Organisation and content of supervised group exercise for people with axial spondyloarthritis in The Netherlands

Supervised group exercise (SGE) is recommended for people with axial spondyloarthritis (axSpA). Recent literature suggests that its contents and dosage must probably be revised. As a first step towards renewal, this study examined the current SGE organisation and content for people with axSpA in The Netherlands. A pen-and-paper survey was sent to the boards of the 82 local patient associations affiliated with the Dutch Arthritis Society in 2016. One member of each board was asked to complete questions on the nature and organisation of SGE and one of the supervising therapists to complete questions on the SGE supervision and contents. The questionnaire was returned by representatives of 67/82 (82%) local patient associations, of which 17 (25%) provided axSpA-specific SGE (16/17 SGE programmes with both land-based exercise and hydrotherapy and 1/17 with only hydrotherapy). These involved in total 56 groups with 684 participants and 59 supervisors, of whom 54 were physical therapists and 21 had had postgraduate education on rheumatic and musculoskeletal diseases (RMDs). Besides mobility and strengthening exercises and sports (17/17), most programmes included aerobic exercise (10/17), but rarely with heart rate monitoring (1/17), patient education (8/17), periodic assessments (2/17), or exercise personalisation (1/17). In the Netherlands, a quarter of local patient associations organised axSpA-specific SGE, mostly containing land-based exercises combined with sports and hydrotherapy. Most supervisors lacked postgraduate education on RMDs and most programmes lacked intensity monitoring, patient education, periodic assessments, and personalisation, which are needed for optimising exercise programmes according to current scientific insights.Orthopaedics, Trauma Surgery and Rehabilitatio

Implementing enhancements in supervised group exercise for people with axial spondyloarthritis: a hybrid effectiveness-implementation study

Objectives: The content of supervised group exercise (SGE) for axial spondyloarthritis (axSpA) has hardly changed in recent decades, despite new evidence-based insights to improve SGE quality. This pilot implementation study evaluated the effects and feasibility of enhancements in axSpA-specific SGE in four regions in the Netherlands. Method: The implemented enhancements included: more high-intensity aerobic exercise; exercise personalization with periodic assessments; and patient education on home exercise. The implementation strategy included a one-day supervisor training course and telephone support. To evaluate effects, aerobic capacity [Six-Minute Walk Test (6MWT)], physical functioning [Ankylosing Spondylitis Performance-based Improvement (ASPI); improved/not improved], health status [Assessment of SpondyloArthritis international Society Health Index (ASAS HI) questionnaire], and home exercise engagement [Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH)] were assessed at baseline and after one year in 60 participants. Changes were analysed with the Wilcoxon signed-rank test. To evaluate feasibility, a survey of participants and semi-structured interviews with four SGE supervisors assessed uptake and satisfaction with the enhancements. Results: Aerobic capacity increased significantly and 35% of participants improved functioning, whereas health status and home exercise engagement did not change. The participants' survey and supervisors' interviews showed that high-intensity aerobic exercise was implemented successfully, exercise personalization and periodic assessments were implemented partially, and patient education was not implemented at all. Most participants were satisfied with the changes. Conclusions: After this pilot implementation, SGE enhancements were only partially implemented. Nevertheless, aerobic capacity improved significantly and satisfaction with accomplished changes was high. Nationwide implementation would require adaptations to improve feasibility.Orthopaedics, Trauma Surgery and Rehabilitatio

Predictors of orphan drug approval in the European Union

Objective: To encourage the development of drugs for rare diseases, orphan drug legislation has been introduced in the USA (1983) and in the EU (2000). Recent literature discusses factors that may influence the development of new orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential orphan drugs in the EU. Methods: A comparison between randomly selected authorised and a matched sample of not-yet-authorised orphan drug designations has been performed. Determinants in the study included characteristics of the indication, of the product and of the sponsor. Data were collected from the public domain only. Results: Orphan drug approval was strongly associated with previous experience of the sponsor in obtaining approval for another orphan drug (OR=17.3, 95% CI=5.6-53.1). Furthermore, existing synthetic entities compared to biotechnology products tended to have a higher likelihood of reaching approval status (OR=3.9, 95% CI=0.9-16.6). Conclusion: This study showed that experience of a company in developing orphan drugs is an important predictor for subsequent authorisation of other orphan drugs. The same applies for existing (synthetic) molecules, for which much knowledge is available. Further research should be directed towards studying the quality of the clinical development program of those designated orphan medicinal products not reaching approval status

Role of pH in determining the cell-type-specific residual activity of glucocerebrosidase in type 1 Gaucher disease.

