Kerstin Hellwig

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open‐label, baseline‐controlled pilot study

An exploratory, prospective, open‐label study of fumaric acid esters (FAE, Fumaderm®) was conducted in patients with relapsing–remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6‐week baseline, 18‐week treatment (target dose of 720 mg/day), 4‐week washout, and a second 48‐week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0–6.0 and at least one gadolinium‐enhancing (Gd+) lesion on T1‐weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine‐hole peg test (9‐HPT). Effects of FAE on intracellular cytokine profiles, T‐cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non‐compliance, and follow‐up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4‐week washout period. EDSS scores, AI, and 9‐HPT remained stable or slightly improved from baseline in all patients. Measures of T‐cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica

OBJECTIVE To describe first experiences with the integrin inhibitor natalizumab, given to patients with suspected relapsing-remitting multiple sclerosis (MS) who were later diagnosed with aquaporin 4-positive neuromyelitis optica (NMO). DESIGN Retrospective case series. SETTING Neurology departments at tertiary referral centers in Germany. PATIENTS Patients with NMO who tested positive for antibodies to aquaporin 4. INTERVENTION Treatment with natalizumab. MAIN OUTCOME MEASURES Relapses and accumulation of disability. RESULTS We identified 5 patients (4 female; median age, 45 years) who were initially diagnosed with MS and treated with natalizumab before diagnosis of NMO was established. Natalizumab was given as escalation therapy after failure of first- or second-line immunomodulatory therapies for MS. During natalizumab therapy (median duration, 8 infusions; range, 2-11 infusions), all 5 patients displayed persisting disease activity; a total of 9 relapses occurred (median duration to relapse, 120 days; range, 45-230 days) after the start of treatment. Four patients had an accumulation of disability and 1 patient died 2 months after cessation of natalizumab treatment. CONCLUSIONS Our results suggest that natalizumab fails to control disease activity in patients with NMO. Neuromyelitis optica should be considered as a differential diagnosis in patients with suspected MS who are unresponsive to natalizumab therapy.

Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort

Objective: To investigate the rate of seropositivity of anti-JC virus (JCV) antibodies in a German multiple sclerosis (MS) cohort treated with natalizumab in the postmarketing setting and to assess anti-JCV serostatus in samples obtained before diagnosis of progressive multifocal leukoencephalopathy (PML). Methods: This was a blinded, retrospective cross-sectional and longitudinal analysis for anti-JCV antibodies using a confirmatory 2-step ELISA on 2,782 blood samples obtained from 2,253 patients nationwide for routine testing for anti-natalizumab antibodies during open-label treatment between 2007 and 2010. Results: Of the natalizumab-treated patients with MS, 58.8% tested positive for anti-JCV antibodies. The rate of seropositivity was higher in males and increased with age, with a plateau between age intervals 20–29 and 30–39 years. In longitudinal analyses, 19 of 194 (9.8%) patients converted from anti-JCV antibody-negative to seropositive status over 7.7 months; 4.7% reverted from antibody-positive to seronegative status over 7.9 months. Antibody levels, especially in the latter group, were low, indicating fluctuations around the lower cut point of the assay. Neither anti-JCV serostatus nor antibody levels were associated with immunosuppressive pretreatment, duration of natalizumab treatment, or anti-natalizumab antibodies. All samples obtained from 10 patients who developed PML were seropositive (13 samples before PML diagnosis [2.0–37.6 months]; 2 samples at diagnosis). Antibody levels in these samples were higher than those in samples from seropositive patients who did not develop PML. Conclusions: These data argue for the potential clinical utility of JCV serology for PML risk stratification. However, further investigations of fluctuations in serostatus and of antibody levels for a more precise understanding of the predictive value are warranted.

Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment

Background: Natalizumab, a therapeutic monoclonal antibody approved for the treatment of relapsing–remitting multiple sclerosis (RRMS), is recommended to be withdrawn 3 months prior to a planned pregnancy. Our aim was to analyse the safety and impact of natalizumab exposure on course of disease and pregnancy outcome. Objectives: Prospective follow-up of women with MS who became accidentally pregnant during natalizumab treatment in comparison with pregnancies of women with MS not exposed to disease-modifying treatments (DMT). Method: 35 women with MS who became accidentally pregnant while treated with natalizumab, and 23 women with MS who became pregnant devoid of any DMT as a control group, were chosen. Results: All pregnancies except one were followed in a prospective fashion. Of the women exposed to natalizumab during pregnancy, 29 women gave birth to 28 healthy children; one child was born with hexadactyly. Five pregnancies ended in an early miscarriage and one woman decided to undergo an elective termination of pregnancy. MS activity did not rebound during pregnancy or post partum after natalizumab was withdrawn, and no significant differences were observed when compared with the non-DMT-exposed control group. Conclusion: Our data may support the notion that an elective termination of pregnancy due to natalizumab exposure may not be necessary, but rather requires careful monitoring. Women should still be advised to stop natalizumab in the course of planned pregnancy until more data on long-term outcomes are available.

