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1.
J Neurol ; 265(8): 1850-1859, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29948245

ABSTRACT

BACKGROUND: Dimethyl-fumarate (DMF) demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (MS) in randomized clinical trials. OBJECTIVES: To track and evaluate post-market DMF profile in real-world setting. MATERIALS AND METHODS: Patients receiving DMF referred to Italian MS centres were enrolled and prospectively followed, collecting demographic clinical and radiological data. RESULTS: Among the 735 included patients, 45.4% were naïve to disease-modifying therapies, 17.8% switched to DMF because of tolerance, 27.4% switched to DMF because of lack of efficacy, and 9.4% switched to DMF because of safety concerns. Median DMF exposure was 17 months (0-33). DMF reduced the annual relapse rate (ARR) by 63.2%. At 12 and 24 months, 85 and 76% of patients were relapse-free. NEDA-3 status after 12 months of DMF treatment was maintained by 47.5% of patients. 89 and 70% of patients at 12 and 24 months regularly continued DMF. Most frequent adverse events (AEs) were flushing (37.2%) and gastro-enteric AEs (31.1%). CONCLUSION: Our post-market study corroborated that DMF is a safe and effective drug. Additionally, the study suggested that naïve patients strongly benefit from DMF and that DMF improved ARR also in patients who were horizontally switched from injectable therapies due to tolerability and efficacy issues.


Subject(s)
Dimethyl Fumarate/adverse effects , Dimethyl Fumarate/therapeutic use , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Adolescent , Adult , Female , Follow-Up Studies , Humans , Italy , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Prospective Studies , Treatment Outcome , Young Adult
2.
J Neuroinflammation ; 14(1): 11, 2017 01 17.
Article in English | MEDLINE | ID: mdl-28095856

ABSTRACT

BACKGROUND: B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS. METHODS: Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh). RESULTS: Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes (p < 0.01), lower values of BAFF Index (11.9 ± 6.1 vs 17.5 ± 5.2, p < 0.01), and higher CSF CXCL13 levels (27.7 ± 33.5 vs 0.9 ± 1.5, p < 0.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis (r > 0.5 and p < 0.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB- (p < 0.05) and HC (p < 0.01), and correlated to CSF CXCL13 concentrations (r 0.77, p < 0.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41 ± 0.1 vs 2.49 ± 0.1 mm, p < 0.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB-. CONCLUSIONS: The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by higher leukocyte counts in the CSF and early evidence of cortical thinning, further suggesting a role for this chemokine as a possible marker of disease severity.


Subject(s)
B-Cell Activating Factor/cerebrospinal fluid , Cerebral Cortex/pathology , Chemokine CXCL13/cerebrospinal fluid , Chemokine CXCL13/immunology , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/complications , Oligoclonal Bands/cerebrospinal fluid , Adult , Atrophy , B-Cell Activating Factor/blood , B-Cell Activating Factor/immunology , Cerebral Cortex/diagnostic imaging , Chemokine CXCL13/blood , Cytokines/blood , Cytokines/cerebrospinal fluid , Female , Humans , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/diagnostic imaging , Oligoclonal Bands/blood , Severity of Illness Index , Statistics as Topic
3.
J Neuroimmunol ; 297: 63-7, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27397077

ABSTRACT

B-cells are thought to play a relevant role in multiple sclerosis (MS) pathology. BAFF (B cell activating factor of the TNF family) is a B-cell survival factor constitutively produced inside the CNS by astrocytes. We studied the intrathecal synthesis of BAFF in MS at clinical onset. Paired serum and cerebrospinal fluid (CSF) specimens from 40 clinically isolated syndromes (CIS) suggestive of MS or early relapse-onset MS (eRRMS) and from 18 healthy controls (HC) were analysed. Patients were classified based on the detection of oligoclonal IgG bands in the CSF (IgGOB+ and IgGOB-). BAFF was detected by highly sensitive ELISA and its ratio (CSF-BAFF/serum-BAFF, QBAFF) and Index (QBAFF/QAlb, BAFF-Index) were calculated. IgGOB+ presented lower CSF concentrations of BAFF compared to both HC and IgGOB- (p<0.05). BAFF Index was significantly lower in IgGOB+ compared to both HC and IgGOB- (p<0.01). A significant inverse correlation between QIgG and QBAFF (r: -0.4, p<0.05) and between BAFF index and IgGIF (r: -0.4, p<0.05) or IgG Index (r: -0.4, p=0.05) was found in IgGOB+. The decreased CSF levels of BAFF in IgGOB+ at clinical onset suggest the absorption of this factor by intrathecally recruited B cells since the early disease phases.


Subject(s)
B-Cell Activating Factor/cerebrospinal fluid , Multiple Sclerosis/cerebrospinal fluid , Oligoclonal Bands/cerebrospinal fluid , Adolescent , Adult , B-Cell Activating Factor/blood , B-Cell Activating Factor/immunology , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Multiple Sclerosis/blood , Oligoclonal Bands/blood , Statistics, Nonparametric , Young Adult
4.
Am J Physiol ; 259(4 Pt 1): L320-7, 1990 Oct.
Article in English | MEDLINE | ID: mdl-1699434

ABSTRACT

Bronchial epithelial cells release chemotactic factors for lymphocytes and express HLA-DR antigens. Thus they may contribute to the T-cell-mediated inflammatory responses involved in a number of pulmonary diseases such as asthma. In this study, the in vitro exposure of human bronchial epithelial cells to toluene 2,4-diisocyanate (TDI), an inflammatory and asthmogenic stimulus presumed to act at least in part through immunological mechanisms, provoked cell damage followed by proliferation of the cells that survived the injury. At the time of the proliferative response, epithelial cells released factors that upregulated the activation and proliferation of T lymphocytes presensitized by antigen receptor triggering. The T-cell activating factors were interleukin (IL) 1- and 6-like substances, as demonstrated by the ability of specific antisera to inhibit most of the biological effect, and by the ability of recombinant IL-1 and IL-6 to reproduce it. Appreciable amounts of immunoreactive IL-1 and IL-6 were indeed recovered in the supernatants of TDI-exposed epithelial cells. The release of these cytokines may represent an important mechanism by which epithelial cells respond to some environmental stimuli and contribute to the persistence of inflammatory responses in the airways.


Subject(s)
Bronchi/immunology , Lymphocyte Activation , T-Lymphocytes/immunology , Toluene 2,4-Diisocyanate/pharmacology , Alkaline Phosphatase/analysis , Cell Adhesion/drug effects , Cell Survival/drug effects , Cells, Cultured , Epithelial Cells , Epithelium/drug effects , Epithelium/immunology , HLA-DR Antigens/analysis , Humans , Immunohistochemistry , Isomerism , Keratins/analysis , Mucous Membrane/immunology , Receptors, Interleukin-2/analysis
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