Mads Ravnborg

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis.

BACKGROUND Interferon beta is the first-line treatment for relapsing-remitting multiple sclerosis, but the drug can induce neutralising antibodies against itself, which might reduce effectiveness. We aimed to assess the clinical effect of neutralising antibodies. METHODS We measured neutralising antibodies every 12 months for up to 60 months in 541 patients with multiple sclerosis, randomly selected from all patients who started treatment with interferon beta between 1996 and 1999. Patients left the study if they changed or discontinued therapy. Antibodies were measured blindly, using antiviral neutralisation bioassays with high, medium, and low sensitivity, and with different neutralising capacities as cutoff value for definition of a neutralising-antibody-positive result. FINDINGS Patients developed neutralising antibodies independent of age, sex, disease duration, and progression index at start of treatment. Relapse rates were significantly higher during antibody-positive periods (0.64-0.70) than they were during antibody-negative periods (0.43-0.46; p<0.03). When comparing the number of relapses in the neutralising-antibody-positive and neutralising-antibody-negative periods we found odds ratios in the range 1.51 to 1.58 (p<0.03). Time to first relapse was significantly increased by 244 days in patients who were antibody-negative at 12 months (log rank test 6.83, p=0.009). During this short-term study, presence of neutralising antibodies did not affect disease progression measured with the expanded disability status scale. INTERPRETATION Our findings suggest that the presence of neutralising antibodies against interferon beta reduces the clinical effect of the drug. In patients who are not doing well on interferon beta, the presence of such antibodies should prompt consideration about change of treatment.

4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review.

This systematic review summarizes the existing evidence on the effect of 4-aminopyridine (4-AP) as a symptomatic treatment of decreased walking capacity in patients with multiple sclerosis (MS) when administered as an immediate release compound and a slow release compound. It summarizes existing evidence on the basic mechanisms of 4-AP from experimental studies and evidence on the clinical use of the compound. A systematic literature search was conducted of the following databases: PubMed and EMBASE. Thirty-five studies were included in the review divided into 16 experimental studies, two clinical studies with paraclinical endpoints and 17 clinical studies with clinical endpoints. Animal studies show that 4-AP can improve impulse conduction through demyelinated lesions. In patients with MS this translates into improved walking speed and muscle strength of the lower extremities in a subset of patients at a level that is often of clinical relevance. Phase III trials demonstrate approximately 25% increase in walking speed in roughly 40% and improved muscle strength in the lower extremities. Furthermore, 4-AP might have an effect on other domains such as cognition, upper extremity function and bowel and bladder, but this warrants further investigation. Side effects are mainly mild to moderate, consisting primarily of paraesthesia, dizziness, nausea/vomiting, falls/balance disorders, insomnia, urinary tract infections and asthenia. Side effects are worse when administered intravenously and when administered as an immediate release compound. Serious adverse events are rarely seen in the marketed clinical dosages. In conclusion, 4-AP is easy and safe to use. Slow release 4-AP shows more robust clinical effects and a more beneficial side-effect profile than immediate release 4-AP.

Persistence of neutralizing antibodies after discontinuation of IFNβ therapy in patients with relapsing-remitting multiple sclerosis

Objective The main objective was to follow serum levels of neutralizing antibodies (NABs) against interferon-beta (IFNβ) after discontinuation of IFNβ therapy. Background A large proportion of patients treated with recombinant IFNβ for multiple sclerosis (MS) develop therapy-induced NABs. Knowledge of persistence of NABs after discontinuation of therapy is limited. Design/patients: A retrospective follow-up study of patients treated in Denmark for relapsing-remitting (RR) MS with IFNβ for at least 12 months. NAB-positive patients, who discontinued therapy, were followed up with measurements of NABs. Methods We measured NAB-neutralizing capacity and NAB titres a.m. Kawade using a clinically validated cytopathic effect assay. Results Thirty-seven patients were included. Mean follow-up time was 22 months. Of the 29 patients with a NAB titre at or above 25 prior to termination of therapy, only three patients reverted to a titre below 25. Of these, two had a titre below 200 and one patient a titre of 600 at the last examination before treatment stop. The longest post-treatment follow-up during which a patient maintained NAB positivity was 59 months. Conclusion NABs against IFNβ, especially with high titres, tend to persist for a long time after discontinuation of IFNβ therapy. NABs should always be measured before reinstitution of IFNβ treatment in NAB-positive patients.

