scholarly journals The Potential of Computational Modeling to Predict Disease Course and Treatment Response in Patients with Relapsing Multiple Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 586 ◽  
Author(s):  
Francesco Pappalardo ◽  
Giulia Russo ◽  
Marzio Pennisi ◽  
Giuseppe Alessandro Parasiliti Palumbo ◽  
Giuseppe Sgroi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Computational Modeling ◽  
Response To Treatment ◽  
Oligoclonal Bands ◽  
Host Immune System ◽  
Immunological Parameters ◽  
Disease Modifying Drugs ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Multiple Sclerosis

As of today, 20 disease-modifying drugs (DMDs) have been approved for the treatment of relapsing multiple sclerosis (MS) and, based on their efficacy, they can be grouped into moderate-efficacy DMDs and high-efficacy DMDs. The choice of the drug mostly relies on the judgment and experience of neurologists and the evaluation of the therapeutic response can only be obtained by monitoring the clinical and magnetic resonance imaging (MRI) status during follow up. In an era where therapies are focused on personalization, this study aims to develop a modeling infrastructure to predict the evolution of relapsing MS and the response to treatments. We built a computational modeling infrastructure named Universal Immune System Simulator (UISS), which can simulate the main features and dynamics of the immune system activities. We extended UISS to simulate all the underlying MS pathogenesis and its interaction with the host immune system. This simulator is a multi-scale, multi-organ, agent-based simulator with an attached module capable of simulating the dynamics of specific biological pathways at the molecular level. We simulated six MS patients with different relapsing–remitting courses. These patients were characterized based on their age, sex, presence of oligoclonal bands, therapy, and MRI lesion load at the onset. The simulator framework is made freely available and can be used following the links provided in the availability section. Even though the model can be further personalized employing immunological parameters and genetic information, we generated a few simulation scenarios for each patient based on the available data. Among these simulations, it was possible to find the scenarios that realistically matched the real clinical and MRI history. Moreover, for two patients, the simulator anticipated the timing of subsequent relapses, which occurred, suggesting that UISS may have the potential to assist MS specialists in predicting the course of the disease and the response to treatment.

scholarly journals The Potential of Computational Modeling to Predict Disease Course and Treatment Response in Patients with Relapsing Multiple Sclerosis

2020 ◽  
Author(s):  
Francesco Papparlardo ◽  
Giulia Russo ◽  
Marzio Pennisi ◽  
Giuseppe Alessandro Parasiliti Palumbo ◽  
Giuseppe Sgroi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Computational Modeling ◽  
Response To Treatment ◽  
Oligoclonal Bands ◽  
Host Immune System ◽  
Immunological Parameters ◽  
Disease Modifying Drugs ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Multiple Sclerosis

As of today, 20 disease modifying drugs (DMD) have been approved for the treatment of relapsing multiple sclerosis (MS) and, based on their efficacy, they can be grouped into moderate-efficacy DMDs and high-efficacy DMDs. The choice of the drug mostly relies on the judgement and experience of neurologists and the evaluation of therapeutic response can only be obtained by monitoring clinical and magnetic resonance imaging (MRI) status during follow up. In an era where therapies are focused on personalization, the aim of this study is to develop a modeling infrastructure to predict the evolution of relapsing MS and the response to treatments. We built a computational modeling infrastructure named UISS (Universal Immune System Simulator) able to simulate the main features and dynamics of the immune system activities. We extended UISS to simulate all the underlying MS pathogenesis and its interaction with the host immune system. This simulator is a multi-scale, multi-organ, agent based simulator with an attached module capable of simulating the dynamics of specific biological pathways at the molecular level. We simulated six MS patients with different relapsing-remitting courses. These patients were characterized on the basis of their age, sex, presence of oligoclonal bands, therapy and MRI lesion load at onset. The simulator framework is made freely available and can be used following the links provided in the availability section. Even though the model can be further personalized employing immunological parameters and genetic information, based on the available data we generated a few simulation scenarios for each patient, including those who matched the real clinical and MRI history. Moreover, for two patients, the simulator anticipated the timing of subsequent relapses, which really occurred, suggesting that UISS may have the potential to assist MS specialists in predicting the course of the disease and the response to treatment.

