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Advances in Therapy Jun 2024The management of patients affected by moderate-to-severe psoriasis may be challenging, in particular in patients with serious infectious diseases [tuberculosis (TB),... (Review)
Review
The management of patients affected by moderate-to-severe psoriasis may be challenging, in particular in patients with serious infectious diseases [tuberculosis (TB), hepatitis B and C, HIV, COVID-19]. Indeed, these infections should be ruled out before starting and during systemic treatment for psoriasis. Currently, four conventional systemic drugs (methotrexate, dimethyl fumarate, acitretin, cyclosporine), four classes of biologics (anti-tumour necrosis factor alpha, anti-interleukin (IL)12/23, anti-IL-17s, and anti-IL-23], and two oral small molecules (apremilast, deucravacitinib) have been licensed for the treatment of moderate-to-severe psoriasis. Each of these drugs is characterized by a unique safety profile which should be considered before starting therapy. Indeed, some comorbidities or risk factors may limit their use. In this context, the aim of this manuscript was to evaluate the management of patients affected by moderate-to-severe psoriasis with serious infectious diseases.
Topics: Humans; Psoriasis; COVID-19; Hepatitis B; Tuberculosis; SARS-CoV-2; HIV Infections; Hepatitis C
PubMed: 38709397
DOI: 10.1007/s12325-024-02873-2 -
Journal of Neuroinflammation Apr 2024Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU)...
BACKGROUND
Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking.
METHODS
To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF.
RESULTS
Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells.
CONCLUSIONS
DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.
Topics: Dimethyl Fumarate; Uveitis; Autoimmune Diseases; Single-Cell Gene Expression Analysis; Disease Models, Animal; Animals; Mice; Female; Mice, Inbred C57BL; Receptors, CXCR4; Proto-Oncogene Proteins c-pim-1; Transcription, Genetic; T-Lymphocyte Subsets; Atlases as Topic; Immunosuppressive Agents; Anti-Inflammatory Agents, Non-Steroidal; Retina; Lymph Nodes
PubMed: 38684986
DOI: 10.1186/s12974-024-03096-6 -
Neurology International Mar 2024We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing...
BACKGROUND
We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing ocrelizumab to other disease-modifying treatments (DMTs) and within different DMT sequences.
METHODS
We included 3371 people with MS who first received or switched DMT prescriptions from January 2018 to December 2022; they were identified through hospital discharge records, drug prescriptions, and exemption codes from the Campania Region (South Italy). We calculated persistence (time from the first prescription to discontinuation or switching to another DMT), adherence (proportion of days covered (PDC)), DMT costs, and MS hospital admissions and related costs.
RESULTS
The most frequently prescribed DMT was dimethyl fumarate (n = 815; age 38.90 ± 11.91 years; 69.5% females), followed by ocrelizumab (n = 682; age 46.46 ± 11.29 years; 56.3%); 28.8% of the patients treated with ocrelizumab were naïve to DMTs. Using ocrelizumab as a statistical reference, the risk of discontinuation was higher for other highly active (HR = 6.32; 95%CI = 3.16, 12.63; < 0.01) and low-/medium-efficacy DMTs (HR = 10.10; 95%CI = 5.10, 19.77; < 0.01); adherence was lower for other highly active DMTs (Coeff = -0.07; 95%CI = -0.10, -0.04; < 0.01) and low-/medium-efficacy DMTs (Coeff = -0.16; 95%CI = -0.19, -0.14; < 0.01). monthly DMT costs were higher for other highly active DMTs (Coeff = 77.45; 95%CI = 29.36, 125.53; < 0.01) but lower for low-/medium-efficacy DMTs (Coeff = -772.31; 95%CI = -816.95, -727.66; < 0.01). The hospital admissions and related costs of MS were similar between ocrelizumab, other highly active DMTs, and other low-/medium-efficacy DMTs, and with ocrelizumab as the first-line DMT after other highly active DMTs and after low-/medium-efficacy DMTs, which was possibly due to the low number of observations.
CONCLUSIONS
From 2018 to 2022, ocrelizumab was among the most frequently prescribed DMTs, with 28.8% prescriptions to incident MS patients, confirming its relevance in clinical practice. Ocrelizumab was associated with the highest persistence and adherence, pointing towards its favorable benefit-risk profile. The costs of ocrelizumab were lower than those of other highly active DMTs.
