Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases

Hoevenaren IA, de Vries LC, Rijnders RJP, Lotgering FK. Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases.
Acta Neurol Scand: 2011: 123: 430–433.
© 2010 John Wiley & Sons A/S. Background – In current literature, no data on safety in pregnancy for new drugs in the treatment of multiple sclerosis (MS) like natalizumab (Tysabri^®), a humanized monoclonal antibody against α4 integrins, are yet available. In the management of MS, natalizumab is the first monoclonal antibody approved to the market. Methods – We describe the pregnancy and outcome in two women with MS using natalizumab. The first patient used it in the periconceptional period, and the second patient used it in both the periconceptional period and throughout gestation. Results – The antenatal course of the first patient was complicated by an exacerbation of MS. The second patient did not experience MS relapses during pregnancy, while still using natalizumab. The newborns did not show any abnormalities postnatal and at 6 weeks’ follow‐up. Conclusions – This is the first detailed report on pregnancy and delivery of two babies after maternal treatment of MS with natalizumab. From the small number of cases on the usage of natalizumab during pregnancy in literature, we cannot conclude whether the use of natalizumab is safe, and long‐term effects are not known. Further research is needed to establish the exact effects on pregnancy and intrauterine development as well as the long‐term effects. Prenatal counseling with thorough explanation of the risks and careful decision making is advisable.     

Efficacy of natalizumab in second line therapy of relapsing–remitting multiple sclerosis: results from a multi-center study in German speaking countries

Background:  Natalizumab has been recommended for the treatment of relapsing–remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population.
Method:  Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab ≥12 months prior to study conduction.
Results:  Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 ± 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >/= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>/= 2 relapses in the year and >/= 1 Gadolinium (Gd)+ lesion at study entry, n  = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity).
Conclusion:  Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.     

Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis

Bayas A, Penzien J, Hellwig K. Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis.
Acta Neurol Scand: 2011: 124: 290–292.
© 2011 John Wiley & Sons A/S. Background: Natalizumab is neither licensed for the use in adolescents nor during pregnancy. There are no reports of accidental natalizumab exposure during pregnancy continued as long as to the third trimester of pregnancy. Aims: We report the outcome of pregnancy in a 17‐year‐old adolescent patient with multiple sclerosis (MS) treated with natalizumab from the age of 16, who was diagnosed to be pregnant in the 31st gestational week (gw) of pregnancy. To our knowledge, this report describes the first patient receiving natalizumab to the third trimester of pregnancy. Case report: Because of high relapse activity, natalizumab treatment was administered in an adolescent patient with MS. Pregnancy was diagnosed in the 31st gw after 17 natalizumab infusions, seven of them accidentally during pregnancy. Results: Pre‐ and postnatal development of the child was normal. Conclusions: The case reported indicates that accidentally continued natalizumab treatment until few weeks before delivery may have no negative impact on the developing foetus.     

The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL

The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNβ)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, ≥ 3), Expanded Disability Status Scale score (≤ 3.5, > 3.5), number of T2 lesions (< 9, ≥ 9), presence of gadolinium-enhancing (Gd+) lesions (0, ≥ 1), age (< 40, ≥ 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., ≥ 2 relapses in the year before study entry and ≥ 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: ≥ 9 T2 lesions at baseline, ≥ 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNβ-1a treatment. These results indicate that natalizumab is effective in reducing disability progres- sion and relapses in patients with relapsing MS, particularly in patients with highly active disease. An erratum to this article is available at .     

A longitudinal uncontrolled study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis

Objective: Brain atrophy in multiple sclerosis (MS) selectively affects gray matter (GM), which is highly relevant to disability and cognitive impairment. We assessed cerebral GM volume (GMV) during one year of natalizumab therapy. Design/methods: Patients with relapsing–remitting (n = 18) or progressive (n = 2) MS had MRI ～1 year apart during natalizumab treatment. At baseline, patients were on natalizumab for (mean ± SD) 16.6 ± 10.9 months with age 38.5 ± 7.4 and disease duration 9.7 ± 4.3 years. Results: At baseline, GMV was 664.0 ± 56.4 ml, Expanded Disability Status Scale (EDSS) score was 2.3 ± 2.0, timed 25-foot walk (T25FW) was 6.1±3.4 s; two patients (10%) had gadolinium (Gd)-enhancing lesions. At follow-up, GMV was 663.9 ± 60.2 mL; EDSS was 2.6 ± 2.1 and T25FW was 5.9 ± 2.9 s. One patient had a mild clinical relapse during the observation period (0.052 annualized relapse rate for the entire cohort). No patients had Gd-enhancing lesions at follow-up. Linear mixed-effect models showed no significant change in annualized GMV [estimated mean change per year 0.338 mL, 95% confidence interval ?9.66, 10.34, p = 0.94)], GM fraction (p = 0.92), whole brain parenchymal fraction (p = 0.64), T2 lesion load (p = 0.64), EDSS (p = 0.26) or T25FW (p = 0.79). Conclusions: This pilot study shows no GM atrophy during one year of natalizumab MS therapy. We also did not detect any loss of whole brain volume or progression of cerebral T2 hyperintense lesion volume during the observation period. These MRI results paralleled the lack of clinical worsening.     

