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

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.

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

Neurology ◽

10.1212/wnl.0000000000005067 ◽

2018 ◽

Vol 90 (10) ◽

pp. e823-e831 ◽

Cited By ~ 39

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).

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

Neurology ◽

10.1212/wnl.0000000000005068 ◽

2018 ◽

Vol 90 (10) ◽

pp. e832-e839 ◽

Cited By ~ 31

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.

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

Journal of Neurology ◽

10.1007/s00415-020-10074-4 ◽

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.

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Treatment of Multiple Sclerosis with Natalizumab: Experiences from a Real-Life Cohort Over 15 Years

10.21203/rs.3.rs-924628/v1 ◽

2021 ◽

Author(s):

Michael Auer ◽

Anne Zinganell ◽

Harald Hegen ◽

Gabriel Bsteh ◽

Franziska Di Pauli ◽

...

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Real Life ◽

Disease Course ◽

Highly Active ◽

Potential Risk Factors ◽

Risk Of Disease ◽

Disease Reactivation ◽

Therapeutic Decision Making ◽

Medical University

Abstract BackgroundNatalizumab (NTZ) has been used for treatment of highly active relapsing-remitting multiple sclerosis (MS). When stopping NTZ the risk of severe rebound phenomenon has to be considered. We aimed to investigate the use of NTZ in clinical routine and focused on identification of potential risk factors for disease reactivation after treatment discontinuation.MethodsAt the Medical University of Innsbruck, Austria, we identified all MS patients who were treated with NTZ and performed a retrospective analysis on therapeutic decision making, disease course before, during and after treatment with NTZ and on risk factors for disease reactivation after NTZ discontinuation.Results235 NTZ treated MS patients were included, of whom 105 had discontinued treatment. At NTZ start disease duration was 5.09 (IQR 2.09-10.57) years, average number of total relapses was 4 (IQR 3-6) and median EDSS 2.0 (range 0-6.5), whereby these values significantly decreased over time. Reduction of annualized relapse rate (ARR) on treatment was 93% and EDSS remained stable in 64%. In a multivariate regression model only conversion to secondary progressive MS (SPMS) on treatment was significantly associated with lower risk of disease reactivation after NTZ, while ARR before treatment was associated with earlier disease reactivation. ConclusionsWe could confirm the high therapeutic efficacy of NTZ which trends to be used earlier in the disease course nowadays. Discontinuation of NTZ seems safe only in patients who convert to SPMS during treatment, while higher ARR before NTZ increases the risk of disease reactivation after treatment discontinuation.

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Pregnancy and the Use of Disease-Modifying Therapies in Patients with Multiple Sclerosis: Benefits versus Risks

Multiple Sclerosis International ◽

10.1155/2016/1034912 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Raed Alroughani ◽

Ayse Altintas ◽

Mohammed Al Jumah ◽

Mohammadali Sahraian ◽

Issa Alsharoqi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Current Evidence ◽

Disease Modifying Therapies ◽

Increased Risk ◽

Pregnancy And Lactation ◽

Risk Of Disease ◽

Disease Reactivation ◽

Disease Modifying ◽

Adverse Pregnancy ◽

In Pregnancy

The burden of multiple sclerosis (MS) in women of childbearing potential is increasing, with peak incidence around the age of 30 years, increasing incidence and prevalence, and growing female : male ratio. Guidelines recommend early use of disease-modifying therapies (DMTs), which are contraindicated or recommended with considerable caution, during pregnancy/breastfeeding. Many physicians are reluctant to prescribe them for a woman who is/is planning to be pregnant. Interferons are not absolutely contraindicated during pregnancy, since interferon-βappears to lack serious adverse effects in pregnancy, despite a warning in its labelling concerning risk of spontaneous abortion. Glatiramer acetate, natalizumab, and alemtuzumab also may not induce adverse pregnancy outcomes, although natalizumab may induce haematologic abnormalities in newborns. An accelerated elimination procedure is needed for teriflunomide if pregnancy occurs on treatment or if pregnancy is planned. Current evidence supports the contraindication for fingolimod during pregnancy; data on other DMTs remains limited. Increased relapse rates following withdrawal of some DMTs in pregnancy are concerning and require further research. The postpartum period brings increased risk of disease reactivation that needs to be carefully addressed through effective communication between treating physicians and mothers intending to breastfeed. We address the potential for use of the first- and second-line DMTs in pregnancy and lactation.