Early predictors of multiple sclerosis after a typical clinically isolated syndrome

2014 ◽  
Vol 20 (13) ◽  
pp. 1721-1726 ◽  
Author(s):  
Aurélie Ruet ◽  
Georgina Arrambide ◽  
Bruno Brochet ◽  
Cristina Auger ◽  
Eva Simon ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
At Risk ◽  
High Specificity ◽  
Clinically Isolated Syndrome ◽  
Oligoclonal Bands ◽  
Mcdonald Criteria ◽  
Early Predictors ◽  
Patients At Risk ◽  
Magnetic Resonance Imaging Mri ◽  
Periventricular Lesions

Background: The 2010 McDonald criteria allow diagnosing multiple sclerosis (MS) with one magnetic resonance imaging (MRI) scan. Nevertheless, not all patients at risk fulfil criteria at baseline. Other predictive factors (PFs) are: age ≤40 years, positive oligoclonal bands (OBs), and ≥3 periventricular lesions. Objective: The purpose of this study was to evaluate the 2010 McDonald criteria performance and to assess other PFs in patients without dissemination in space (DIS). Methods: Patients with clinically isolated syndrome (CIS) underwent baseline MRI and OB determination with clinical and radiological follow-up. Adjusted hazard ratios (aHRs) for clinically definite MS were estimated for DIS, dissemination in time (DIT), and DIS+DIT. Diagnostic properties at two years were calculated. In cases without DIS, combinations of ≥2 PFs were assessed. Results: A total of 652 patients were recruited; aHRs were 3.8 (2.5–5.8) for DIS, 4.2 (1.9–9.2) for DIT, and 8.6 (5.4–13.8) for DIS+DIT. Sensitivities were 69.6%, 42.3%, and 36.4%, and specificities were 67.3%, 87.9%, and 90.2%, respectively. In patients without DIS, aHRs varied between 2.7–5.5 and specificities ranged from 73.5–89.7% for PF combinations. Conclusion: The high specificity of the 2010 McDonald criteria is confirmed. In patients without DIS, PF combinations could be helpful in identifying those at risk for MS.

The Organophosphate Paraoxon Has No Demonstrable Effect on the Murine Immune System following Subchronic Low Dose Exposure

2008 ◽  
Vol 21 (4) ◽  
pp. 891-901 ◽  
Author(s):  
M.J. Fernandez-Cabezudo ◽  
S. Azimullah ◽  
S.M. Nurulain ◽  
M. Mechkarska ◽  
D.E. Lorke ◽  
...  
Keyword(s):  
Body Weight ◽  
Immune System ◽  
Ache Activity ◽  
Body Weight Gain ◽  
Fold Increase ◽  
Spleen Weight ◽  
Host Immune System ◽  
Immunological Parameters ◽  
Subchronic Exposure ◽  
Significant Difference

Paraoxon is the bioactive metabolite of the organophosphate pesticide parathion. Desulphuration of parathion by liver enzymes or sunlight results in the formation of paraoxon which inhibits acetylcholine esterase (AChE) activity. In the present study, we analyzed the effect of a 6-week, subchronic treatment with two different daily intraperitoneal doses (30 or 40 nmol) of paraoxon on the immune system of BALB/c mice. At a dose of 30 nmol/day, body weight of treated animals was unchanged compared to the controls. In contrast, the higher dose (40 nmol/day) induced a reduction in body growth, particularly in the first 3 weeks of treatment, peaking at week 2 when the saline group showed a 14.2-fold increase in body weight gain compared to paraoxon-treated animals. Moreover, mice treated with either dose of paraoxon had a >50% reduction in AChE activity during the first 3 weeks of treatment, but by the end of the treatment (week 6), AChE activity returned to normal. With regard to immunological parameters, there was no significant difference in either total spleen weight or in the ratios of various spleen cell populations between control and paraoxon-treated animals. Furthermore, no changes were observed in mitogen-induced cytokine secretion from splenocytes of paraoxon-treated mice. Finally, subchronic exposure to paraoxon did not alter mortality of mice exposed to a bacterial infection with Salmonella typhimurium. These data suggest that although subchronic exposure to paraoxon induced a transient inhibition in AChE activity, it had no demonstrable effect on the host immune system.

