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International Journal of Molecular... Aug 2023This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin...
This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin disease. In this case, progressive GAD was treated with DMF, resulting in significant improvement of skin lesions within 5 weeks and complete healing within 7 months. Clinical response was associated with a reduction in inflammatory cells, including both T cell subsets (CD4+ > CD8+), CD183/CXCR3 cells, Langerhans cells (CD1a+), myeloid DCs, M1- and M2-like macrophages and the activation marker HLA-DR in immunohistochemical analysis. These findings support the use of DMF as a promising treatment option for this rare skin condition.
Topics: Humans; Granuloma Annulare; Dimethyl Fumarate; Treatment Outcome; Skin; Dermatitis; Rare Diseases
PubMed: 37686161
DOI: 10.3390/ijms241713355 -
Clinical & Translational Immunology 2023Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to myelin sheaths. While all current disease-modifying treatments (DMTs)...
OBJECTIVES
Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to myelin sheaths. While all current disease-modifying treatments (DMTs) are very effective at reducing relapses, they do not slow the progression of the disease, and there is little evidence that these treatments are able to repair or remyelinate damaged axons. Recent evidence suggests that activating kappa opioid receptors (KORs) has a beneficial effect on the progression of MS, and this study investigates the effects of KOR agonists treatment in combination with two current DMTs.
METHODS
Using the well-established murine model for immune-driven demyelination of MS, experimental autoimmune encephalomyelitis, the effect of KOR agonists in combination with DMTs fingolimod or dimethyl fumarate on disease progression, immune cell infiltration and activation as well as myelination were analysed.
RESULTS
Fingolimod in combination with the KOR agonist, nalfurafine, significantly increased each individual beneficial effect as measured by increased recovery of mice and reduced relapses. These beneficial effects correlated with a reduction in immune cell infiltration into the CNS as well as peripheral immune cell alterations including a reduction in autoreactive CD4 T-cell cytokine production as well as increased myelination in the spinal cords of co-treated animals. In contrast, while the use of dimethyl fumarate in combination with nalfurafine did not adversely affect the benefits of nalfurafine, the combination did not significantly enhance those benefits.
CONCLUSION
This study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine-fingolimod combination providing enhanced benefits.
PubMed: 38090669
DOI: 10.1002/cti2.1480 -
BMC Research Notes Oct 2023Multiple sclerosis (MS) is a progressing neurodegenerative disease marked by chronic central nervous system inflammation and degeneration.This study investigates gene...
OBJECTIVE
Multiple sclerosis (MS) is a progressing neurodegenerative disease marked by chronic central nervous system inflammation and degeneration.This study investigates gene expression profiles of T-box transcription factor TBX21 (T-bet), interferon-gamma (IFN-γ), and long non-coding RNA MEG3 in peripheral blood mononuclear cells (PBMCs) from treatment-naïve Relapsing-Remitting Multiple Sclerosis patients (RRMS), healthy controls, and RRMS patients on different Disease Modifying Therapies (DMTs). The aim is to understand the role of T-bet, IFN-γ, and MEG3 in MS pathogenesis and their potential as diagnostic and therapeutic targets.
RESULTS
Elevated T-bet expression is observed in treatment-naïve RRMS patients compared to healthy individuals. RRMS patients treated with Interferon beta-1alpha (IFNβ-1a) and fingolimod exhibit downregulated T-bet and MEG3 expression levels, respectively, with more pronounced effects in females. Healthy individuals show a moderate positive correlation between T-bet and MEG3 and between IFN-γ and T-bet. In RRMS patients treated with Glatiramer Acetate (GA), a strong positive correlation is observed between MEG3 and IFN-γ. Remarkably, RRMS patients treated with Dimethyl Fumarate (DMF) exhibit a significant positive correlation between T-bet and MEG3. These findings underscore the diagnostic potential of T-bet in RRMS, warranting further exploration of MEG3, T-bet, and IFN-γ interplay in RRMS patients.
