Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial.

BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients.

OBJECTIVE: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients. METHODS: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3-4 days during week 1. Based on lymphocyte count at week 4, patients received another 0-3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. RESULTS: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17-72) years and EDSS 0-8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data (n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data (n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. CONCLUSIONS: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

Neurotoxicity of Inhalation Anesthetics in the Neonatal Rat Brain: Effects on Behavior and Neurodegeneration in the Piriform Cortex.

There is concern that clinical use of anesthetic drugs may cause neurotoxicity in the developing brain and subsequent abnormal neurobehavior. We therefore evaluated neurotoxic effects of inhalation anesthetics in the neonatal rat brain, using in vivo histological and neurobehavioral outcomes. Wistar rats (n=79, postnatal day 15) were subjected to a clinically relevant single exposure of urethane, isoflurane, sevoflurane, or placebo, without surgery. At 48 h and 96 h, behavioral parameters were recorded and the animals were sacrificed. In cryosectioned brains, total cells and dying cells in layer II of the piriform cortex were counted using unbiased stereology. At 48 h, cell numbers in layer II of the piriform cortex of all drug-treated animals were reduced versus controls (p=0.01). The effect persisted at 96 h in isoflurane- and urethane-exposed animals. Piriform cortical layer II neurons undergoing degeneration, detected histologically by pyknotic nuclei and eosinophilic cytoplasm, were increased in the animals treated with isoflurane (1.9 ± 0.7 at 96 h) and urethane (2.4 ± 0.8 at 96 h) versus sevoflurane (0.8 ± 0.3 at 96 h) and controls (0.9 ± 0.2 at 96 h). Sevoflurane- and isoflurane-treated animals exhibited increased activity and decreased suckling compared with controls, and sevoflurane-exposed animals also displayed increased rearing behavior at both timepoints.

The case for measuring anti-drug antibodies in people with multiple sclerosis.

The advent of biopharmaceuticals (BPs) has led to significant improvements in the treatment of many chronic inflammatory diseases, and the number of BPs on the market and of diseases treated reflects their success. However, repetitive parenteral administration and intrinsic immunogenic properties of the drug can elicit an immune response, leading to production of anti-drug antibodies (ADA). This is a major limitation of the use of BPs and has to be taken into consideration in clinical practice and during drug development. With increasing knowledge about the immunogenicity of BPs and regular ADA testing in patients, we ensure optimized long-term treatment for the individual and thus optimal use of health care resources. This field has already been extensively investigated in the treatment of multiple sclerosis with IFN-ß, but there is a clear need for consensus from academia, health care providers and the BP industry in managing ADA across all BPs and diseases.

Clinical testing for neutralizing antibodies to interferon-ß in multiple sclerosis.

Biopharmaceuticals are drugs which are based on naturally occurring proteins (antibodies, receptors, cytokines, enzymes, toxins), nucleic acids (DNA, RNA) or attenuated microorganisms. Immunogenicity of these agents has been commonly described and refers to a specific antidrug antibody response. Such immunogenicity represents a major factor impairing the efficacy of biopharmaceuticals due to biopharmaceutical neutralization. Indeed, clinical experience has shown that induction of antidrug antibodies is associated with a loss of response to biopharmaceuticals and also with hypersensitivity reactions. The first disease-specific agent licensed to treat multiple sclerosis (MS) was interferon-ß (IFNß). In its various preparations, it remains the most commonly used first-line agent. The occurrence of antidrug antibodies has been extensively researched in MS, particularly in relation to IFNß. However, much controversy remains regarding the significance of these antibodies and incorporation of testing into clinical practice. Between 2% and 45% of people treated with IFNß will develop neutralizing antibodies, and this is dependent on the specific drug and dosing regimen. The aim of this review is to discuss the use of IFNß in MS, the biological and clinical relevance of anti-IFNß antibodies (binding and neutralizing antibodies), the incorporation of testing in clinical practice and ongoing research in the field.

Development of resistance to biologic therapies with reference to IFN-ß.

All biotherapeutics have the potential to generate anti-drug antibodies (ADAs) in patients. The main factors leading to an immune response are thought to be product, treatment and patient related. In this review, reasons for the formation of ADAs, and particularly neutralizing antibodies (NAbs), are considered, with a focus on IFN-ß as a well-studied example. The time course for the production of NAbs, the measurement of NAbs, the defining of IFN-ß responders and non-responders, the implications for disease progression in patients, and future methods for avoiding the production of ADAs and of tolerizing patients are considered.

Current and future role of interferon beta in the therapy of multiple sclerosis.

Interferon beta was the first specific disease-modifying therapy licensed for multiple sclerosis (MS) and in its many forms remains the most commonly prescribed agent worldwide. It, however, has a modest effect in reducing relapse rates, magnetic resonance imaging activity, and disability, and many patients are unable to tolerate it because of the associated side effects or mode of administration. With the licensing of glatiramer acetate, natalizumab and mitoxantrone as disease-modifying therapies for MS alternative options are available to people with MS. Many exciting new therapies are also in the pipeline, namely, the monoclonal antibodies alemtuzumab, rituximab, and daclizumab and the promising oral agents BG00012, cladribine, fingolimod, laquinimod, and teriflunomide. In this article we review the immunopathology of MS and the proposed mechanisms of action of currently available and anticipated treatments. We also review the efficacy of each drug, use of combination therapy strategies, and the potential role of the interferon beta preparations in the future.

Measuring and management of anti-interferon beta antibodies in subjects with multiple sclerosis.

Interferon Beta is well established as a first line agent to treat relapsing remitting Multiple Sclerosis. It frequently induces the formation of neutralising anti-Interferon Beta Antibodies (Nabs) which may abrogate the clinical efficacy of the drug. Numerous studies have shown a loss of bioactivity of the drug in the presence of Nabs. The focus has shifted to reliable quantification of Nabs and their appropriate incorporation into clinical practice. Here we review the development and persistence of Nabs, the effect on Interferon beta bioactivity, clinical and para-clinical autocome measures in trials, Nab assays and discuss management strategies to optimise the use of Interferon beta in relapsing remitting MS.