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CNS Drugs Jul 2024Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including...
Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.
PubMed: 38951463
DOI: 10.1007/s40263-024-01098-9 -
Applied Health Economics and Health... Jul 2024Rheumatoid arthritis (RA) is a progressive and debilitating disease, causing persistent joint pain that limits daily activities requiring long-term treatment. Newer...
INTRODUCTION
Rheumatoid arthritis (RA) is a progressive and debilitating disease, causing persistent joint pain that limits daily activities requiring long-term treatment. Newer targeted therapies expand RA treatment options, but their high cost necessitates a focus on cost effectiveness. To address this, we aim to conduct a cost-utility analysis of these newer RA pharmacotherapies to support evidence-based policy decision-making.
METHODS
We analyzed the cost-utility of sequential treatment with TNF-α, B cell and JAK-inhibitors compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for RA treatment in methotrexate (MTX) nonresponders. We used a Markov model with lifetime horizon and 6-month cycles from an Indian health system perspective. Costs (INR 2022) and quality-adjusted life years (QALYs) were used to determine the incremental cost-effectiveness ratios (ICERs) at a cost-effectiveness threshold of India's gross domestic product (GDP) per capita (2022). We assessed uncertainty using univariate, probabilistic sensitivity, and scenario analyses.
RESULTS
Despite additional QALYs, TNF-α, B cell, and JAK inhibitors were not cost-effective for treating moderate-to-severe patients with RA unresponsive to csDMARDs (including MTX) in India, as increased costs outweighed their clinical benefits. ICERs ranged from 10,46,206 to 31,09,207 Indian Rupees in the base case analysis, exceeding three times India's GDP per-capita [approximately USD $13,287 to $39,487 and GBP £10,776 to £32,025]. Sensitivity analyses confirmed the results' robustness. Scenario analysis suggested that a cost reduction of over 75% in drug prices could make most of the interventions cost effective compared with csDMARDs.
CONCLUSIONS
TNF-α, B cell, and JAK-inhibitors are not cost-effective compared with csDMARDs for patients with RA who have not responded to MTX in India at the current prices. Cost-effectiveness estimates were highly influenced by drug pricing variations. Therefore, reducing the prices of these interventions could enhance affordability, potentially leading to their inclusion in publicly funded health programs.
PubMed: 38951442
DOI: 10.1007/s40258-024-00898-w -
Clinical Rheumatology Jun 2024Enhancing access to healthcare remains a formidable challenge in rural regions of low- and lower-middle-income countries. Amid evolving healthcare challenges,... (Review)
Review
Enhancing access to healthcare remains a formidable challenge in rural regions of low- and lower-middle-income countries. Amid evolving healthcare challenges, telerheumatology provides opportunities to bridge gaps and expand access to rheumatology care, particularly in remote areas. We describe a pilot telerheumatology program and its cost-, time-, and travel-saving potential in a remote rural setting in northern Pakistan. The telerheumatology program commenced at the Pakistan Institute of Medical Sciences Islamabad, providing services through video consultations to a basic health unit in the Gilgit-Baltistan region. Patients visiting from the Gilgit-Baltistan region willing to participate were recruited in the program. Demographics and logistical metrics were recorded in a dedicated registry. A total of 533 consultations were carried out from April 2022 to April 2023. The majority of the patients were female (318/533, 59.7%). The median age of patients was 50 ± 15.7 years. The average wait time for consultation was 20 ± 13 min. The average travel time to reach telecentre was 59 ± 53 min. The average travel cost to reach telecentre was 379 ± 780 PKR (1.85 ± 3.81 USD). The average duration of consultation was 15 ± 5 min. The most common diagnosis for consultation was knee osteoarthritis (237, 44.5%), chronic low back pain (118, 22.1%), and rheumatoid arthritis (42, 7.9%). On average, patients saved 787 ± 29 km of distance, 15 ± 1 h of traveling, and 6702 ± 535 PKR (33 ± 3 USD) that would have been required to travel to our tertiary care hospital. Telerheumatology substantially reduced travel time, distance, and cost for patients. It has the potential to deliver outpatient rheumatology consultation in an economically efficient manner, effectively breaking geographical barriers and expanding access to essential services for patients in remote areas.