Topics: Female; Humans; Glatiramer Acetate; Multiple Sclerosis, Relapsing-Remitting; Fingolimod Hydrochloride; Dimethyl Fumarate; Leukocytes, Mononuclear; Interferon-gamma; Neurodegenerative Diseases; Multiple Sclerosis
PubMed: 37845751
DOI: 10.1186/s13104-023-06556-z -
Heliyon Mar 2024To explore the current status and trends of disease-modifying therapies (DMTs) for multiple sclerosis through bibliometric and visual analyses of the related literature. (Review)
Review
OBJECTIVE
To explore the current status and trends of disease-modifying therapies (DMTs) for multiple sclerosis through bibliometric and visual analyses of the related literature.
METHODS
Relevant literature from the Web of Science Core Collection from 2017 to 2022 was retrieved, and a bibliometric analysis was performed using CiteSpace 6.1. R2. Thesoftware was used to generate visual graphs of the author, institution, country, keyword co-occurrence, and literature co-citation network.
RESULTS
A total of 1719 manuscripts were retrieved, including 1397 original studies and 322 reviews. In the past five years, Patti F and the University of London were the authors and institutions generating the largest number of publications, respectively, and there was active collaboration between authors and institutions. The United States was the largest contributor to the relevant literature, and the high-frequency keywords in the field of multiple sclerosis disease-modifying therapies in the past five years mainly included multiple sclerosis, disease-modifying therapy, double-blind, disability, natalizumab, effectiveness, fingolimod, glatiramer acetate, and dimethyl fumarate.
CONCLUSIONS
Current research hotspots and trends in DMTs in multiple sclerosis focus on the effectiveness of different DMTs drugs in treating patients with MS and how to optimise treatment strategies. In the context of the COVID-19 pandemic, the correlation between MS and COVID-19 infection and the method to manage and address the adverse effects of DMTs on multiple sclerosis patients is also future research trends.
PubMed: 38434405
DOI: 10.1016/j.heliyon.2024.e26173 -
Advanced Science (Weinheim,... May 2024Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the...
Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra-conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory-polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein-based conduits. Moreover, the NGC can gradually regulate the intra-conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.
Topics: Animals; Nerve Regeneration; Rats; Peripheral Nerve Injuries; Fibroins; Disease Models, Animal; Rats, Sprague-Dawley; Schwann Cells; Guided Tissue Regeneration; Inflammation; Tissue Scaffolds; Sciatic Nerve
PubMed: 38430538
DOI: 10.1002/advs.202302988 -
Therapeutic Advances in Neurological... 2024The spectrum of disease-modifying therapies (DMTs) for people with multiple sclerosis (PwMS) has expanded over years, but data on treatment strategies is largely...
BACKGROUND
The spectrum of disease-modifying therapies (DMTs) for people with multiple sclerosis (PwMS) has expanded over years, but data on treatment strategies is largely lacking. DMT switches are common clinical practice.
OBJECTIVE
To compare switchers and non-switchers, characterize the first DMT switch and identify reasons and predictors for switching the first DMT.
METHODS
Data on 2722 PwMS from the German MS Registry were retrospectively analyzed regarding sociodemographic/clinical differences between 1361 switchers (PwMS discontinuing the first DMT) and non-switchers matched according to age, sex, and observation period. Frequencies of first and second DMTs were calculated and switch reasons identified. Predictors for DMT switches were revealed using univariable and multivariable regression models.
RESULTS
Switchers and non-switchers differed significantly regarding time to first DMT, education, calendar period of the first DMT start (2014-2017 2018-2021), first DMT class used [mild-to-moderate efficacy (MME) high-efficacy (HE) DMT], time on first DMT, and disease activity at first DMT start or cessation/last follow-up. The majority of PwMS started with MME DMTs (77.1%), with the most common being glatiramer acetate, dimethyl/diroximel fumarate, and beta-interferon variants. Switchers changed treatment more often to HE DMTs (39.6%), most commonly sphingosine-1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, and natalizumab. Fewer PwMS switched to MME DMTs (35.9%), with the most common being dimethyl/diroximel fumarate, teriflunomide, or beta-interferon. Among 1045 PwMS with sufficient data (76.8% of 1361 switchers), the most frequent reasons for discontinuing the first DMT were disease activity despite DMT (63.1%), adverse events (17.1%), and patient request (8.3%). Predictors for the first DMT switch were MME DMT as initial treatment [odds ratio (OR) = 2.83 (1.76-4.61), < 0.001; reference: HE DMT], first DMT initiation between 2014 and 2017 [OR = 11.55 (6.93-19.94), < 0.001; reference: 2018-2021], and shorter time on first DMT [OR = 0.22 (0.18-0.27), < 0.001].
