Dataset Information

Development of a Model Care Pathway for Myasthenia Gravis.

ABSTRACT: Myasthenia Gravis (MG) is a chronic, life-lasting condition that requires high coordination among different professionals and disciplines. The diagnosis of MG is often delayed and sometimes misdiagnosed. The goal of the care pathway (CP) is to add value to healthcare reducing unnecessary variations. The quality of the care received by patients affected with MG could benefit from the use of CP. We conducted a study aimed to define an inclusive, comprehensive, and multidisciplinary CP for the diagnosis, treatment, and care of MG. The development of the model CP, key interventions, and process indicators is based on the literature review and 85 international MG experts were involved in their evaluation, expressing a judgment of relevance through the Delphi study. 60 activities are included in the model CP and evaluated by the MG experts were valid and feasible. The 60 activities were then translated into 14 key interventions and 24 process indicators. We believe that the developed model CP will help for MG patients to have a timely diagnosis and high-quality, accessible, and cost-effective treatments and care. We also believe that the development of model CPs for other rare diseases is feasible and could aid in the integration of evidence-based knowledge into clinical practice.

SUBMITTER: Payedimarri AB

PROVIDER: S-EPMC8582978 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Development of a Model Care Pathway for Myasthenia Gravis.

Payedimarri Anil Babu AB Ratti Matteo M Rescinito Riccardo R Vasile Alessandra A Seys Deborah D Dumas Hervé H Vanhaecht Kris K Panella Massimiliano M

International journal of environmental research and public health 20211104 21

Myasthenia Gravis (MG) is a chronic, life-lasting condition that requires high coordination among different professionals and disciplines. The diagnosis of MG is often delayed and sometimes misdiagnosed. The goal of the care pathway (CP) is to add value to healthcare reducing unnecessary variations. The quality of the care received by patients affected with MG could benefit from the use of CP. We conducted a study aimed to define an inclusive, comprehensive, and multidisciplinary CP for the diag ...[more]

PMID: 34770107

Similar Datasets

Project description:Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction, whose clinical hallmark is muscle weakness and early fatigability. Azathioprine (AZA) is commonly used in Myasthenia Gravis therapy. AZA is a purine antagonist, which inhibits the cell cycle in the resting and DNA synthesis phases. It is usually used as an immunosuppressant to block T- and B-cell proliferation. AZA, bioconverted to 6-mercaptopurine by glutathione S-transferase (GST), can be metabolized either through the hypoxanthine phosphoribosyl transferase pathway to active 6-thioguanine nucleotides (6-TGN) or through the thiopurine S-methyltransferase (TPMT) pathway to inactive methyl-thiopurine metabolites. The incorporation of active 6-TGNs into DNA, causing breaks in DNA strands resulting in interference with RNA production and thereby protein synthesis, is responsible for the drug effect. The response to AZA is determined by which metabolic pathway is being favored. While balanced use of both HPRT and TPMT pathways results in responsiveness to AZA, hyperactivity of TPMT skews the balance towards the TPMT pathway and results in unresponsiveness to AZA with no pharmacological effect. In contrast, low TPMT activity skews the balance towards the HPRT pathway, resulting in increasing side-effects due to the accumulation of 6-TGNs. Current treatments for MG therapy are often inadequate because less than 40% of patients achieve complete remission with available drugs. This reflects the lack of drugs acting on target sites for which there is strong evidence of pathogenicity and the inability to identify responder patients. No criteria for responsiveness are available, exposing patients to unpredictable failures and unpredictable side effects. These individuals are at particular risk for adverse drug reaction (ADRs) or therapeutic failure. Genetic profiling with the Affymetrix drug metabolizing enzymes and transports genotyping array offers the ability to determine 1,931 variants and 225 genes involved in drug metabolism and disposition. Accordingly, the study of well-known drug-metabolizing genes can be involved in the specific metabolic pathway of a drug, which is more likely to define genotype-phenotype association and thereby genotype profiles relevant to drug response that can be applied as predictive biomarkers for pharmacological treatment.

Project description:Myasthenia gravis (MG) is a chronic and progressive neuromuscular disease where autoantibodies target essential proteins such as the nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction (NMJ) causing muscle fatigue and weakness. Autoantibodies directed against nAChRs are proposed to work by three main pathological mechanisms of receptor disruption: blocking, receptor internalization, and downregulation. Current in vivo models using experimental autoimmune animal models fail to recapitulate the disease pathology and are limited in clinical translatability due to disproportionate disease severity and high animal death rates. The development of a highly sensitive antibody assay that mimics human disease pathology is desirable for clinical advancement and therapeutic development. To address this lack of relevant models, an NMJ platform derived from human iPSC differentiated motoneurons and primary skeletal muscle was used to investigate the ability of an anti-nAChR antibody to induce clinically relevant MG pathology in the serum-free, spatially organized, functionally mature NMJ platform. Treatment of the NMJ model with the anti-nAChR antibody revealed decreasing NMJ stability as measured by the number of NMJs before and after the synchrony stimulation protocol. This decrease in NMJ stability was dose-dependent over a concentration range of 0.01-20 μg/mL. Immunocytochemical (ICC) analysis was used to distinguish between pathological mechanisms of antibody-mediated receptor disruption including blocking, receptor internalization and downregulation. Antibody treatment also activated the complement cascade as indicated by complement protein 3 deposition near the nAChRs. Additionally, complement cascade activation significantly altered other readouts of NMJ function including the NMJ fidelity parameter as measured by the number of muscle contractions missed in response to increasing motoneuron stimulation frequencies. This synchrony readout mimics the clinical phenotype of neurological blocking that results in failure of muscle contractions despite motoneuron stimulations. Taken together, these data indicate the establishment of a relevant disease model of MG that mimics reduction of functional nAChRs at the NMJ, decreased NMJ stability, complement activation and blocking of neuromuscular transmission. This system is the first functional human in vitro model of MG to be used to simulate three potential disease mechanisms as well as to establish a preclinical platform for evaluation of disease modifying treatments (etiology).

Dataset Information

Development of a Model Care Pathway for Myasthenia Gravis.

Publications

Development of a Model Care Pathway for Myasthenia Gravis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets