Comparative study of clinical grade human tolerogenic dendritic cells

<p>Abstract</p> <p>Background</p> <p>The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) for <it>in vitro </it>experiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (<it>Good Manufacturing Practice</it>) or clinical grade reagents with the aim of defining their use for human cell therapy.</p> <p>Methods</p> <p>Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-β and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced.</p> <p>Results</p> <p>Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells.</p> <p>Conclusions</p> <p>Our results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.</p

Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression

Background and Objectives: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem. Methods: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used. Results: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features. Conclusions: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS

Comparative effectiveness of autologous hematopoietic stem cell transplant vs fingolimod, natalizumab, and ocrelizumab in highly active relapsing-remitting multiple sclerosis

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

Supported by F. Hoffmann–La Roche

Análisis del dolor en pacientes con esclerosis múltiple

Resumen: Introducción: El dolor es un síntoma común en la esclerosis múltiple (EM) pero su prevalencia y características no están bien definidas. El objetivo de este trabajo fue describir la prevalencia, las características del dolor en pacientes con EM y determinar variables clínicas y radiológicas asociadas. Métodos: Se realizó un estudio prospectivo y descriptivo de pacientes con EM. Se evaluó la presencia de dolor en el momento de inclusión. A aquellos pacientes que referían dolor se les analizó el tipo (neuropático, nociceptivo o ambos), la localización y la intensidad (medida por la escala visual analógica) del dolor, así como la analgesia recibida. Se recogieron variables demográficas, tipo de EM, disfunción neurológica (EDSS), frecuencia de brotes, años de evolución, síntomas depresivos (evaluados por el test de Hamilton), tratamiento inmunomodulador, fatiga, espasticidad, presencia de lesiones en resonancia medular y un test de calidad de vida. Resultados: Se incluyeron 134 pacientes. Se realizó resonancia medular en 105. El 55% (74) presentaron dolor. Mayoritariamente fue neuropático, urente, en las extremidades y percibido como grave. De ellos recibió analgesia el 38%. Los pacientes con dolor presentaban mayor discapacidad (EDSS 4,5 [3-6] frente a 1,5 [1-2]; p < 0,001), mayor número de brotes (7,13 ± 3,4 frente a 3,75 ± 2,9; p < 0,001), mayor tiempo de evolución (14,6 ± 7,8 frente a 8,43 ± 5,9 meses; p < 0,001), formas progresivas (86,7% frente a 13,3%, p < 0,001), depresión (91,9% frente a 8,1%; p < 0,001) y mayor presencia de lesiones en la resonancia medular (84,3% frente a 15,7%; p < 0,001). En el análisis multivariante las lesiones en resonancia medular (OR: 3,5 [1,5-24,5]; p = 0,001) y la discapacidad (OR: 1,7 [1,1-2,7]; p = 0,014) se asociaron de forma independiente con dolor. Conclusiones: El dolor en la EM es frecuente y percibido como grave. Se asocia con la presencia de lesiones en la resonancia medular y con mayor discapacidad. Abstract: Introduction: Despite pain being a disabling symptom in patients with multiple sclerosis (MS), its prevalence and characteristics are not well established. The aim of this study is to describe the characteristics and prevalence of pain in patients with MS, and to assess the associated clinical variables and radiological findings. Methods: We prospectively studied patients with MS. A structured questionnaire which evaluated depression symptoms, type of pain, location, intensity (defined according to a visual analogue scale (VAS) as severe (VAS 7-10), moderate (VAS 4-6) and mild (VAS 0-4), and pain therapy was recorded in patients who referred to pain at the time of interview. Protocol variables were demographic data, MS clinical forms (remitting-relapsing, progressive-secondary and progressive-primary), neurological dysfunction (defined according to EDSS scale), symptoms at onset, attack frequency, illness duration, disease modifying treatment, fatigue, spasticity, oligoclonal bands in CSF, visual evoked potentials, depression symptoms (Hamilton test) and presence of lesions in spinal cord MRI. Results: A total of 134 MS patients were included, and MRI was performed on 105 of them. Pain was reported by 74 (55%) patients and was most frequently neuropathic, located in limbs, severe and burning/spiky. Of these 28 (38%) received therapy for their pain, based predominantly in anti-inflammatory drugs. Patients with pain had a worse functional state (EDSS score, 4.5 [3-6] vs 1.5 [1-2], p < 0.001), higher number of relapses (7.13 ± 3.4 vs 3.75 ± 2.9, p < 0.001), progressive forms of MS (86.7% vs 13.3%, p < 0.001), depression (91.9% vs 8.1%, p < 0.001), spinal cord involvement at onset (79.2% vs 20.8%, p = 0.009), spinal cord lesions by MRI (84.3% vs 15.7%, p < 0.001) and longer duration of disease (14.6 ± 7.8 vs 8.43 ± 5.9 months, p < 0.001). In a logistic regression model, the presence of lesions in spinal cord MRI (OR 3.5 [1.5-24.5]) and higher EDSS score (OR 1.7 [1.1-2.7]) were independently associated with pain.Conclusions: Pain is a frequent disabling symptom in MS and is associated with disability and spinal cord lesions. Palabras clave: Esclerosis múltiple, Dolor, Resonancia medular, Keywords: Multiple sclerosis, Pain, Spinal cor