PubMed: 38668126
DOI: 10.3390/neurolint16020029 -
Pharmacological Research May 2024Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor,... (Review)
Review
Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases.
Topics: Humans; Pyroptosis; Protein Processing, Post-Translational; Epigenesis, Genetic; Animals; Inflammation; Anti-Inflammatory Agents
PubMed: 38614373
DOI: 10.1016/j.phrs.2024.107182 -
Multiple Sclerosis (Houndmills,... Apr 2024Lymphopenia is a known adverse effect in patients with relapsing multiple sclerosis (RMS) treated with fumaric acids. We present a case series of four patients diagnosed...
Lymphopenia is a known adverse effect in patients with relapsing multiple sclerosis (RMS) treated with fumaric acids. We present a case series of four patients diagnosed with RMS with prolonged lymphocyte stability on dimethyl fumarate for over 1 year who developed significant lymphopenia after transitioning to diroximel fumarate. This case series highlights the need for further research to elucidate the risk of lymphopenia in patients switching between fumaric acids.
PubMed: 38605496
DOI: 10.1177/13524585241242027 -
IScience Apr 2024The NLRP3 inflammasome plays a pivotal role in various chronic inflammation-driven human diseases. However, no drugs specifically targeting NLRP3 inflammasome have been...
The NLRP3 inflammasome plays a pivotal role in various chronic inflammation-driven human diseases. However, no drugs specifically targeting NLRP3 inflammasome have been approved by the Food and Drug Administration (FDA) of the United States. In our current study, we showed that dimethyl fumarate (DMF) efficiently suppressed the activation of the NLRP3 inflammasome induced by multiple agonists and covalently modified Cys673 of NLRP3, thereby impeding the interaction between NLRP3 and NEK7. The inhibitory effect of DMF was nullified by anaplerosis of the Cys673 mutant (but not the wild-type) NLRP3 in THP-1 cells. experiments, DMF demonstrated protective effects in the dextran sodium sulfate (DSS)-induced ulcerative colitis of WT mice, but not in mice. In summary, our study identified DMF as a direct covalent inhibitor of NLRP3 and a potential candidate for the treatment of NLRP3 inflammasome-mediated diseases.
PubMed: 38585664
DOI: 10.1016/j.isci.2024.109544 -
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 -
Nature Communications Mar 2024Disease-modifying therapies (DMT) administered to patients with multiple sclerosis (MS) can influence immune responses to SARS-CoV-2 and vaccine efficacy. However, data...
Disease-modifying therapies (DMT) administered to patients with multiple sclerosis (MS) can influence immune responses to SARS-CoV-2 and vaccine efficacy. However, data on the detailed phenotypic, functional and metabolic characteristics of antigen (Ag)-specific cells following the third dose of mRNA vaccine remain scarce. Here, using flow cytometry and 45-parameter mass cytometry, we broadly investigate the phenotype, function and the single-cell metabolic profile of SARS-CoV-2-specific T and B cells up to 8 months after the third dose of mRNA vaccine in a cohort of 94 patients with MS treated with different DMT, including cladribine, dimethyl fumarate, fingolimod, interferon, natalizumab, teriflunomide, rituximab or ocrelizumab. Almost all patients display functional immune response to SARS-CoV-2. Different metabolic profiles characterize antigen-specific-T and -B cell response in fingolimod- and natalizumab-treated patients, whose immune response differs from all the other MS treatments.
Topics: Humans; Multiple Sclerosis; Immunosuppressive Agents; Fingolimod Hydrochloride; SARS-CoV-2; Natalizumab; Vaccine Efficacy; mRNA Vaccines; COVID-19; Immunosenescence
PubMed: 38553477
DOI: 10.1038/s41467-024-47013-0 -
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 -
PloS One 2024Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel...
Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework.
Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies-which was statistically significant for the comparison with teriflunomide-this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis.
Topics: Adult; Humans; Immunosuppressive Agents; Dimethyl Fumarate; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Retrospective Studies; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Incidence; NF-E2-Related Factor 2; Fingolimod Hydrochloride; Renal Insufficiency, Chronic; Crotonates; Hydroxybutyrates; Nitriles; Toluidines
PubMed: 38517926
DOI: 10.1371/journal.pone.0300708