PubMed: 38951289
DOI: 10.1007/s10067-024-07037-9 -
Zhonghua Yi Xue Za Zhi Jul 2024To investigate the role and underlying mechanisms of intercellular adhesion molecule-1 (ICAM-1) in the adhesion and migration of mesenchymal stem cells (MSCs) in...
To investigate the role and underlying mechanisms of intercellular adhesion molecule-1 (ICAM-1) in the adhesion and migration of mesenchymal stem cells (MSCs) in patients with ankylosing spondylitis (AS). Bone marrow and ligament tissues were collected during surgery from patients with AS and thoracolumbar fractures (as controls, HC) treated from October 2021 to October 2022 at Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital. MSCs were isolated and cultured from the bone marrow using the Ficoll separation method. Cell morphology was observed under high-resolution microscopy, and differences in the cytoskeletal features between AS-and HC-MSCs were analyzed through immunofluorescence staining. The expression of ICAM-1 was quantified in both groups using real-time quantitative polymerase chain reaction (RT-qPCR) and flow cytometry. Transwell migration assays and wound healing experiments were conducted to evaluate the differences in migration rates between the two groups of MSCs. The interspinous ligament and bone marrow was acquired in AS (2 males and 1 female; 33, 37, 32 years old, respectively) and no-AS patients (2 males and 1 female; 35, 32, 38 years old, respectively). AS-MSCs exhibited broader cell morphology compared to HC-MSCs under bright field and fluorescence microscopy. Immunofluorescence staining of the interspinous ligament showed higher expression of ICAM-1 (68.38±3.42 vs 48.31±2.43) and CD105 (37.97±2.16 vs 23.36±2.06) in AS patients (both <0.001). Western blot and RT-qPCR analysis revealed significantly stronger protein expression and transcription levels of ICAM-1 in AS-MSCs when compared to those in HC-MSCs (both <0.001). Flow cytometry confirmed greater mean fluorescence intensity of ICAM-1 in AS-MSCs than in that in HC-MSCs (924.30±54.99 vs 636.47±40.03, =0.002). Regarding cell adhesion efficiency, it showed no significant difference between AS-MSCs and HC-MSCs in the early stage of adhesion (0.5 h: 1 496±213 vs 1 205±163, =0.133), but they were all significantly higher in AS-MSCs in the later stage (1 h: 2 894±172 vs 1 908±155, =0.002; 2 h: 4 540±286 vs 3 334±188, =0.004; 3 h: 5 212±281 vs 4 208±303, =0.014). Finally, cell migration experiments demonstrated a stronger migration capability of AS-MSCs compared to HC-MSCs (5 449±172 vs 4 016±155, <0.001), and the inhibition efficiency of A-205804 on the migration rate of AS-MSCs was stronger than that on HC-MSCs (2 145±239 vs 3 539±316, =0.004). The aberrant expression of ICAM-1 markedly influences the adhesion and migration dynamics of MSCs. Elevated ICAM-1 levels in MSCs derives from patients with AS significantly enhance their migratory capabilities.
Topics: Humans; Intercellular Adhesion Molecule-1; Spondylitis, Ankylosing; Mesenchymal Stem Cells; Cell Movement; Adult; Cell Adhesion; Female; Male; Bone Marrow Cells; Retrospective Studies; Cells, Cultured
PubMed: 38951108
DOI: 10.3760/cma.j.cn112137-20231115-01101 -
Zhonghua Yi Xue Za Zhi Jul 2024To explore the menopause status of patients with rheumatoid arthritis (RA) and clinical characteristics of perimenopausal RA patients. A cross-sectional study. Female...