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Maintenance of natalizumab during the first trimester of pregnancy in active multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520912637 ◽

2020 ◽

pp. 135245852091263

Author(s):

Sarah Demortiere ◽

Audrey Rico ◽

Adil Maarouf ◽

Clémence Boutiere ◽

Jean Pelletier ◽

...

Keyword(s):

Multiple Sclerosis ◽

Congenital Anomaly ◽

Disease Activity ◽

First Trimester ◽

Disability Progression ◽

Risk Of Disease ◽

First Trimester Of Pregnancy ◽

Disease Reactivation ◽

Active Multiple Sclerosis

Background: Planning pregnancy in patients with active multiple sclerosis (MS) is highly challenging because treatment withdrawn may be associated with dramatic disease reactivation. Objective: To compare two strategies for women with active MS who were planning pregnancy: stopping natalizumab (1) at the end of the first trimester and (2) at conception. Methods: Standardized strategy for women with active MS was initiated in our department. Maintenance of natalizumab until the end of first trimester was recommended (“secured first trimester” (SFT)). When patients refused, they were advised to continue until conception (“secured conception” (SC)). Predictors of disease activity during pregnancy were assessed. Results: Forty-six pregnancies were prospectively followed (30 with SFT and 16 with SC). One congenital anomaly occurred in the SC group. The proportions of patients with relapse and disability progression during pregnancy were lower in the SFT than in the SC group (3.6% vs 38.5%, p < 0.005 and 3.6% vs 30.8%, p < 0.05, respectively). Predictors of relapse and disability progression during pregnancy were the time when natalizumab was stopped (conception vs end of first trimester) and the number of relapses during the year before natalizumab. Conclusion: Maintaining natalizumab during the first trimester may reduce the risk of disease reactivation during pregnancy in patients with active MS.

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Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: the VIAADISC score

European Journal of Neurology ◽

10.1111/ene.14705 ◽

2020 ◽

Author(s):

Gabriel Bsteh ◽

Harald Hegen ◽

Katharina Riedl ◽

Patrick Altmann ◽

Michael Auer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Glatiramer Acetate ◽

Risk Of Disease ◽

Disease Reactivation

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Experiences in treatment of multiple sclerosis with natalizumab from a real-life cohort over 15 years

Scientific Reports ◽

10.1038/s41598-021-02665-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Michael Auer ◽

Anne Zinganell ◽

Harald Hegen ◽

Gabriel Bsteh ◽

Franziska Di Pauli ◽

...

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Real Life ◽

Treatment Discontinuation ◽

Disease Course ◽

Highly Active ◽

Potential Risk Factors ◽

Risk Of Disease ◽

Disease Reactivation ◽

Therapeutic Decision Making

AbstractNatalizumab (NTZ) has been used for treatment of highly active relapsing–remitting multiple sclerosis (MS). When stopping NTZ the risk of severe rebound phenomenon has to be considered. We aimed to investigate the use of NTZ in clinical routine and focused on identification of potential risk factors for disease reactivation after treatment discontinuation. At the Medical University of Innsbruck, Austria, we identified all MS patients who were treated with NTZ and performed a retrospective analysis on therapeutic decision making, disease course before, during and after treatment with NTZ and on risk factors for disease reactivation after NTZ discontinuation. 235 NTZ treated MS patients were included, of whom 105 had discontinued treatment. At NTZ start disease duration was 5.09 (IQR 2.09–10.57) years, average number of total relapses was 4 (IQR 3–6) and median EDSS 2.0 (range 0–6.5), whereby these values significantly decreased over time. Reduction of annualized relapse rate (ARR) on treatment was 93% and EDSS remained stable in 64%. In multivariate regression models only conversion to secondary progressive MS (SPMS) on treatment was significantly associated with lower risk of disease reactivation after NTZ, while ARR before treatment was associated with earlier disease reactivation. We could confirm the high therapeutic efficacy of NTZ which trends to be used earlier in the disease course nowadays. Discontinuation of NTZ seems safe only in patients who convert to SPMS during treatment, while higher ARR before NTZ increases the risk of disease reactivation after treatment discontinuation.

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