Pulsed corticosteroid treatment in MS patients stabilizes disease activity following natalizumab withdrawal prior to switching to fingolimod

Purpose: Interruption of natalizumab (NTM) treatment in multiple sclerosis (MS) patients may be followed by disease reactivation. On the other hand, patients with positive John Cunningham virus (JCV) antibodies treated with NTM over 24 months demonstrate a higher risk for developing progressive multifocal encephalopathy (PML). No established therapeutic approach is available for treating these patients to prevent disease reactivation. Materials and methods: Of the MS patients treated with NTM at the authors’ institution, 30 were found positive for JCV abs. NTM was interrupted followed by a washout period of 6 months. During this period, 20/30 patients received monthly intravenous (i.v.) methylprednisolone (MPD) 1000 mg infusion and regular clinical assessment. On months 3 and 6, brain MRI was performed and 1000 mg MPD was administered for 5 days. Results: All patients were clinically and radiologically stable at the time of NTM break. No clinical relapse was observed during the six-month washout period for the MS patients under monthly MPD treatment, while one patient had a relapse and active lesions in the MRI on month 6. Of the other patients not receiving i.v. MPD regularly after NTM withdrawal, one showed several active lesions in brain MRI and the other had a severe relapse. Conclusions: Despite the limited size of this patients’ cohort, the results of this study support that monthly MPD treatment for 6 months may result in a clinically stable disease status, thus ensuring safe transition to another second-line therapy such as fingolimod, following NTM withdrawal.     

Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study

Background – No head‐to‐head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). Aim – To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 μg; Rebif^®) on clinical and radiological findings in two matched cohorts of patients with MS. Patients and methods – We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing‐remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast‐enhancing lesions (CELs) at magnetic resonance imaging (MRI). Results – In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab‐treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a‐treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). Conclusions – After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head‐to‐head studies would be helpful to further evaluate the differences observed in the MRI outcomes.     

Car accidents in drivers with Parkinson's disease or multiple sclerosis: A Swedish nationwide study

Background and purpose

Parkinson's disease (PD) and multiple sclerosis (MS) can impair driving. However, we lack evidence on car accidents associated with these diseases. The aims of this study were to examine what types of car accident were associated with drivers with PD and MS, compared to individuals with ulcerative colitis (UC; the comparison group), and to evaluate the occurrence of car accidents in relation to years since diagnosis.

Methods

This retrospective nationwide, registry-based study included drivers involved in car accidents between 2010 and 2019, based on the Swedish Traffic Accident Data Acquisition database. Data on pre-existing diagnoses were retrieved retrospectively from the National Patient Registry. Data analyses included group comparisons, time-to-event analysis, and binary logistic regression.

Results

In total, 1491 drivers, including 199 with PD, 385 with MS, and 907 with UC, were registered to have been involved in a car accident. The mean time from diagnosis to the car accident was 5.6 years for PD, 8.0 years for MS, and 9.4 years for UC. Time to car accident since diagnosis differed significantly (p < 0.001) among groups (adjusted for age). Drivers with PD had more than twice the odds of a single-car accident than drivers with MS or UC, but no differences were observed between MS and UC.

Conclusions

Drivers with PD were older and experienced the car accident within a shorter timeframe after disease diagnosis. Although several factors may cause a car accident, fitness to drive could be more thoroughly evaluated for patients with PD by physicians, even early after the diagnosis.     

Upregulated survivin expression in activated T lymphocytes correlates with disease activity in multiple sclerosis

Programmed cell death (apoptosis) is critical for the normal development and homeostasis of the immune system. There is emerging evidence that failure of apoptosis to eliminate potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). This failure is related to multiple abnormalities of apoptosis-regulatory molecules that involve survivin, a recently described cell cycle-regulated anti-apoptosis protein. In this study, we investigated the relationship between survivin expression in peripheral T lymphocytes and clinical features of MS. We detected a significant over-expression of survivin in mitogen stimulated T lymphocytes from patients with active MS when compared with corresponding expression in patients with stable MS or those with inflammatory and non-inflammatory neurologic disorders. This over-expression of survivin in patients with active MS correlated with cellular resistance to apoptosis and with features of disease activity, such as disease duration and the number of enhanced lesions on cranial magnetic resonance imaging. There was no correlation between cellular survivin levels and the expression of other apoptosis-inhibitory proteins, such as Bcl-2 and Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP). Our findings indicate that cellular over-expression of the novel anti-apoptosis protein survivin is a feature of clinically active MS.