A Septuagenarian With Progressive Hemiparesis

2021 ◽  
pp. 48-50
Author(s):  
Roman Kassa ◽  
B. Mark Keegan
Keyword(s):  
Multiple Sclerosis ◽  
Late Onset ◽  
Progressive Multiple Sclerosis ◽  
Oligoclonal Bands ◽  
Hyperintense Lesion ◽  
Fluid Analysis ◽  
Hemiparetic Gait ◽  
Magnetic Resonance Imaging Mri ◽  
Disease Modifying Agents ◽  
The Right

A 78-year-old man with no pertinent medical history sought care for an 18-month history of progressive right lower extremity weakness, gait impairment, and falls. On neurologic examination, he had a hemiparetic gait. He had normal higher cognitive function and cranial nerve function. Motor examination showed decreased bulk over the right hand with no fasciculations, mild spasticity over the right leg, and right hemiparesis with an upper motor neuron pattern. Deep tendon reflexes were brisk throughout his limbs, and he had an extensor plantar reflex on the right side. He had impaired vibratory sense at the toes, with otherwise normal sensory and coordination examinations. Magnetic resonance imaging (MRI) of the brain showed ovoid periventricular and punctate subcortical and deep white matter T2 hyperintense foci. Some of these had corresponding T1 hypointensity. MRI of the cervical spine showed 1 eccentrically located T2 hyperintense lesion over the right lateral aspect of C2. Cerebrospinal fluid analysis showed no pleocytosis, an increased protein concentration of 66 mg/dL, and 4 unique oligoclonal bands. A diagnosis of primary progressive multiple sclerosis, very late onset, was made. With any diagnosis of late-onset multiple sclerosis, a decision about whether multiple sclerosis disease-modifying agents are indicated should be carefully considered. Our older patient had a progressive disease course, and neuroimaging studies did not reveal evidence of active disease. Based on this, a decision was made to monitor him clinically and radiologically. Management of spasticity with regular daily stretching exercises was discussed with him. A first clinical manifestation of multiple sclerosis can occur at a later-than-typical age. Most studies consider an onset at age 50 years or older to be late-onset multiple sclerosis, whereas first symptoms occurring at age 60 years or older are commonly referred to as very late–onset MS.

040 An analysis of malignancy risk in the clinical development programme of cladribine tablets in patients with relapsing multiple sclerosis

2018 ◽  
Vol 89 (6) ◽  
pp. A17.1-A17
Author(s):  
Andrew Galazka ◽  
Axel Nolting ◽  
Stuart Cook ◽  
Thomas Leist ◽  
Giancarlo Comi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Case Reports ◽  
Meta Analysis ◽  
Reference Population ◽  
Phase Iii ◽  
Disease Modifying Drugs ◽  
Malignancy Risk ◽  
Phase Iii Trials ◽  
Relapsing Multiple Sclerosis

IntroductionAn independent meta-analysis; Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158) in Phase III trials (with a 2 year duration) of disease modifying drugs (DMDs) in patients with relapsing multiple sclerosis found no increased rate of malignancy with cladribine tablets (CT) versus other DMD treatments. Data from additional trials involving CT 3.5 mg/kg (CT3.5) and a safety registry (up to 8 years’ follow-up) allow further insights into malignancy risk. Objective is to assess malignancy risk with CT3.5 monotherapy and placebo (PBO) in data from 3 Phase III trials and a registry, and compare the incidence rate with a global database.MethodsThe CT 3.5 population comprised 923 patients (3433 patient-years’ [PY] total exposure time) and the PBO group comprised 641 patients (2026 PY). Individual case reports of malignancies were reviewed by independent, blinded adjudication committee. Standardised incidence ratios (SIR) were calculated using the GLOBOCAN reference population (excluding non-melanoma skin cancers [NMSCs]) and a Danish reference population for NMSC rates.ResultsThe incidence per 100 PY of confirmed malignancy was CT3.5 0.293 (95%CI 0.158–0.544) and PBO 0.148 (95%CI 0.048–0.460); the risk difference 95% CI included 0 (−0.166–0.414). The CT 3.5 malignancy SIR was almost identical (0.97, 95% CI 0.44–1.85) to the GLOBOCAN matched reference population. The PBO group SIR was numerically lower (0.48, 95% CI 0.14–1.53). There were no cases of haematological, lymphoproliferative or virus-induced cancers. There was no clustering of specific tumour types, and the incidence of skin cancer was not increased after treatment with CT3.5 versus PBO. The incidence of malignancies with CT3.5 was constant and did not increase over time.ConclusionAnalysis of malignancy rates in a cohort that includes patients with up to 8 years’ follow-up confirms the Conclusion of the earlier meta-analysis; the incidence of malignancies with CT3.5 is similar to a matched reference population.

