Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, preexisting disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

Objective:Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Beyond long-term immunologic and clinical data, little is known about acute changes in immunologic and routine laboratory parameters and their clinical relevance during the initial alemtuzumab infusion.Methods:Fifteen patients with highly active MS were recruited. In addition to parameters including heart rate, blood pressure, body temperature, and monitoring of adverse events, complete blood cell count, liver enzymes, kidney function, acute-phase proteins, serum cytokine profile, complement activation, peripheral immune cell distribution, and their potential of cytokine release were investigated prior to and after methylprednisolone and after alemtuzumab on each day of alemtuzumab infusion.Results:After the first alemtuzumab infusion, both the total leukocyte and granulocyte counts markedly increased, whereas lymphocyte counts dramatically decreased. In addition to lymphocyte depletion, cell subtypes important for innate immunity also decreased within the first week after alemtuzumab infusion. Although patients reported feeling well, C-reactive protein and procalcitonin peaked at serum levels consistent with septic conditions. Increases in liver enzymes were detected, although kidney function remained stable. Proinflammatory serum cytokine levels clearly rose after the first alemtuzumab infusion. Alemtuzumab led to impaired cytokine release ex vivo in nondepleted cells. Normal clinical parameters and mild adverse events were presented.Conclusions:Dramatic immunologic effects were observed. Standardized infusion procedure and pretreatment management attenuated infusion-related reactions. Alemtuzumab-mediated effects led to artificially altered parameters in standard blood testing. We recommend clinical decision-making based on primarily clinical symptoms within the first alemtuzumab treatment week.

BackgroundThe number of multiple sclerosis (MS) information websites, online communities, and Web-based health education programs has been increasing. However, MS patients’ willingness to use new ways of communication, such as websites, mobile phone application, short message service, or email with their physician, remains unknown.ObjectivesWe designed a questionnaire to evaluate the a priori use of electronic communication methods by MS patients and to assess their acceptance of such tools for communication with their health care providers.MethodsWe received complete data from 586 MS patients aged between 17 and 73 years. Respondents were surveyed in outpatient clinics across Germany using a novel paper-and-pencil questionnaire. In addition to demographics, the survey items queried frequency of use of, familiarity with, and comfort with using computers, websites, email, and mobile phones.ResultsAbout 90% of all MS patients used a personal computer (534/586) and the Internet (527/586) at least once a week, 87.0% (510/586) communicated by email, and 85.6% (488/570) communicated by mobile phone. When asked about their comfort with using electronic communication methods for communication with health care providers, 20.5% (120/586) accepted communication by mobile Internet application or short message service via mobile phone, 41.0% (240/586) by websites, 54.3% (318/586) by email service, and 67.8% (397/586) by at least one type of electronic communication. The level of a priori use was the best predictor for the acceptance of electronic communication with health care providers. Patients who reported already searching online for health information (odds ratio 2.4, P < .001) and who had already communicated with a physician through a website (odds ratio 3.3, P = .03) reported higher acceptance for Web-based communication. Patients who already scheduled appointments with their mobile phones (odds ratio 2.1, P = .002) were more likely to accept the use of mobile phone applications or short message service for communicating with their physician.ConclusionsThe majority of MS patients seen at specialist centers already use modern communication technology regularly. New forms of electronic communication appear to have high levels of acceptance for exchanging information about MS between patients and health care providers. Such methods should be integrated into eHealth services such as electronic health records and patient relationship management systems.

Multiple sclerosis (MS) is a highly heterogeneous disease as it can present inter-individually as well as intra-individually, with different disease phenotypes emerging during different stages in the long-term disease course. In addition to advanced immunological, genetic and magnetic resonance imaging (MRI) profiling of the patient, the clinical profiling of MS patients needs to be widely implemented in clinical practice and improved by including a greater range of relevant parameters as patient-reported outcomes. It is crucial to implement a high standard of clinical characterization of individual patients as this is key to effective long-term observation and evaluation.To generate reliable real-world data, individual clinical data should be collected in specific MS registries and/or using intelligent software instruments as the Multiple Sclerosis Documentation System 3D. Computational analysis of biological processes will play a key role in the transition to personalized MS treatment. Major breakthroughs in the areas of bioinformatics and computational systems biology will be required to process this complex information to enable improved personalization of treatment for MS patients.

ObjectivesDysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has frequently been reported in multiple sclerosis (MS). So far, HPA axis function in MS has predominantly been studied under pharmacological stimulation which is associated with a series of methodological caveats. Knowledge of circadian cortisol patterns and cortisol awakening response (CAR) is still limited.MethodsA total of 77 MS patients (55 relapsing-remitting MS (RRMS)/22 secondary-progressive MS (SPMS)) as well as 34 healthy control (HC) subjects were enrolled. Diurnal cortisol release was assessed by repeated salivary cortisol sampling. Neurological disability was rated by the Kurtzke’s Expanded Disability Status Scale (EDSS). Depressive symptoms and perceived stress were assessed by self-report measures.ResultsRRMS but not SPMS patients differed in circadian cortisol release from HC subjects. Differences in cortisol release were restricted to CAR. Treated and treatment naïve RRMS patients did not differ in CAR. In a RRMS follow-up cohort (nine months follow-up), RRMS patients with EDSS progression (≥0.5) expressed a significantly greater CAR compared to HC subjects. RRMS patients with a stable EDSS did not differ from HC subjects. Neither depressive symptoms nor perceived stress ratings were associated with CAR in RRMS patients. In a step-wise regression analysis, EDSS at baseline and CAR were predictive of EDSS at follow-up (R2 = 67%) for RRMS patients.ConclusionsCircadian cortisol release, in particular CAR, shows a course specific pattern with most pronounced release in RRMS. There is also some evidence for greater CAR in RRMS patients with EDSS progression. As a consequence, CAR might be of predictive value in terms of neurological disability in RRMS patients. The possible role of neuroendocrine-immune interactions in MS pathogenesis is further discussed.

NAT can pass placental barrier before delivery and into breast milk. Measurable NAT on neonatal lymphocytes may have functional impact. Further investigations are needed to clarify safety and risk of NAT exposure during pregnancy and lactation.

This study provides new information on the use of fampridine in a real-world setting with a large patient sample on the potential benefit of using more definitive responder criteria to fampridine for the clinical setting.

BackgroundThe monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood–brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens.MethodsWe developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy.ResultsIn paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro.ConclusionsIncorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0635-2) contains supplementary material, which is available to authorized users.