Immunomodulatory treatment of multiple sclerosis in Denmark: a prospective nationwide survey

Objective: The aim of the present study was to provide data on the use of immunomodulatory therapies in a population comprising all treated patients with relapsing-remitting multiple sclerosis (RRMS) in Denmark. Patients and methods: From the introduction of immunomodulatory therapy in Denmark in 1996 through 2003, all patients that started immunomodulatory therapy were followed prospectively with neurological examination and standard laboratory tests every six months, and clinical data were reported to the MS Treatment Register, including relapses, Expanded Disability Status Scale scores and side effects. Results: From 1996 through 2003 in all 2393 patients had started immunomodulatory therapy for RRMS, of whom 1252 (52.3%) were still on therapy with the same product at follow-up on 1 January 2005, whereas 1141 patients had discontinued or changed immunomodulatory therapy. Multiple Cox regression analysis of the risk of suffering a relapse showed a hazard ratio of 1.48 in patients with three or more relapses in the 24 months prior to onset compared with patients with two relapses or less; the hazard ratio was 0.84 in patients with age ≥ 38 years at treatment start compared with patients of age <38, and 1.17 for females compared with males. For disease progression the hazard ratio was 1.24 for age = 38 years compared with age ≥ 37 years. Significant differences were observed in the hazard ratios between the different preparations, probably due to selection bias. Conclusion: The response to immunomodulatory therapy can be predicted to some extent from demographic variables. Differences between preparations can mainly be ascribed to selection bias, and open studies are not suited for comparison of efficacy between different preparations.

Changes in cognition, arm function and lower body function after Slow-Release Fampridine treatment

Objective: We aimed to evaluate the effect of slow-release (SR) Fampridine on multiple outcome measures reflecting different domains, and to compare the responsiveness of the Six Spot Step Test (SSST) and the Timed 25 Foot Walk (T25FW). Methods: For this study 108 participants were included. On day 0 they were tested with the T25FW, the SSST, the 9-Hole Peg Test (9-HPT), the 5 Times Sit-To-Stand test (5-STS) and the Symbol Digit Modalities Test (SDMT). Four weeks of treatment with SR Fampridine 10 mg BID was commenced. Participants were tested again after 26–28 days of treatment. Results: Mean changes observed were: SSST −3.4±6.4s (p<0.001), T25FW −1.2±3.7s (p<0.001), 9-HPT −1.2±6.0s (p<0.001), 5- STS −3.4±7.2s (p<0.001) and SDMT 1.4±4.8 a.u. (p=0.003). Change on the SSST differed significantly from T25FW (SSST 17.0±19.6% vs. T25FW 11.2±17.1%, p=0.0013). Some 48.6% were found to have a meaningful change on the SSST compared with 25.7% on the T25FW. The response to treatment with SR Fampridine did not correlate with age, sex, Expanded Disability Status Scale and disease duration. Conclusion: SR Fampridine treatment has significant effects on different domains including upper and lower body and cognition. Furthermore, the SSST is more responsive to the effect of SR Fampridine than is the T25FW. ClinicalTrials.gov identifier: NCT01656148

Distribution-based estimates of minimum clinically important difference in cognition, arm function and lower body function after slow release-fampridine treatment of patients with multiple sclerosis

OBJECTIVE To provide distribution-based estimates of the minimal clinical important difference (MCID) after slow release fampridine treatment on cognition and functional capacity in people with MS (PwMS). METHOD MCID values were determined after SR-Fampridine treatment in 105 PwMS. Testing included the Timed 25 Foot Walk (T25FW), the Symbol Digit Modalities Test (SDMT), the Six Spot Step Test (SSST), the 9-Hole-Peg-Test (9-HPT), and the 5-Time-Sit-To-Stand test (5-STS). RESULTS MCID values: T25FW 17.8% (9.1-17.8), SDMT 17.1% (9.2-17.1), SSST 16.7% (8.5-16.7), 9-HPT 15.3% (0-15.3), and 5-STS 34.6% (16.9-34.6). CONCLUSION This study presents distribution-based estimates of MCID values for the SSST, the 9-HPT, and the 5-STS and confirms MCID estimates for the T25FW and the SDMT.