scholarly journals Optimizing treatment strategies in paediatric, adult and late-onset multiple sclerosis

Brain ◽  
2020 ◽  
Vol 143 (10) ◽  
pp. 2866-2868
Author(s):  
Cristina Gaudioso ◽  
Robert T Naismith
Keyword(s):  
Multiple Sclerosis ◽  
Late Onset ◽  
Treatment Strategies ◽  
Disability Progression ◽  
Disease Modifying Drugs ◽  
Disease Modifying ◽  
Relapsing Multiple Sclerosis

This scientific commentary refers to ‘Disease-modifying drugs can reduce disability progression in paediatric, adult and late-onset relapsing multiple sclerosis’, by Amato etal. (doi:10.1093/brain/awaa251).

Alemtuzumab—A New Efficacy Benchmark in Relapsing–Remitting Multiple Sclerosis?

US Neurology ◽  
2010 ◽  
Vol 06 (02) ◽  
pp. 82
Author(s):  
Omar A Khan ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Phase Iii ◽  
Mri Findings ◽  
Disability Score ◽  
Disease Modifying Drugs ◽  
Relapsing Remitting ◽  
Phase Iii Trials ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Ongoing Phase

The disease-modifying drugs (DMDs) available for the treatment of multiple sclerosis (MS) have been used effectively for nearly two decades. These treatments delay the neurorodegenerative process, but do not restore lost neurological function. New oral DMDs are becoming available that offer improved convenience over existing injectable DMDs. Recently, several monoclonal antibody treatments have been developed for MS; the furthest developed is alemtuzumab (Campath-1H). In a landmark phase II clinical trial (CAMMS223) on patients with relapsing–remitting MS (RRMS), short cycles of alemtuzumab given at baseline, at 12 months, and optionally at 24 months, demonstrated superior and sustained efficacy in terms of relapse rates and magnetic resonance imaging (MRI) findings over the comparator compound, interferon beta-1a (IFNβ-1a), which was given subcutaneously and continuously. Most notably, the mean disability score for patients receiving alemtuzumab showed an unprecedented improvement, whereas for IFNβ-1a it deteriorated. Alemtuzumab in treating RRMS is the subject of two ongoing phase III trials, the results of which have the potential to change future treatments and prognoses for many patients.

Three-year clinical outcomes of relapsing multiple sclerosis patients treated with dimethyl fumarate in a United States community health center

2017 ◽  
Vol 24 (7) ◽  
pp. 942-950 ◽  
Author(s):  
Kyle Smoot ◽  
Kateri J Spinelli ◽  
Tamela Stuchiner ◽  
Lindsay Lucas ◽  
Chiayi Chen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Duration ◽  
Community Health Center ◽  
Dimethyl Fumarate ◽  
Clinical Relapse ◽  
Disease Modifying Therapy ◽  
Magnetic Resonance Imaging Mri ◽  
Multiple Sclerosis Patients ◽  
Previous Disease ◽  
Relapsing Multiple Sclerosis

