Hospital Universitario Ramón y Cajal
Immunology

Author Of 1 Presentation

Disease Modifying Therapies – Risk Management Oral Presentation

PS09.03 - Predictive biomarkers of the development of autoimmunity in patients treated with alemtuzumab

Speakers
Presentation Number
PS09.03
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
09:45 - 09:57

Abstract

Background

Alemtuzumab has proven to be an effective treatment for patients with highly active multiple sclerosis (MS). However, its use has been limited by adverse events (AEs) as secondary autoimmunity, being the most frequent those involving the thyroid gland, observed in around 40% of patients.

Objectives

To explore whether patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity.

Methods

A multicentre prospective longitudinal study was performed, including fifty‐four Relapsing-Remitting MS (RRMS) patients diagnosed in five Spanish hospitals. Patient blood samples were collected before initiating treatment with alemtuzumab. Autoimmune AEs were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia and/or autoimmune nephropathy. Differences were assessed using Man-Whitney U tests. Cut-off values were established using ROC curves to predict autoimmune AEs. Odds ratios were calculated by Fisher tests.

Results

Fifty‐four RRMS patients, 36 (66.7%) women, with a median (range) age of 28 (13–67) years and median (range) follow-up of 6 (0-20) years. Fourteen patients (25.9%) experienced autoimmune AEs, and all of them were dysthyroidism. No immune thrombocytopenia or nephropathies were observed. No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune AEs and those who did not. Patients who experienced autoimmune AEs before treatment onset had a higher percentage of blood CD19+ B cells (p=0.001), with a higher relative percentage of naïve B cells and plasmablasts. When explored total cell numbers, only plasmablast levels remained significant (p=0.02). A lower risk of autoimmune AEs after alemtuzumab was observed among patients with less than 7.6% of blood CD19+ B cells [odds ratio (OR) 16, confidence interval (CI) 3.86–58.95, p<0.0001] or less than 0.13% of plasmablast cells [OR 9.33, CI 2.17–42.65, p=0.002].

Conclusions

A low percentages of blood CD19+ B cells or plasmablasts before Alemtuzumab treatment predicted a lower risk of autoimmune AEs.

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Author Of 5 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0066 - Dimethyl fumarate decreases serum neurofilament light chain in relapsing-remitting multiple sclerosis patients. (ID 924)

Presentation Number
P0066
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) levels are associated with disease activity and prognosis in relapsing-remitting multiple sclerosis (RRMS) patients. Treatment with second-line disease modifying therapies (DMTs) leads to a reduction of sNfL, but little is known regarding first-line DMTs as dimethyl fumarate (DMF).

Objectives

To explore changes of sNfL levels in RRMS patients during treatment with DMF. To evaluate the potential role of sNfL measurement to predict an optimal treatment response.

Methods

Blood samples from 64 consecutive RRMS patients initiating DMF at Hospital Universitario Ramón y Cajal were collected at baseline and at 3, 6 and 12 months thereafter. sNfL levels were measured using a sensitive Single Molecular Array (SIMOA) assay (Quanterix). Patients were classified into No Evidence of Disease Activity (NEDA) and Ongoing Disease Activity (ODA) according the presence/absence of relapses, EDSS progression and/or MRI activity during the first year.

Results

Age at treatment initiation was 40.6 [33.2-46.3] years (median [25-75%IQR]) and EDSS was 1.5 [1.5-2.5]. Forty eight (75%) patients received other previous DMTs, seven of them were second-line DMTs. 66% of patients had evidence of disease activity at DMF initiation. Baseline sNfL levels were higher in patients who had evidence of disease activity at that time compared with patients who had not (12.2 pg/ml Vs. 8.8 pg/ml, p=0.024). No differences were found in baseline sNfL levels between naïve and previously treated patients, or between patients treated with first and second line DMTs. After 12 months of DMF treatment, 44 (69%) patients were NEDA and 20 (31%) were ODA. Baseline sNfL levels were higher in ODA patients compared to NEDA patients (14.6 pg/ml Vs. 9.2 pg/ml, p=0.016). A cut-off value of 12 pg/ml was established to predict NEDA status (OR=4.7; 95%CI: 1.6–15.7; p=0.008). After one year of DMF, sNfL levels decreased by 34.4% (p<0.0001). Both NEDA and ODA patients experienced a progressive sNfL reduction during the first year of treatment. However, this reduction was observed earlier in NEDA patients (three months after DMF initiation) than in ODA patients (six months).