To explore the menopause status of patients with rheumatoid arthritis (RA) and clinical characteristics of perimenopausal RA patients. A cross-sectional study. Female RA patients were recruited retrospectively in the Sun Yat-Sen Memorial Hospital from August 2015 to August 2023. Clinical data were collected, including onset age, disease duration, RA disease activity indicators, functional assessment, and radiographic scores. According to menopausal status, the patients were categorized as pre-menopausal, perimenopausal and post-menopausal groups to explore their menopausal and clinical characteristics. A total of 1 151 female patients were enrolled, with a mean age of (50.2±13.0) years. At enrollment, there were 470 (40.8%), 140 (12.2%) and 541 (47.0%) patients in pre-menopause, perimenopause and post-menopause status, respectively. The mean age of menopause was (49.0±4.2) years. Compared with pre-menopausal group, perimenopausal RA patients had higher disease activity indicators [clinical disease activity index (CDAI) 17 (6, 26) vs 10 (3, 19) ], higher levels of inflammation [erythrocyte sedimentation rate (ESR) 35 (21, 65) vs 26 (14, 44) mm/1h, C-reactive protein (CRP) 6.2 (3.2, 16.8) vs 3.3 (3.2, 13.6) mg/L], and a higher proportion of functional limitation [25.0%(35/140) vs 10.4%(49/470)] (all <0.016 7); while there was no significant differences in disease activity[(, )] [CDAI 17 (6, 26) vs 14 (6, 25)], levels of inflammation [ESR 35(21, 65) vs 42 (23, 72) mm/1h, CRP 6.2 (3.2, 16.8) vs 6.2 (3.3, 23.9) mg/L] and functional limitation [25.0%(35/140) vs 28.8%(156/541)] when compared with those in post-menopausal group (all >0.016 7). In RA patients during the perimenopausal period, 49 cases (35.0%) developed RA during this period. Compared with patients with RA onset during reproductive age, patients with RA onset during the perimenopausal period had higher numbers of 28-joint tender joints [7 (2, 10) vs 4 (0, 8)], higher CDAI [20 (12, 29) vs 14 (4, 24)], and higher ESR [45 (25, 72) vs 32 (18, 56) mm/1h] (all <0.05). Perimenopausal patients with RA have severe disease activity and functional limitation.
Topics: Humans; Female; Arthritis, Rheumatoid; Middle Aged; Perimenopause; Cross-Sectional Studies; Retrospective Studies; C-Reactive Protein; Blood Sedimentation; Postmenopause; Severity of Illness Index
PubMed: 38951107
DOI: 10.3760/cma.j.cn112137-20231109-01042 -
Zhonghua Yi Xue Za Zhi Jul 2024The interleukin-6 (IL-6) pathway plays a crucial role in various rheumatic diseases. Tocilizumab, a biologic targeting IL-6 receptor, has been widely used in clinical...
The interleukin-6 (IL-6) pathway plays a crucial role in various rheumatic diseases. Tocilizumab, a biologic targeting IL-6 receptor, has been widely used in clinical practice, though it's officially approved in China for only three indications. To address clinical challenges associated with the off-label use of tocilizumab in treating rheumatic diseases, the Committee of Chinese Primary Health Care Foundation for Rheumatologists and Immunologists engaged multidisciplinary experts and highlight 12 related clinical issues. We aggregated the drug specifications, the guidelines for clinical management of rheumatic diseases and the evidence from clinical research. Recommendations were formed through voting with the consensus conference method incorporating the Oxford evidence-based medicine criteria to evaluate the strength of evidence and recommendations. We have formulated 10 recommendations for off-label use of tocilizumab related to giant cell arteritis, polymyalgia rheumatica, Takayasu arteritis, systemic sclerosis, adult-onset Still's disease, rheumatoid arthritis, and juvenile idiopathic arthritis. This consensus aims to provide references for the rational use of tocilizumab in clinical practice and enhance pharmacovigilance monitoring.
