that consisted only of the history and physical examination data of patient suffering from heart failure.

ORCA: the versatile CPR.

The introduction of computer-based patient records (CPRs) that fully replace paper records proves especially difficult in specialized care, despite the potential advantages of CPRs for patient care and research. Improved data legibility, availability, sharing of records, and decision support may directly benefit patient care. Barriers to the introduction of CPR applications at institutions may be caused by lack of infrastructure, or by financial or organizational issues. To have clinicians interactively enter data at the point of care is still a big challenge. This paper presents an overview of ORCA (Open Record of CAre): a generic CPR, designed for integration with existing systems, presentation of multi-media patient data, and the collection of structured data, directly by clinicians. ORCA can easily be tailored to the needs of a variety of medical specialists without the need for changes to its data model, functionality, or interface. The paper describes the essence of the architecture of ORCA and the user benefits with emphasis on the support of structured data entry.

UMLS-based access to CPR data.

This paper describes the results of a project that explores the use the Unified Medical Language System (UMLS) for knowledge-driven tasks, such as browsing a computer-based patient record (CPR). The project consisted of a number of steps: the mapping between CPR terms and UMLS concepts, the development of an algorithm that explores the CPR data using this mapping, and the implementation of a first prototype browser that visualizes "found" data. A second task addressed in this project has been the direct access to online medical literature (MEDLINE) using the UMLS concepts found in the CPR data. In this project, we used a preliminary version of the Open Records for Patient Care (ORCA) CPR that consisted only of the history and physical examination data of patient suffering from heart failure.

Virtual electronic patient records for shared care.

Systems that primarily serve health-care organizations are changing into systems that support patient care. The core of this change is shaped by systems for computer-based patient records (CPRs), which are part of local or regional networks, giving access to data in different information systems. In principle, it should not matter where the patient data are located as long as data can be transferred to the physical location where patients and clinicians meet. Networking and electronic communication enable to realize an environment that makes all systems where patient data reside, acting as one integrated, virtual CPR-system from the user's perspective. The patient record itself needs not to be physically located at one place, but may be virtual. A development in this direction is the European 14C project, which aims at integrating patient record data, images, and biosignals from whatever system they are stored and on whatever computer they are processed in the network.

Clinical data entry.

Routine capture of patient data for a computer-based patient record system remains a subject of study. Time constraints that require fast data entry and maximal expression power are in favor of free text data entry. However, using patient data directly for decision support systems, for quality assessment, etc. requires structured data entry, which appears to be more tedious and time consuming. In this paper, a prototype clinical data entry application is described that combines free text and structured data entry in one single application and allows clinicians to smoothly switch between these two different input styles. A knowledge base involving a semantic network of clinical data entry terms and their properties and relationships is used by this application to support structured data entry. From structured data, sentences are generated and shown in a text processor together with the free text. This presentation metaphor allows for easy integrated presentation of structured data and free text.

Can data representation and interface demands be reconciled? Approach in ORCA.

Research in the domain of computer-based patient records had always faced the conflicting demands of efficiency for the practicing physician and suitability of the record contents for data analysis in view of decision support, research, and quality assessment. Interface and contents pose different demands on the data model underlying the record. The challenge is to combine the most suitable model for data representation with the interface that best fits the clinical setting. ORCA (Open Record for CAre) provides a solution by making the distinction between domain dependent and domain independent data and letting domain dependence be decisive for the choice of model. Interactive definition of custom-views provides interface flexibility for domain dependent data. Views on domain independent data need not cope with the limitations of multiple table views in relational DBMSs. A standard set of single table queries can support recording of domain independent data, irrespective of the clinical setting.

The economic motivations for clinical information systems.

