A genetic variant of the anti-apoptotic protein Akt predicts natalizumab-induced lymphocytosis and post-natalizumab multiple sclerosis reactivation

2012 ◽  
Vol 19 (1) ◽  
pp. 59-68 ◽  
Author(s):  
Silvia Rossi ◽  
Caterina Motta ◽  
Valeria Studer ◽  
Fabrizia Monteleone ◽  
Valentina De Chiara ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
At Risk ◽  
Genetic Variant ◽  
Apoptotic Pathway ◽  
Apoptotic Protein ◽  
Natalizumab Treatment ◽  
Patients At Risk ◽  
Risk Of Disease ◽  
Disease Reactivation ◽  
Natalizumab Discontinuation

Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation. Objective: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation. Methods: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade. Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation. Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.

Switching to ocrelizumab in RRMS patients at risk of PML previously treated with extended interval dosing of natalizumab

2020 ◽  
pp. 135245852094601
Author(s):  
Chiara Rosa Mancinelli ◽  
Cristina Scarpazza ◽  
Cinzia Cordioli ◽  
Nicola De Rossi ◽  
Sarah Rasia ◽  
...  
Keyword(s):  
At Risk ◽  
Resonance Imaging ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Patients At Risk ◽  
Risk Of Disease ◽  
Previously Treated ◽  
Disease Reactivation ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Remitting Multiple Sclerosis

Discontinuation of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) at risk of progressive multifocal leukoencephalopathy (PML) is associated with disease reactivation. Forty-two RRMS patients, who switched from an extended interval dose (EID) of natalizumab to ocrelizumab, underwent magnetic resonance imaging (MRI) and clinical monitoring during washout and after ocrelizumab starting. During the first 3 months, disease reactivation was observed in five (12%) patients; 6 months after ocrelizumab starting, no further relapses were recorded, and Expanded Disability Status Scale (EDSS) remained stable in 38 (90%) patients. In conclusion, ocrelizumab could be considered a choice to mitigate the risk of disease reactivation in patients previously treated with natalizumab-EID.

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.

Biomarkers of Ischemic Stroke

US Neurology ◽  
2010 ◽  
Vol 05 (02) ◽  
pp. 52
Author(s):  
Glen Jickling ◽  
Huichun Xu ◽  
Frank Sharp ◽  
◽  
◽  
...  
Keyword(s):  
At Risk ◽  
Ischemic Stroke ◽  
Clinical Diagnosis ◽  
Clinical Assessment ◽  
Molecular Biomarkers ◽  
Patient Treatment ◽  
Diagnosis And Management ◽  
Genomic Markers ◽  
Patients At Risk ◽  
Risk Of Disease

The diagnosis and management of patients with ischemic stroke is primarily based on clinical assessment in conjunction with imaging tests. Development of molecular biomarkers as additional tools to support a clinical diagnosis, identify patients at risk of disease, and help guide patient treatment and prognosis would be of great value. Currently, no such biomarkers are used in the management of patients with ischemic stroke; however, several promising proteomic and genomic markers have been identified, as presented in this review.

scholarly journals Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis

2018 ◽  
Vol 25 ◽  
pp. 14-20 ◽  
Author(s):  
Y. Naegelin ◽  
M. Rasenack ◽  
M. Andelova ◽  
S. Von Felten ◽  
B. Fischer-Barnicol ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Risk Of Disease ◽  
Disease Reactivation

Pregnancy decision-making in women with multiple sclerosis treated with natalizumab

Neurology ◽  
2018 ◽  
Vol 90 (10) ◽  
pp. e823-e831 ◽  
Author(s):  
Emilio Portaccio ◽  
Pietro Annovazzi ◽  
Angelo Ghezzi ◽  
Mauro Zaffaroni ◽  
Lucia Moiola ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
General Population ◽  
Spontaneous Abortion ◽  
Multivariable Analysis ◽  
Italian Population ◽  
Linear Regression Models ◽  
Class Iii ◽  
Increased Risk ◽  
Risk Of Disease ◽  
Disease Reactivation

ObjectiveTo assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA).MethodsData of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed.ResultsA total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9–8.5, p < 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) was associated with lower length and weight of the babies (p < 0.001).ConclusionOur results showed that natalizumab exposure to up 12 weeks of gestation is associated with an increased risk of SA, although within the limits expected in the general population, whereas the risk of CA needs further investigation. Taking into account the high risk of disease reactivation after natalizumab suspension, pregnancy could be planned continuing natalizumab while strictly monitoring conception.Classification of evidenceThis study provides Class III evidence that in women with MS, natalizumab exposure increases the risk of spontaneous abortion as compared to IFN-β-exposed or untreated patients (OR 3.9, 95% CI 1.9–8.5).

scholarly journals Cognitive Performance in Relapsing-Remitting Multiple Sclerosis: At Risk or Impaired?