Mielitis. Diferencias entre esclerosis múltiple y otras etiologías

Resumen: Introducción: Un primer brote de mielitis puede ocurrir en el contexto de enfermedades desmielinizantes, inflamatorias sistémicas o infecciosas. Nuestro objetivo fue analizar las diferencias entre mielitis asociadas a esclerosis múltiple (EM) y mielitis por otras etiologías. Métodos: Análisis retrospectivo, unicéntrico, de pacientes con primer brote de mielitis (2000-2013). Se analizaron variables demográficas, etiológicas, clínicas, radiológicas y pronósticas, y se compararon entre mielitis por EM y mielitis por otras etiologías. Resultados: Se incluyó un total de 91 pacientes. Tiempo medio de seguimiento: 7 años. Diagnósticos: EM 57 (63%), mielitis transversa idiopática 22 (24%), asociada a enfermedades sistémicas 6 (7%), otros diagnósticos (6%). Mielitis por EM: menor edad de inicio (35 ± 11 vs .41 ± 13; p = 0,02), mayor afectación esfinteriana (40,4 vs. 27,3%; p = 0,05), mayor afectación multifocal en la RM medular (77,2 vs. 26,5%; p = 0,001), menor extensión de la lesión (segmentos vertebrales 2,4 vs. 1,4; p = 0,001), localización cervical (82,5 vs. 64,7%; p = 0,05) y localización posterior (89,5 vs. 41,2%; p = 0,001). Mielitis por otras etiologías: mayor localización anterior (47,1 vs. 24,6%; p = 0,02) y centromedular (47,1 vs. 14,1%; p = 0,001) y mejor recuperación al año (EDSS 2,0 vs. 1,5; p = 0,01). Análisis multivariante: la afectación multifocal medular (OR 9,38; IC 95%: 2,04-43,1) y del cordón posterior (OR 2,16; IC 95%: 2,04-2,67) se asociaron de forma independiente al diagnóstico de EM. Conclusiones: Un alto porcentaje de pacientes con un primer brote de mielitis serán diagnosticados de EM. La presencia de lesiones medulares multifocales y en el cordón posterior se asocian de forma significativa a este diagnóstico. Abstract: Background: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. Methods: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. Results: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs. 41 ± 13; P  =  .02), more pronounced sphincter involvement (40.4 vs. 27.3%; P=.05), greater multifocal involvement in spinal MRI (77.2 vs. 26.5%; P=.001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P=.001), cervical location (82.5 vs. 64.7%; P=.05) and posterior location (89.5 vs. 41.2%; P=.001). Myelitis due to other aetiologies more frequently showed anterior location (47.1 vs. 24.6%; P=.02), and central cord involvement (47.1 vs. 14.1%; P=.001), with better recovery at one year of follow up (EDSS 2.0 vs. 1.5; P=.01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. Conclusions: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS. Palabras clave: Mielitis, Esclerosis múltiple, Mielitis idiopáticas, Enfermedades sistémicas, Keywords: Myelitis, Multiple sclerosis, Idiopathic myelitis, Systemic disease

Myelitis: Differences between multiple sclerosis and other aetiologies

Background: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. Methods: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. Results: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs 41 ± 13; P = .02), more pronounced sphincter involvement (40.4% vs 27.3%; P = .05), greater multifocal involvement in spinal MRI (77.2% vs 26.5%; P = .001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P = .001), cervical location (82.5% vs 64.7%; P = .05) and posterior location (89.5% vs 41.2%; P = .001). Myelitis due to other aetiologies more frequently showed anterior location (47.1% vs 24.6%; P = .02), and central cord involvement (47.1% vs 14.1%; P = .001), with better recovery at one year of follow up (EDSS 2.0 vs 1.5; P = .01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. Conclusions: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS. Resumen: Introducción: Un primer brote de mielitis puede ocurrir en el contexto de enfermedades desmielinizantes, inflamatorias sistémicas o infecciosas. Nuestro objetivo fue analizar las diferencias entre mielitis asociadas a esclerosis múltiple (EM) y mielitis por otras etiologías. Métodos: Análisis retrospectivo, unicéntrico, de pacientes con primer brote de mielitis (2000-2013). Se analizaron variables demográficas, etiológicas, clínicas, radiológicas y pronósticas, y se compararon entre mielitis por EM y mielitis por otras etiologías. Resultados: Se incluyó un total de 91 pacientes. Tiempo medio de seguimiento: 7 años. Diagnósticos: EM 57 (63%), mielitis transversa idiopática 22 (24%), asociada a enfermedades sistémicas 6 (7%), otros diagnósticos (6%). Mielitis por EM: menor edad de inicio (35 ± 11 vs .41 ± 13; p = 0,02), mayor afectación esfinteriana (40,4 vs 27,3%; p = 0,05), mayor afectación multifocal en la RM medular (77,2 vs 26,5%; p = 0,001), menor extensión de la lesión (segmentos vertebrales 2,4 vs 1,4; p = 0,001), localización cervical (82,5 vs 64,7%; p = 0,05) y localización posterior (89,5 vs 41,2%; p = 0,001). Mielitis por otras etiologías: mayor localización anterior (47,1 vs 24,6%; p = 0,02) y centromedular (47,1 vs 14,1%; p = 0,001) y mejor recuperación al año (EDSS 2,0 vs 1,5; p = 0,01). Análisis multivariante: la afectación multifocal medular (OR 9,38; IC 95%: 2,04-43,1) y del cordón posterior (OR 2,16; IC 95%: 2,04-2,67) se asociaron de forma independiente al diagnóstico de EM. Conclusiones: Un alto porcentaje de pacientes con un primer brote de mielitis serán diagnosticados de EM. La presencia de lesiones medulares multifocales y en el cordón posterior se asocian de forma significativa a este diagnóstico. Keywords: Myelitis, Multiple sclerosis, Idiopathic myelitis, Systemic diseases, Palabras clave: Mielitis, Esclerosis múltiple, Mielitis idiopáticas, Enfermedades sistémica