For three decades (1960-1990) the primary use of computers in hospitals' in the U.S. was to ease the task of reimbursement for care rendered and to automate results reporting for high-volume, time-critical tests such as clinical laboratory procedures. Hospitals were regarded as independent organizations/revenue centers which could pass costs to third party payers. Beginning in the mid-eighties, U.S. hospitals were no longer reimbursed on a fee-for-service basis for many patients, but received a fixed payment regardless of the actual cost of treating a patient. The size of the payment depended upon the patients' type of illness (Diagnostically related group). This approach gave hospitals incentives to reduce costs, but did not foster a fully competitive environment. Now, in the mid-nineties, hospitals in the U.S. are seen as cost centers in an integrated health care delivery system. Within this environment, a longitudinal patient record is necessary to increase levels of communication between healthcare providers. While certain management functions remain hospital-centered, clinical information systems must now cover a spectrum of patient activities within the ambulatory and inpatient arena. Several of the leading healthcare providers use computer-based logic to alert care givers whenever standards of care are not being achieved. These institutions feel that such capability will be the real impetus to reduce cost and improve the quality of care. Based upon observations over four decades, it appears that economic considerations play the major role in determining which kinds of information systems are deployed in the healthcare arena.

Trends in Integrated Clinical Workstations.

During the last decade, several projects aiming at integrated clinical workstations have been described and several prototypes have been demonstrated. In most of these projects, the clinical workstation accesses information and functionality provided by the present proprietary legacy systems of health-care institutions. We discuss trends in integrated clinical workstations from the viewpoints of software engineering and integration, considering that the clinical workstation itself basically consists of three layers: a presentation layer, a data integration layer, and a communication layer. The software engineering view on clinical workstations focuses on the development of basic building blocks from which clinical workstations, specific to a particular medical domain, can be composed. The integration view on clinical workstations addresses methods and techniques to deal with the, in general, intrinsically closed information systems in health-care institutions.

ARIS: integrating multi-source data for research in andrology.

Although the concept of distributed systems for the storage of patient data is more and more commonly accepted, for some considerable time yet most patient data will be stored in centralized rather than departmental systems. An important advantage of storage in a central system is hospital-wide access to much of the patient data. Disadvantages are however that these data cannot be reviewed through one user interface, and that the structure of the data does not lend itself to exploitation for other purposes. We describe the implementation of an Andrology Research Information System in which these data are integrated in a well-structured database facilitating multiple views on the patient data through a graphical user interface, and clinical research, quality control and summary reports. The data can be analyzed directly using the Hermes workstation. In this way the strengths of the centralized system are combined with those of the dedicated ARIS system.

Problems with integrating legacy systems.

The economic and organizational impact of imposing state-of-the-art technology to the large number of proprietary legacy systems operational in most hospitals requires integrated clinical professional workstations to provide flexible encapsulation mechanisms for these systems rather than reengineering these systems to this new technology. In this paper the implications of different input/output and translation models of legacy systems for their integration into a clinical workstation is described. Examples of legacy systems that have been integrated in the HERMES clinical workstation are presented as examples of the range of difficulties one might encounter. The features that an integrated workstation should offer for integrating a broad range of legacy systems are also addressed in this paper.

A flexible approach to client-server computing.

The number of standards for client-server computing almost equals the number of client-server applications. Although there are some standardization efforts, there is hardly any experience with applying these solutions to (medical) practice. The layering approach of the integration architecture HERMES anticipates the inclusion of commercial standards (when available and evaluated); it currently supports already the development of client-server applications. The toolkit provides support for the development of the communication between client and server through a callback mechanism. Stubs created with the HERMES toolkit contain a number of built-in callbacks that manage sessions between clients and services. An important feature of HERMES is the ability to include existing legacy systems as if they are true open services. In this way, the growth path from stand-alone to client-server computing can be shortened and the implementation of the client-server architecture can begin immediately. Moreover, the existing legacy systems remain available as a stand-alone solution for daily practice. Clients and services are connected through the HERMES kernel. This kernel uses a database to find the best server match for a request from a client. Moreover, it completes requests with mandatory data and tries to optimize performance. Special features are included to minimize the memory burden of the session-oriented client-server model. Currently, a system for the outpatient clinic cardiology, occupational health care, and clinical data analysis is available.

HERMES: a health care workstation integration architecture.

An architecture is described that facilitates integration of existing databases and applications without modifying them. By means of this architecture, data from different sources dispersed in a network can be combined and directly used in existing applications or applications that have been developed specially for integration. This feature of combining data from different sources into one workstation is viewed as the enabling technology on which computer-based patient records can be built. The abstraction of computer-, network- and application-specific details is completely dealt with by the integration architecture. This integration architecture has been developed with extendibility and flexibility in mind, and allows for a growth-path towards application of the open system paradigm in medicine.