Effect of slow release-Fampridine on muscle strength, rate of force development, functional capacity and cognitive function in an enriched population of MS patients. A randomized, double blind, placebo controlled study

DESIGN This study was conducted as a randomized, double blind, placebo-controlled parallel group trial preceded by open label enrichment phase. OBJECTIVES The objectives of this study were 1) to examine the effect of SR-Fampridine treatment on muscle strength in terms of maximal voluntary contraction (MVC) and rate of force development (RFD) of the lower extremities and 2) to replicate previously published data on the effect of slow release-Fampridine (SR-Fampridine) on the functional capacity of the lower limbs, the upper limb and cognitive function, in persons with multiple sclerosis (pwMS). METHODS Previously identified responders to SR-Fampridine were randomized to SR- Fampridine or placebo treatment for four weeks. On days 0 and 26-28 participants underwent testing by isokinetic dynamometry, Nine Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Six Spot Step Test (SSST), Timed 25 Foot Walk Test (T25FW) and 5-Times Sit-to-Stand (5-STS). RESULTS A statistical significant effect of SR-Fampridine on MVC was demonstrated during knee extension, knee flexion and hip flexion of the weakest leg, as well as on RFD during knee extension and knee flexion of the weakest leg. Furthermore, a significant effect of SR-Fampridine on T25FW, SSST and 5-STS was demonstrated. CONCLUSION Gold standard dynamometry assessment of muscle strength showed improved MVC and RFD in persons with MS treated with SR-Fampridine compared to placebo. Furthermore, previous findings on the effects of SR-Fampridine on functional capacity of the lower limbs were replicated. ClinicalTrials.gov identifier: NCT01656148.

FAME - Fampridine outcome Measure study - an ongoing study

S Multiple Sclerosis Journal 2012; 18: S25–S28

Reliability and Validity of a Danish Version of the Multiple Sclerosis Neuropsychological Screening Questionnaire

Background More than half of all patients with multiple sclerosis (MS) acquire cognitive impairment as part of their disease progression. Because cognitive dysfunction adds substantially to disability and coping strategies, a cost-effective screening tool is needed for cognitive impairment. The Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) has previously shown good validity in American, Argentinean, and Dutch MS cohorts. We sought to test reliability and validity of a Danish translation of the MSNQ compared with formal neuropsychological testing, and measures of depression and disability, and to compare self-reported cognition with Symbol Digit Modalities Test (SDMT) results. Methods Of 126 patients with MS and their informants tested with the MSNQ, 77 also underwent formal neuropsychological testing. All patients were tested with the SDMT and assessed clinically using the Expanded Disability Status Scale and MS Impairment Scale. Results The test-retest reliability of the MSNQ-P was significant (R2 = 0.79, P < .0001). R2 of informants (MSNQ-I) and patients (MSNQ-P) was much lower (R2 = 0.22, P < .0001). Compared with formal neuropsychological testing, the MSNQ-P and MSNQ-I performed poorly, with no correlation to individual neuropsychological tests, combined neuropsychological tests, or disability scores (Expanded Disability Status Scale and MS Impairment Scale). Depression/anxiety (Beck Depression Inventory) showed a weak linear relationship (R2 = 0.25, P < .0001), suggesting that the MSNQ-P measures these items more than the cognitive abilities of the patients. Conclusions This study does not support use of the MSNQ as a sensitive or valid screening tool for cognitive impairment in Danish patients with MS.