Natalizumab is effective as second line therapy in the treatment of relapsing remitting multiple sclerosis

Background:  Natalizumab has been recommended for the treatment of patients with relapsing remitting multiple sclerosis with insufficient response to interferon-beta (IFN-beta) or glatiramer acetate (GA).
Method:  Prospective, observational study.
Results:  We found a reduction of the annualized relapse rate from 2.1 under IFN-beta or GA to 0.2 one year after switching to natalizumab. There were 94% fewer gadolinium enhancing lesions with natalizumab.
Conclusion:  Natalizumab reduced short term clinical and MRI activity in second line therapy and efficacy is comparable to first line therapy as demonstrated in the pivotal trials.     

Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped

Natalizumab is frequently used as a treatment for multiple sclerosis (MS). The occurrence of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients indicates that its prominent beneficial effects need to be balanced against the risks. Also, cessation of the drug seems to be associated with recurrence of disease activity. Both the moment of rebound disease activity and the outcome of PML are related to clearance of the drug. Specific features of this IgG4 antibody (i.e. half-antibody exchange) may result in underestimated drug levels. Here, we demonstrate natalizumab levels in 10 patients with relapsing MS, using a recently developed sensitive assay. Remarkably, natalizumab was detectable up to 200 days after cessation of therapy.     

Identifying disease modifying genes in multiple sclerosis

Evidence is mounting that genetic variation influences not only susceptibility to multiple sclerosis (MS), but also its course and severity. Identification of disease modifying genes, however, poses unique challenges, especially on how to classify the course and outcome of the disease in ways that may be relevant to analysis of biological factors that might be influenced by genes. The power of the statistical approaches to detect small effects of individual genes in complex disorders such as MS is problematic, and approaches to estimate power must be appropriate for the data. Nonetheless, using contemporary schemes of classification, genetic variants that influence disease course have been found; in fact, a small number have been confirmed to influence disease course in two or more independent studies. This review addresses strategies relevant to identification of disease modifying genes in MS, and summarizes and critically evaluates the current state of knowledge in this area.     

Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis

Identifying predictors of clinical progression in patients with relapsing-remitting multiple sclerosis (RRMS) is complicated in the era of disease modifying therapy (DMT) because patients follow many different DMT regimens. To investigate predictors of progression in a treated RRMS sample, a cohort of RRMS patients was prospectively followed in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB). Enrollment criteria were exposure to either interferon-β (IFN-β, n=164) or glatiramer acetate (GA, n=114) for at least 6 months prior to study entry. Baseline demographic and clinical features were used as candidate predictors of longitudinal clinical change on the Expanded Disability Status Scale (EDSS). We compared three approaches to account for DMT effects in statistical modeling. In all approaches, we analyzed all patients together and stratified based on baseline DMT. Model 1 used all available longitudinal EDSS scores, even those after on-study DMT changes. Model 2 used only clinical observations prior to changing DMT. Model 3 used causal statistical models to identify predictors of clinical change. When all patients were considered using Model 1, patients with a motor symptom as the first relapse had significantly larger change in EDSS scores during follow-up (p=0.04); none of the other clinical or demographic variables significantly predicted change. In Models 2 and 3, results were generally unchanged. DMT modeling choice had a modest impact on the variables classified as predictors of EDSS score change. Importantly, however, interpretation of these predictors is dependent upon modeling choice.     

Predicting ongoing adherence to disease modifying therapies in multiple sclerosis: utility of the health beliefs model

OBJECTIVE: To evaluate ongoing adherence to disease modifying therapies (DMT) among individuals with multiple sclerosis and test the utility of the Health Beliefs Model (HBM) to predict adherence. DESIGN: Telephone survey completed at baseline with monthly telephone follow-up for 6 months. SETTING: Veterans Health Administration. PARTICIPANTS: Eighty-nine veterans with MS actively enrolled in a regional VA MS outpatient clinic currently prescribed DMT. MEASURES: Demographic information. Selected items from the Adherence Determinants Questionnaire (ADQ) and Barriers to Care Scale (BACS). RESULTS: Adherence in this population of ongoing DMT users was relatively high (over 80% achieved 80% adherence at follow-up time points). Logistic regression and hierarchical multiple regression analyses controlling for demographics and disease duration were employed to examine the relationship of HBM constructs of perceived susceptibility, severity, benefits, and barriers to DMT adherence and satisfaction at 2-, 4- and 6-month follow-up. Of the four HBM constructs, only perceived benefits uniquely predicted both outcomes across multiple time points. CONCLUSION: Sustained adherence to DMT remains a challenge for an important minority of individuals with MS. The Health Beliefs Model provides insight into psychosocial mechanisms that maintain adherence behavior. In particular, focus upon the perceived benefits of ongoing DMT therapy may be a promising focus for future interventions.     