Conclusions

DMF induced a progressive decrease in sNfL concentration during the first year of treatment. This reduction was delayed in ODA patients. Patients with basal sNFL values ≤ 12 pg/ml showed increased probability to achieve NEDA status at 12 months.

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Biomarkers and Bioinformatics Poster Presentation

P0172 - The prognostic value of lipid-specific IgM oligoclonal bands versus IgM index in patients with a clinical isolated syndrome: a comparative study. (ID 1114)

Speakers
Presentation Number
P0172
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The value of intrathecal IgM synthesis (ITMS) is increasingly recognized as a prognostic biomarker in patients with a clinically isolated syndrome (CIS). However, no comparative studies between different methods to assess ITMS have been described previously evaluating the prognosis of patients with CIS.

Objectives

To compare the predictive value of IgM Reibergram (IR) and the presence of lipid-specific IgM oligoclonal bands (LS-OCMB) in CSF to predict conversion to clinically defined multiple sclerosis (CDMS), and the onset of EDSS of 3, 6 and a secondary progressive MS (SPMS).

Methods

An observational single-center study with CIS patients with at least 2 years of follow-up attended at Hospital Universitario Ramón y Cajal was performed. Demographics, clinical, radiological and immunological variables were collected.

Results

196 patients were included, 131 (66.8%) women, with a median (range) age of 31 (12–63) years and mean (SD) follow-up of 13.2 (±7.0) years. Overall, positive LS-OCMB was observed in 52 (26.5%) patients and IR in 32/193 (16.6%), reaching a concordance of 59.4% between both. The risk of CDMS was significantly higher exclusively among LS-OCMB (adjusted HR 1.80 (95%CI 1.24-2.62), p=0.002), but not for IR. In addition, LS-OCMB predicted a higher risk of reaching an EDSS of 3 (OR 1.97, p=0.044), an EDSS of 6 (OR 3.82, p=0.001) and a SPMS (OR 2.67, p=0.013) among MS patients. No significant differences were observed with IR.

Conclusions

LS-OCMB are a more sensitive and reliable CSF biomarker to predict the natural history of CIS patients compare to semi-quantitative IR.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0324 - Effect of ocrelizumab treatment in peripheral blood leukocyte subsets of Primary Progressive Multiple Sclerosis patients (ID 1613)

Abstract

Background

Ocrelizumab is the first drug approved as disease modifying treatment for primary progressive (PP) multiple sclerosis (MS). As a humanized monoclonal antibody targeting CD20 cells, it is widely known that ocrelizumab treatment results in B cells depletion, but less is known about the effects of this drug in other blood leukocyte subsets of PPMS patients.

Objectives

To explore the changes induced by ocrelizumab in blood immune cells of PPMS patients to further understand their effects in the abnormal inflammatory response.

Methods

Multi-centre prospective longitudinal study including fifty‐three PPMS patients who initiated ocrelizumab treatment. Effector, memory, and regulatory cells were analyzed by flow cytometry at baseline and after 6 months of treatment. To assess differences between baseline and after 6 months, Wilcoxon matched paired tests were used and p values were corrected using Bonferroni test.

Results

Ocrelizumab decreased numbers of naïve and memory B cells (p<0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (p<0.0001 in all cases). A reduction of CD20+ T cell numbers (p=0.02) and percentages (p<0.0001) was also observed. We also detected a clear remodelation of the T cell compartment characterized by relative increases of the naïve/effector ratio in CD4+ (p=0.002) and CD8+ (p=0.002) T cells, and relative decreases of CD4+ (p=0.03) and CD8+ (p=0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p=0.002), with no changes in those producing inflammatory cytokines. All these changes resulted in a reduction of serum neurofilament light chain (sNfL) levels (p=0.009).

Conclusions

Effector B cell depletion by ocrelizumab treatment induces changes in the T cell response of PPMS patients towards a low inflammatory profile. This resulted in a decrease of sNfL levels.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0327 - Effectiveness and safety profile of the Natalizumab extended interval dosing in a Spanish cohort (ID 1815)

Presentation Number
P0327
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Previous Biogen analyses of the US TOUCH Registry showed that the risk of developing natalizumab-associated progressive multifocal leukoencephalopathy (PML) among anti-JCV antibody positive natalizumab-treated patients was significantly lower with extended interval dosing (EID) compared with standard interval dosing (SID). However, the efficacy of EID was not evaluated in these analyses. Real-world studies and modelling data suggest that a patient population stable on natalizumab SID who is then switched to EID is more likely to maintain efficacy with EID as compared to a population who initiates natalizumab on EID.