2020 ◽  
Vol 49 (6) ◽  
pp. 539-543
Author(s):  
Marta Altieri ◽  
Mariangela Fratino ◽  
Ilaria Maestrini ◽  
Claudia Dionisi ◽  
Rosanna Annecca ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
At Risk ◽  
Cognitive Assessment ◽  
Screening Test ◽  
Neuropsychological Battery ◽  
Relapsing Remitting ◽  
Patients At Risk ◽  
Risk Patients ◽  
Lower Education ◽  
Relapsing Remitting Multiple Sclerosis

<b><i>Introduction:</i></b> Since cognitive impairment (CI) occurs on average in 45% of multiple sclerosis (MS) patients, the early detection of patients “at risk” of CI is important in order to promptly apply preventive strategies. The aim of the present study was to investigate the prevalence and risk factors for CI in MS patients using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) as a screening test. <b><i>Methods:</i></b> During the 1-year period, CI was evaluated in 82 consecutives mild relapsing-remitting MS (EDSS ≤ 3.5) patients. Patients with 1 altered BICAMS test were defined “at risk.” Both “at risk” and CI patients underwent an extensive neuropsychological battery. <b><i>Results:</i></b> We found that: (i) 23% had CI, (ii), 25% were “at risk” of CI, and (iii) 76% of the “at risk” patients were already impaired at the NP assessment. In particular, the Symbol Digit Modalities Test was the most compromised (70% of “at risk” and 79% of CI patients). Patients with CI had more frequently an EDSS ≥ 2.5 (<i>p</i> = 0.05), lower education (<i>p</i> = 0.05), and relapses in the last 12 months (<i>p</i> = 0.03). <b><i>Conclusions:</i></b> CI is a significant issue in MS and integration of a screening test, such as the SDMT, into routine clinical practice could be of worth to identify “at risk” patients and to promote an early therapeutic intervention.

Pregnancy decision-making in women with multiple sclerosis treated with natalizumab

Neurology ◽  
2018 ◽  
Vol 90 (10) ◽  
pp. e832-e839 ◽  
Author(s):  
Emilio Portaccio ◽  
Lucia Moiola ◽  
Vittorio Martinelli ◽  
Pietro Annovazzi ◽  
Angelo Ghezzi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Repeated Measures ◽  
Multivariable Analysis ◽  
Disease Modifying Drugs ◽  
Maternal Risk ◽  
Logistic Regression Models ◽  
Repeated Measures Analysis ◽  
Risk Of Disease ◽  
Disease Reactivation

ObjectiveTo assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS).MethodsData of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models.ResultsA total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab (p < 0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (p = 0.001). Relapses in the postpartum year were related to relapses during pregnancy (p = 0.019) and early reintroduction of disease-modifying drugs (DMD; p = 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD (p = 0.024).ConclusionsTaken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation.Classification of evidenceThis study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment.

scholarly journals Should I stop or should I go on? Disease modifying therapy after the first clinical episode of multiple sclerosis

2020 ◽  
Author(s):  
Tobias Monschein ◽  
Sabine Salhofer-Polanyi ◽  
Patrick Altmann ◽  
Tobias Zrzavy ◽  
Assunta Dal-Bianco ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Predictive Factor ◽  
Disease Modifying Therapy ◽  
Clinical Episode ◽  
Risk Of Disease ◽  
Disease Reactivation ◽  
Disease Modifying ◽  
In Cis

Abstract Introduction Treatment with disease-modifying therapies (DMT) in patients with clinically isolated syndrome (CIS) represents standard care in multiple sclerosis (MS) patients nowadays. Since a proportion of patients may show no evidence of disease activity (NEDA) after some time of treatment, the question might arise about the risks of stopping DMT. Methods We present a cohort of 49 patients who started DMT immediately after CIS and had no evidence of disease activity (NEDA-3) for at least five years before discontinuation of therapy. Thereafter, patients underwent clinical and MRI follow-up for at least five consecutive years. Results Of 49 patients discontinuing DMT, 53% (n = 26) had NEDA for at least further five years, while 47% (n = 23) showed either a relapse/disease progression (18.4%, n = 9), MRI activity (14.3%, n = 7) or both (14.3%, n = 7). The main predictive factor for sustained NEDA was age at DMT termination. Patients aged > 45 years had a significantly lower risk of disease reactivation (13% vs. 54% in patients aged < 45 years, p < 0.001) after DMT discontinuation. Discussion In CIS patients with immediate DMT after their first clinical episode, older age at the time of DMT discontinuation is the main predictive factor for sustained NEDA status.

Sign in / Sign up

Export Citation Format

Share Document