Background: Following approval of dimethyl fumarate (DMF), we established a registry of relapsing multiple sclerosis (RMS) patients taking DMF at our community MS center. Objective: To track DMF patients’ tolerability, disease progression, and lymphopenia. Methods: Patients prescribed DMF for RMS from March 2013 to March 2016 were prospectively enrolled ( N = 412). Baseline data, clinical relapses, magnetic resonance imaging (MRI) activity, discontinuation, and lymphocyte counts were captured through chart review. Results: The mean age of patients starting DMF was 49.4 ± 12.0 years and 70% transitioned from a previous disease-modifying therapy (DMT). Of the patients, 38% discontinued DMF, 76% of whom discontinued due to side effects. Clinical relapse and MRI activity were low. Comparing patients who transitioned from interferon-β (IFN), glatiramer acetate (GA), or natalizumab (NTZ), patients previously on NTZ had higher rates of relapse than those previously on GA (annualized relapse rate p = 0.039, percent relapse p = 0.021). Grade III lymphopenia developed in 11% of patients. Lymphopenia was associated with older age ( p < 0.001) and longer disease duration ( p < 0.001). Conclusion: Given the high rates of lymphopenia and discontinuation, it has become our clinical practice to more closely scrutinize older patients and those with a longer disease duration who are potential candidates for initiating DMF therapy.

scholarly journals Disease-Modifying Drugs and Stem Cell Therapies for the Treatment of Myelin Degeneration due to Multiple Sclerosis

2020 ◽  
pp. 1-5
Author(s):  
Darren Ioos ◽  
◽  
Vincent Gallicchio ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Nervous System ◽  
Stem Cell ◽  
Signal Propagation ◽  
Stem Cell Therapies ◽  
Disease Modifying Drugs ◽  
Cell Therapies ◽  
Differentiated Cells ◽  
Pns Myelin ◽  
Magnetic Resonance Imaging Mri

Myelin, a modified plasma membrane wrapped around axons, is an essential part of signal propagation in the nervous system. Formed by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), myelin lowers the amount of energy needed to send or receive signals. Multiple Sclerosis (MS) is an autoimmune, hyperinflammatory disease that attacks the nervous system, specifically myelin. MS is characterized by three types of lesions in the brain and along the blood brain barrier, making it very difficult to diagnose through conventional magnetic resonance imaging (MRI) and even more difficult to treat. It has an unpredictable pathophysiology that cannot be cured by current drug therapies. Stem cell therapies have been heavily researched in recent years to try to combat the autoimmune disease by stopping demyelination and recovering lost function through the regeneration of differentiated cells

scholarly journals Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort

2019 ◽  
Vol 26 (11) ◽  
pp. 1372-1380 ◽  
Author(s):  
Yael Hacohen ◽  
Wallace Brownlee ◽  
Kshitij Mankad ◽  
Wui K ‘Kling’ Chong ◽  
Alan Thompson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Real Life ◽  
Oligoclonal Bands ◽  
Resonance Imaging ◽  
Multi Centre Study ◽  
Mcdonald Criteria ◽  
Improved Performance ◽  
Magnetic Resonance Imaging Mri ◽  
Criteria For Diagnosis ◽  
Higher Sensitivity

Objective: To compare the performance of the 2017 McDonald criteria with that of the 2010 criteria for the diagnosis of multiple sclerosis (MS) in children in the clinical setting. Methods: In this retrospective, multi-centre study, we identified children who presented with symptoms suggestive of a clinically isolated syndrome (CIS) and were followed up for at least 2 years or until their second attack. Results: Of 156 children with CIS followed up for a median of 4.17 years, 94 (60.3%) were diagnosed with MS. In all, 83 (88.3%) of these fulfilled the 2010 dissemination in space (DIS) criteria at onset. Three additional children fulfilled the 2017 DIS criteria because of the inclusion of symptomatic lesions. Of the 59 children with MS who underwent post-gadolinium magnetic resonance imaging (MRI), 44 (74.6%) fulfilled the 2010 dissemination in time (DIT) criteria at baseline. When the presence of oligoclonal bands (OCBs) was used to substitute DIT, an additional 35 children (79/94, 84.0%) were diagnosed with MS according to the 2017 criteria. The 2017 criteria had higher accuracy (87.2% vs 66.7%), higher sensitivity (84.0% vs 46.8%), but reduced specificity (91.9% vs 96.8%) when compared to the 2010 criteria. Conclusion: The improved performance of the 2017 criteria when compared to the 2010 criteria was predominantly due to the inclusion of intrathecal OCBs.

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