Objectives

The main objective of the study is to evaluate the effectiveness (measured by the annualized relapse rate - ARR) of natalizumab EID in subjects who have been previously treated with natalizumab SID during the 12-month list, in relation to continuous SID treatment.

Methods

Observational, open-label study with retrospective analysis of a prospective cohort of patients with relapsing-remitting multiple sclerosis (RRMS) treated at Hospital Ramón y Cajal (Madrid) with natalizumab for 12 months using SID (Infusion every month). All patients were transferred after a period of initial treatment at standard interval doses to a 6-week EID, according to hospital protocol, eliminating a potential selection bias for assigning less active patients to the EID group Demographic, clinical, radiological and immunological variables were collected.

Results

61 patients were included, 33 (54%) women, with a median (range) age at treatment initiation of 35 (17-55) years. Median (range) treatment duration was 5,2 years (2-11,3), 3,47 years (1,4-7,8) in SID, 1,7 years (0,5-4,1) in EID. There was no difference in ARR, mean [95% confidence interval (CI)], (SID: 0.05 [0,01-0,1]; EID: 0.02 [0,02-0,05]; P=0.558), or EDSS (SID: 2,35 [1,9-2,7], EID: 2,67 [2,2-3,9]; p=0,42).

Conclusions

This study does not demonstrate significant differences in relapse outcomes between SID and EID periods of patients who switched to EID from natalizumab after ≥1 year on SID. These results are consistent with previous analyzes without comparison that concluded that efficacy is maintained after switching to EID. Consistent MRI and EDSS results will be shown in the final poster. An ongoing prospective randomized trial of EID versus SID will provide a more complete understanding of the effectiveness of natalizumab EID.

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Pathogenesis – Immunology Poster Presentation

P0975 - Lipid-specific oligoclonal IgM bands condition age-related changes in multiple sclerosis (ID 1396)

Abstract

Background

Age has high influence on clinical course of chronic inflammatory diseases such as multiple sclerosis (MS). Lipid-specific oligoclonal IgM bands (LS-OCBM) in cerebrospinal fluid (CSF) of MS patients are biomarkers of high inflammatory disease. However, the relationship between both variables has not been fully studied.

Objectives

To explore age-related changes in CSF of MS patients leading to senescence and to study the role of LS-OCBM in this process.

Methods

A prospective cross-sectional study of 263 MS patients followed at Ramon y Cajal University Hospital, Madrid. Seventy-two showed (M+) and 191 (M-) lacked CSF LS-OCBM. We explored CSF immune cells, soluble mediators, microRNAs and clinical data.

Results

MS patients older than 45 years (O45) showed significant rises in CSF Programmed death ligand 1 (PD-L1; p=0.001) and T-cell immunoglobulin mucin-3 (TIM-3; p<0.0001), which induce lymphocyte tolerance, and in Chitinase 3-like-1 (p<0.0001) and Activin-A (p<0.0001), which lead to innate cell activation. This associated with low values of pro-inflammatory B cells and of Th17 lymphocytes. In addition, M- O45 patients experienced significant increases in miR-125b-5p (p=0.01) and miR-145-5p (p=0.02), two miRNA associated with immune senescence, an increase of let-7b-5p (p=0.01) that counteract innate-cell activation, a dramatic decrease of CSF lymphocytes (p<0.0001) and of NK cells (p=0.002) and increased serum anti-cytomegalovirus antibodies (p=0.009). However, M+ O45 patients exhibited a reduction of miR-204-5p (p=0.01), that induce innate-cell activation and increased CSF levels of superoxide dismutase (p=0.04) and isoprostane (p=0.03), markers of oxidative stress. These changes resulted in increased Multiple Sclerosis Severity Score (MSSS) on M+ O45 patients.

Conclusions

M- O45 MS patients showed inhibition of the intrathecal adaptive immune response and early immunosenescence. Conversely, M+ O45 MS patients displayed intrathecal innate cell activation and accelerated disability worsening. These data could be relevant for treating aged MS patients.

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