Combination therapies for multiple sclerosis: scientific rationale, clinical trials, and clinical practice

PURPOSE OF REVIEW: To outline the scientific rationale for combination therapy in multiple sclerosis and to discuss the evidence for combination treatment strategies from animal models and clinical trials of multiple sclerosis. RECENT FINDINGS: Experiments conducted in experimental autoimmune encephalomyelitis have recently shown beneficial effects of numerous combination therapies. The combination of approved and experimental drugs and two or more experimental agents may positively impact clinical disease activity, inflammation within the central nervous system, and neurorepair. Clinical trials are currently underway to establish the therapeutic efficacy and safety of various combination therapies for multiple sclerosis patients. SUMMARY: More effective therapies are needed to treat multiple sclerosis. There are good scientific rationales for the use of combination therapy in multiple sclerosis, and the pharmacologic principles for evaluating and understanding their actions are available. The evaluation of specific combination therapies in the controlled setting of clinical trials should be a priority in clinical multiple sclerosis research.     

Natalizumab may improve cognition and mood in multiple sclerosis

Immunomodulating therapies may prevent relapses in multiple sclerosis and stabilize neurological status. However, little is known about the influence particularly of newer drugs on cognitive functions. We conducted an open-label prospective study to demonstrate whether natalizumab is apt to improve cognitive functions and mood in 29 patients tested psychometrically while under treatment for 6 months. We found improvements in some measures of attention, memory, mood, and well-being, but no deterioration, although patients suffered from their diseases for more than 10 years and had an EDSS score of 3.5. It is concluded that natalizumab is able to stabilize or improve cognition and mood even in longer-lasting multiple sclerosis.     

Natalizumab: targeting alpha4-integrins in multiple sclerosis

In 1992, it was shown that monoclonal antibodies blocking alpha(4)-integrins prevent the development of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS). As alpha(4)beta(1)-integrin was demonstrated to mediate the attachment of immune-competent cells to inflamed brain endothelium in experimental autoimmune encephalomyelitis, the therapeutic effect was attributed to the inhibition of immune cell extravasation and inflammation in the central nervous system. This novel therapeutic approach was rapidly and successfully translated into the clinic. The humanized anti-alpha(4)-integrin antibody natalizumab demonstrated an unequivocal therapeutic effect in preventing relapses and slowing down the pace of neurological deterioration in patients with relapsing-remitting MS in phase II and phase III clinical trials. The occurrence of 3 cases of progressive multifocal leukoencephalopathy in patients treated with natalizumab led to the voluntary withdrawal of the drug from the market. After a thorough safety evaluation of all patients receiving this drug in past and ongoing studies for MS and Crohn's disease, natalizumab again obtained approval in the US and the European Community. A treatment targeting leukocyte trafficking in MS has now re-entered the clinic. Further thorough evaluation is necessary for a better understanding of the risk-benefit balance of this new treatment option for relapsing MS. In this review, we discuss the basic mechanism of action, key clinical results of clinical trials and the emerging indication of natalizumab in MS.     

Natalizumab drug holiday in multiple sclerosis: Poorly Tolerated

It has been suggested that natalizumab‐associated progressive multifocal leukoencephalopathy may be prevented by structured interruptions of treatment. Evidence supporting such a drug holiday is not yet available. Here we present initial observations in 10 multiple sclerosis patients who were stringently monitored up to 6 months after discontinuation of the infusions. Cumulatively, a combination of clinical relapse and new and/or enhanced lesions on magnetic resonance imaging had occurred in 7 of 10 patients. Although numbers are small, our data suggest that in patients who were switched to natalizumab because of disease activity despite first‐line treatment, a natalizumab drug holiday without reinstatement of alternate disease‐modifying therapy is poorly tolerated. Ann Neurol 2010     

Adherence to disease-modifying therapies and attitudes regarding disease in patients with multiple sclerosis

Although currently there is no cure for MS the course of the disease can be influenced by disease modifying therapy (DMT). For therapy to be sufficiently efficient, it is crucial that patients take their medication regularly as prescribed. Adherence describes the extent to which a patient acts in accordance with the prescribed timing, dosing, and frequency of medication administration. To date, there are no known data about adherence rates among patients with MS in Slovenia. We wanted to assess adherence in patients with MS, who are treated with first line DMTs and discover reasons for non-adherence. A number of 451 patients were invited to participate. They received two questionnaires via post mail. The adherence rate and putative reasons for non-adherence were assessed by the use of standardized self-report Multiple Sclerosis Treatment Experience Questionnaire (MSTEQ). Patients’ attitudes regarding disease, therapy and relationship with their physician were assessed by another questionnaire. The analysis of results included 299 patients. Among the patients 18.5% missed at least one medication dose in the past 28 days. Patients taking Avonex were significantly more adherent then patients on other DMTs (p = 0.005). Our study showed a higher then expected adherence among Slovenian patients with MS (81.5%). Our research did not confirm the influence of side effects or patients’ attitudes regarding illness and therapy on adherence. However we found unexpectedly high percentage (71.8%) of patients belief that psychological factors are involved in MS aetiology.