CONCLUSION
The initial use of MME DMTs was among the strongest predictors of DMT discontinuation in a large German retrospective MS cohort, arguing for the need for prospective treatment strategy trials, not only but also on the initial broad use of HE DMTs in PwMS.
PubMed: 38560408
DOI: 10.1177/17562864241239740 -
European Journal of Medical Research Jun 2024Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial... (Review)
Review
Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial haemorrhage (ICH) is a rare but highly morbid complication, more common CNS complications include progressive multifocal leukoencephalopathy (PML) and other CNS infections. This severe form of stroke, known for its high morbidity and mortality rates, presents a critical challenge in the management of MS. The use of disease-modifying drugs (DMDs) in treating MS introduces a nuanced aspect to patient care, with certain medications like Dimethyl Fumarate and Fingolimod showing potential in reducing the risk of ICH, while others such as Alemtuzumab and Mitoxantrone are associated with an increased risk. Understanding the intricate relationship between these DMDs, the pathophysiological mechanisms of ICH, and the individualised aspects of each patient's condition is paramount. Factors such as genetic predispositions, existing comorbidities, and lifestyle choices play a crucial role in tailoring treatment approaches, emphasising the importance of a personalised, vigilant therapeutic strategy. The necessity for ongoing and detailed research cannot be overstated. It is crucial to explore the long-term effects of DMDs on ICH occurrence and prognosis in MS patients, aiming to refine clinical practices and promote patient-centric, informed therapeutic decisions. This approach ensures that the management of MS is not only comprehensive but also adaptable to the evolving understanding of the disease and its treatments.
Topics: Humans; Multiple Sclerosis; Cerebral Hemorrhage; Immunosuppressive Agents; Mitoxantrone; Fingolimod Hydrochloride; Dimethyl Fumarate
PubMed: 38918831
DOI: 10.1186/s40001-024-01945-x -
Journal of Medical Economics 2024To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in...
AIM
To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS).
METHODS
Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources.
RESULTS
In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses.
CONCLUSIONS
This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.
Topics: Humans; Natalizumab; Fingolimod Hydrochloride; Multiple Sclerosis, Relapsing-Remitting; Immunosuppressive Agents; Multiple Sclerosis; Cost-Effectiveness Analysis; Cost-Benefit Analysis; State Medicine; United Kingdom
PubMed: 38085684
DOI: 10.1080/13696998.2023.2293379 -
Journal of Cardiothoracic Surgery Feb 2024This study examined the effect of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway on chronic obstructive pulmonary disease (COPD)...
BACKGROUND
This study examined the effect of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway on chronic obstructive pulmonary disease (COPD) and the potential molecular mechanism.
METHODS
A COPD mouse model was established by cigarette smoke exposure and administered with either ML385 or dimethyl fumarate (DMF). Airway resistance of mice was detected. IL-1β and IL-6 levels in mice alveolar lavage fluid were examined by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining and immunohistochemical of lung tissues were utilized to detect lung injury and NLRP3 expression. DMF was used to treat COPD cell model constructed by exposing normal human bronchial epithelial (NHBE) cells to cigarette smoke extract. NHBE cells were transfected by NLRP3-expression vectors. Expression of proteins was detected by Western blot.