Interleukin 6 Receptor Blockade in Patients With Neuromyelitis Optica Nonresponsive to Anti-CD20 Therapy

OBJECTIVE To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). DESIGN Retrospective case series. SETTING Neurology department at a tertiary referral center. PATIENTS Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. MAIN OUTCOME MEASURES Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. RESULTS We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. CONCLUSIONS Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.

Regulated microRNAs in the CSF of patients with multiple sclerosis A case-control study

ABSTRACT Objective: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and serve as promising therapeutic targets in many diseases. MiRNAs are also present in biological fluids and may be of use as disease biomarkers. We evaluated whether miRNAs are differentially regulated in the CSF of patients with multiple sclerosis (MS). Methods: The CSF of 53 patients with MS and 39 patients with other neurologic diseases (OND) was analyzed. First, global miRNA profiling was assessed to screen for reported miRNAs, followed by quantitative reverse transcriptase PCR to validate candidate miRNAs. Results: After global miRNA profiling, we quantitatively confirmed miR-922 (p = 0.0001), miR-181c (p = 0.0007), and miR-633 (p = 0.0014) to be differentially regulated in patients with MS as compared with OND. Importantly, miR-181c and miR-633 differentiated relapsing-remitting from secondary progressive MS courses with specificity up to of 82% and a sensitivity of 69%. Conclusion: CSF-based miRNAs were differentially regulated in patients with MS as compared with OND and in different MS disease courses. Despite the preliminary character of our case-control study, the results provide rationale for a confirmation study in larger MS cohorts.

Multiple sclerosis and pregnancy: experience from a nationwide database in Germany

Objective: The objective of this study was to evaluate exposure to disease-modifying therapies (DMTs) during pregnancy in 335 pregnancies of multiple sclerosis (MS) patients and to further determine whether exclusive breastfeeding of MS mothers has any relevant influence on postpartum relapse rate. Background: Only limited data are available on whether DMT exposure during pregnancy affects relapse rate during pregnancy or after birth. Currently, findings on beneficial effect of exclusive breastfeeding on MS disease course are controversially discussed. Methods: We enrolled pregnant women with MS who contacted us directly or via their treating physicians to be included in our nationwide MS and pregnancy database. Results: We identified 78 pregnancies under interferon-beta (IFNβ) preparations, 41 under glatiramer acetate (GLAT), and 216 pregnancies without DMT exposure during pregnancy. As expected, annualized relapse rate (ARR) decreased continuously during pregnancy in nonexposed mothers (p < 0.001) to then increase after birth. In IFNβ- or GLAT-exposed women this typical pattern was not as obvious. Congenital anomalies were within normal ranges in exposed pregnancies. In total, 170 women were identified who exclusively breastfed (EBF). Significantly reduced postpartum relapse rate during the first 3 months after birth were registered in the EBF group as compared with nonexclusively breastfeeding (NEBF) or nonbreastfeeding women (NBF) women with MS (p < 0.0001). Relapse rate (RR) in the year before pregnancy had been similar throughout all groups. We did not observe any significant differences in RR of NEBF and NBF women. Conclusion: Exclusive breastfeeding showed some beneficial effects on postpartum relapse rate in our cohort. Our data support that IFNβ and GLAT do not seem to represent a major teratogenic risk in pregnancy.

Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients

Objective Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre. Patients and methods Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3–6 monthly intervals. Results The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50–70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis. Conclusions Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

Progressive multifocal leukoencephalopathy and natalizumab

Natalizumab (TYSABRI®), a specific α4-integrin antagonist, is approved as a second-line treatment of relapsing-remitting MS (RRMS) patients who fail therapy with interferons or as first-line treatment of patients with highly active relapsing-remitting disease. Since the market introduction of natalizumab as a monotherapy in July of 2006, 111 cases of PML have been reported in natalizumab-treated MS patients as of April 2011. This review focuses on the available data regarding risk stratification for PML under long-term natalizumab therapy, and summarizes the current approach for PML management, as a natalizumab treatment complication is not necessarily associated with a fatal outcome. There is a need for development of surrogate markers that would help to better define the risk of PML in individual patients.

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.