The properties of control and 370Asn-->Ser glucocerebrosidase, the frequently encountered mutated form of the enzyme in type 1 Gaucher disease, were studied in vitro as well as in situ. The catalytic properties of purified 370Asn-->Ser glucocerebrosidase were highly dependent on the assay conditions. The enzyme was deficient in activity towards substrate and in reactivity with the irreversible inhibitor conduritol B-epoxide (CBE) when activated by the bile salt taurocholate. In the presence of more physiological activators, the lysosomal activator protein saposin C and phosphatidylserine, the 370Asn-->Ser enzyme was near normal in kinetic properties at pH values approximately 5, but not at higher pH. In intact fibroblasts, the enzymic activity of the 370Asn-->Ser glucocerebrosidase and its reactivity with CBE were found to be clearly deficient. However, in intact lymphoblasts from the same patients, the behavior of the mutant enzyme was near normal. The catalytic efficiency of 370Asn-->Ser glucocerebrosidase in situ was also found to be highly pH dependent. When intact lymphoblasts were cultured in the presence of permeant weak bases, which increase the pH of acidic intracellular compartments, the catalytic efficiency of the mutant enzyme, as assessed by its reactivity with CBE, became markedly impaired. Our findings indicate that the intralysosomal pH in the intact cell can be expected to have a critical influence on the activation state of 370Asn-->Ser glucocerebrosidase and its ability to hydrolyse substrate. This phenomenon may partly underly the marked heterogeneity in clinical manifestation of Gaucher disease among patients with this mutated form of glucocerebrosidase.FWN – Publicaties zonder aanstelling Universiteit Leide

Development of ASAS quality standards to improve the quality of health and care services for patients with axial spondyloarthritis

Objectives The Assessment of SpondyloArthritis International Society (ASAS) aimed to develop a set of quality standards (QS) to help improve the quality of healthcare provided to adult patients affected by axial spondyloarthritis (axSpA) worldwide. Methods An ASAS task force developed a set of QS using a stepwise approach. First, key areas for quality improvement were identified, discussed, rated and agreed on. Thereafter, areas were prioritised and statements for the most important key areas were phrased on consensus. Appropriate quality measures were defined to allow quantification of the QS at the community level. Results The ASAS task force, consisting of 20 rheumatologists, two physiotherapists and two patients, selected and proposed 34 potential key areas for quality improvement which were then commented by 140 ASAS members and patients. Within that process three new key areas came up, which led to a re-evaluation of all 37 key areas by 120 ASAS members and patients. Five key areas were identified as most important to determine quality of care: referral including rapid access, rheumatology assessment, treatment, education/self-management and comorbidities. Finally, nine QS were agreed on and endorsed by the whole ASAS membership. Conclusions ASAS successfully developed the first set of QS to help improving healthcare for adult patients with axSpA. Even though it may currently not be realistic to achieve the QS in all healthcare systems, they provide high-quality of care framework for patients with axSpA that should be aimed for

Towards broad spectrum activity-based glycosidase probes: synthesis and evaluation of deoxygenated cyclophellitol aziridines

Activity-based protein profiling has emerged as a powerful tool for visualizing glycosidases in complex biological samples. Several configurational cyclophellitol isomers have been shown to display high selectivity as probes for glycosidases processing substrates featuring the same configuration. Here, a set of deoxygenated cyclophellitols are presented which enable inter-class profiling of [small beta]-glucosidases and [small beta]-galactosidases

High Throughput Screening for Small Molecule Therapy for Gaucher Disease Using Patient Tissue as the Source of Mutant Glucocerebrosidase

Gaucher disease (GD), the most common lysosomal storage disorder, results from the inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCase). Previously, wildtype GCase was used for high throughput screening (HTS) of large collections of compounds to identify small molecule chaperones that could be developed as new therapies for GD. However, the compounds identified from HTS usually showed reduced potency later in confirmatory cell-based assays. An alternate strategy is to perform HTS on mutant enzyme to identify different lead compounds, including those enhancing mutant enzyme activities. We developed a new screening assay using enzyme extract prepared from the spleen of a patient with Gaucher disease with genotype N370S/N370S. In tissue extracts, GCase is in a more native physiological environment, and is present with the native activator saposin C and other potential cofactors. Using this assay, we screened a library of 250,000 compounds and identified novel modulators of mutant GCase including 14 new lead inhibitors and 30 lead activators. The activities of some of the primary hits were confirmed in subsequent cell-based assays using patient-derived fibroblasts. These results suggest that primary screening assays using enzyme extracted from tissues is an alternative approach to identify high quality, physiologically relevant lead compounds for drug development

Development of ASAS quality standards to improve the quality of health and care services for patients with axial spondyloarthritis

Objectives: The Assessment of SpondyloArthritis International Society (ASAS) aimed to develop a set of quality standards (QS) to help improve the quality of healthcare provided to adult patients affected by axial spondyloarthritis (axSpA) worldwide. Methods: An ASAS task force developed a set of QS using a stepwise approach. First, key areas for quality improvement were identified, discussed, rated and agreed on. Thereafter, areas were prioritised and statements for the most important key areas were phrased on consensus. Appropriate quality measures were defined to allow quantification of the QS at the community level. Results: The ASAS task force, consisting of 20 rheumatologists, two physiotherapists and two patients, selected and proposed 34 potential key areas for quality improvement which were then commented by 140 ASAS members and patients. Within that process three new key areas came up, which led to a re-evaluation of all 37 key areas by 120 ASAS members and patients. Five key areas were identified as most important to determine quality of care: referral including rapid access, rheumatology assessment, treatment, education/self-management and comorbidities. Finally, nine QS were agreed on and endorsed by the whole ASAS membership. Conclusions: ASAS successfully developed the first set of QS to help improving healthcare for adult patients with axSpA. Even though it may currently not be realistic to achieve the QS in all healthcare systems, they provide high-quality of care framework for patients with axSpA that should be aimed for