RESULTS
COPD mice showed the enhanced airway resistance, the inactivated Nrf2/HO-1 pathway and the overexpressed NLRP3, Caspase-1 and GSDMD-N proteins in lung tissues, and the increased IL-1β and IL-6 levels in alveolar lavage fluid. ML385 treatment augmented these indicators and lung injury in COPD mice. However, DMF intervention attenuated these indicators and lung injury in COPD mice. Nrf2/HO-1 pathway inactivation and overexpression of NLRP3, Caspase-1 and GSDMD-N proteins were observed in COPD cells. DMF intervention activated Nrf2/HO-1 pathway and down-regulated NLRP3, Caspase-1 and GSDMD-N proteins in COPD cells. However, NLRP3 overexpression abolished the effect of DMF on COPD cells.
CONCLUSION
Nrf2/HO-1 pathway activation may alleviate inflammation in COPD by suppressing the NLRP3-related pyroptosis. Activating the Nrf2/HO-1 pathway may be an effective method to treat COPD.
Topics: Humans; Mice; Animals; NF-E2-Related Factor 2; Lung Injury; Pyroptosis; Interleukin-6; Heme Oxygenase-1; Cigarette Smoking; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Disease, Chronic Obstructive; Inflammation; Caspases
PubMed: 38317168
DOI: 10.1186/s13019-024-02530-3 -
Neurology(R) Neuroimmunology &... May 2024Epstein-Barr virus (EBV) has been strongly implicated in the pathogenesis of multiple sclerosis (MS). Despite this, there are no routinely used tests to measure cellular...
BACKGROUND AND OBJECTIVES
Epstein-Barr virus (EBV) has been strongly implicated in the pathogenesis of multiple sclerosis (MS). Despite this, there are no routinely used tests to measure cellular response to EBV. In this study, we analyzed the cellular response to EBV nuclear antigen-1 (EBNA-1) in people with MS (pwMS) using a whole blood assay.
METHODS
This cross-sectional study took place in a dedicated MS clinic in a university hospital. We recruited healthy controls, people with epilepsy (PWE), and pwMS taking a range of disease-modifying treatments (DMTs) including natalizumab, anti-CD20 monoclonal antibodies (mAbs), dimethyl fumarate (DMF), and also treatment naïve. Whole blood samples were stimulated with commercially available PepTivator EBNA1 peptides and a control virus-cytomegalovirus (CMV) peptide. We recorded the cellular response to stimulation with both interferon gamma (IFN-γ) and interleukin-2 (IL-2). We also compared the cellular responses to EBNA1 with IgG responses to EBNA1, viral capsid antigen (VCA), and EBV viral load.
RESULTS
We recruited 86 pwMS, with relapsing remitting MS, in this group, and we observed a higher level of cellular response recorded with IFN-γ (0.79 IU/mL ± 1.36) vs healthy controls (0.29 IU/mL ± 0.90, = 0.0048) and PWE (0.17 IU/mL ± 0.33, = 0.0088). Treatment with either anti-CD20 mAbs (0.28 IU/mL ± 0.57) or DMF (0.07 IU/mL ± 0.15) resulted in a cellular response equivalent to control levels or in PWE ( = 0.26). The results of recording IL-2 response were concordant with IFN-γ: with suppression also seen with anti-CD20 mAbs and DMF. By contrast, we did not record any differential effect of DMTs on the levels of IgG to either EBNA-1 or VCA. Nor did we observe differences in cellular response to cytomegalovirus between groups.
DISCUSSION
This study demonstrates how testing and recording the cellular response to EBNA-1 in pwMS may be beneficial. EBNA-1 stimulation of whole blood samples produced higher levels of IFN-γ and IL-2 in pwMS compared with controls and PWE. In addition, we show a differential effect of currently available DMTs on this response. The functional assay deployed uses whole blood samples with minimal preprocessing suggesting that employment as a treatment response measure in clinical trials targeting EBV may be possible.
Topics: Humans; Antibodies, Viral; Antigens, Viral; Capsid Proteins; Cross-Sectional Studies; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Herpesvirus 4, Human; Immunity, Cellular; Immunoglobulin G; Interferon-gamma; Interleukin-2; Multiple Sclerosis
PubMed: 38547427
DOI: 10.1212/NXI.0000000000200217