Topics: Humans; Antibodies, Monoclonal, Humanized; Rheumatic Diseases; Off-Label Use; China; Consensus; Interleukin-6; East Asian People
PubMed: 38951103
DOI: 10.3760/cma.j.cn112137-20240207-00294 -
Best Practice & Research. Clinical... Jun 2024The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden... (Review)
Review
The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden methods, are expected to discern the good from the many low-quality studies that make overconfident claims of causality or stretch the plausibility of what MR can investigate. We aim to equip readers with foundational concepts, contextualized using examples in rheumatology, to appraise the many MR papers that are or will appear in their journals. We highlight the importance of assessing whether exposures are under plausibly specific genetic influence, whether the hypothesized causal pathways make biological sense, and whether results stand up to replication and use of control outcomes. Quality of research can vary substantially using MR as with any design, and all methods have inherent limitations. MR studies have provided and can still contribute valuable insights in the context of evidence triangulation.
PubMed: 38951047
DOI: 10.1016/j.berh.2024.101967 -
Cleveland Clinic Journal of Medicine Jul 2024
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Renal Insufficiency, Chronic; Gout; Heart Failure; Hypoglycemic Agents
PubMed: 38950980
DOI: 10.3949/ccjm.91b.07024 -
Journal of Peptide Science : An... Jul 2024Cell-penetrating peptides (CPPs) with better biomolecule delivery properties will expand their clinical applications. Using the MLCPP2.0 machine algorithm, we screened...
Cell-penetrating peptides (CPPs) with better biomolecule delivery properties will expand their clinical applications. Using the MLCPP2.0 machine algorithm, we screened multiple candidate sequences with potential cellular uptake ability from the nuclear localization signal/nuclear export signal database and verified them through cell-penetrating fluorescent tracing experiments. A peptide (NCR) derived from the Rev protein of the caprine arthritis-encephalitis virus exhibited efficient cell-penetrating activity, delivering over four times more EGFP than the classical CPP TAT, allowing it to accumulate in lysosomes. Structural and property analysis revealed that a high hydrophobic moment and an appropriate hydrophobic region contribute to the high delivery activity of NCR. Trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, could improve its anti-tumor activity by enhancing targeted delivery efficiency and increasing lysosomal drug delivery. This study designed a new NCR vector to non-covalently bind T-DM1 by fusing domain Z, which can specifically bind to the Fc region of immunoglobulin G and effectively deliver T-DM1 to lysosomes. MTT results showed that the domain Z-NCR vector significantly enhanced the cytotoxicity of T-DM1 against HER2-positive tumor cells while maintaining drug specificity. Our results make a useful attempt to explore the potential application of CPP as a lysosome-targeted delivery tool.
PubMed: 38950972
DOI: 10.1002/psc.3628 -
The Journal of Rheumatology Jul 2024Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated... (Review)
Review
Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated with highly unfavorable outcomes such as early mortality. The risk of developing RA is based on a perfect storm of gene-environment interactions underpinning this risk. The gene-environment interactions include a high frequency of shared epitope encoding HLA alleles, particularly , in the background population, and prevalent predisposing environmental factors such as smoking and periodontal disease. Together, these provide a compelling rationale for an RA prevention agenda in FN communities. Our research team has worked in partnership with several FN communities to prospectively follow the first-degree relatives of FN patients with RA, with the aim of better understanding the preclinical stages of RA in this population. We have focused on specific features of the anticitrullinated protein antibodies (ACPA) and other proteomic biomarkers as predictors of future development of RA. These studies have now led us to consider interventions having a favorable risk-benefit ratio if applied at a stage prior to a hypothetical "point of no return," when the autoimmunity potentially becomes irreversible. Based on a supportive mouse model and available human studies of curcumin, omega-3, and vitamin D supplements, we are undertaking studies where we screen communities using dried blood spot technology adapted for the detection of ACPA, and then enrolling ACPA-positive individuals in studies that use a combination of these supplements. These studies are guided by shared decision-making principles.
Topics: Humans; Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Biomarkers; Gene-Environment Interaction; HLA-DRB1 Chains; Indians, North American
PubMed: 38950968
DOI: 10.3899/jrheum.2024-0369_dunlop-dottridge