Saúde incorpora o natalizumabe para o tratamento da esclerose

Os pacientes que sofrem de esclerose múltipla ganham mais um aliado no combate à doença. O Ministério da Saúde ampliou o uso do natalizumabe no tratamento da esclerose múltipla remitente-recorrente que representa 85% dos casos da doença.

Vaccine-associated measles in a patient treated with natalizumab: a case report.

BACKGROUND: Safety of live vaccines in patients treated with immunosuppressive therapies is not well known, resulting in contradictory vaccination recommendations. We describe here the first case of vaccine-associated measles in a patient on natalizumab treatment. CASE PRESENTATION: A young female patient with relapsing-remitting multiple sclerosis on natalizumab treatment received the live attenuated measles, mumps, and rubella vaccine in preparation for a change in her treatment in favour of fingolimod, with established immunosuppressive qualities. Seven days after receiving the vaccine, our patient experienced diffuse muscle pain, fatigue, and thereafter developed a fever and then an erythematous maculopapular rash, compatible with vaccine associated measles. This was later confirmed by a positive measles RT-PCR throat swab. The patient's symptoms resolved without any sequelae. CONCLUSION: In this case report we review the immunosuppressive qualities of natalizumab and the evidence in favour and against live vaccines in patients on this treatment. Our findings reveal the insufficient understanding of the immunosuppressive effects of new immunomodulators, and thus of the safety of live vaccines in patients on such medications. While this case triggers precaution, there is insufficient evidence to conclude that natalizumab treatment could favor the onset of vaccine-associated measles.

Treatment of Progressive Multifocal Leukoencephalopathy Using Immune Restoration.

Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the absence of effective anti-viral therapy for the causative JC virus, immune restoration has emerged as the critical therapeutic alternative. The evolving treatment of PML (and other rare JC virus-associated neurologic syndromes) requires consideration of baseline immune functioning and comorbid diseases while selecting from a number of therapeutic options to restore an effective immune response. This review focuses on the current options for management of PML in typical situations where this disease presents, including several where immune restoration is a standard therapeutic approach such as in PML associated with HIV/AIDS and in multiple sclerosis associated with natalizumab. Other circumstances in which PML occurs including associated with primary immunodeficiencies, malignancies, and transplants present greater challenges to immune reconstitution, but emerging concepts may enhance therapeutic options for these situations. Particular attention is focused on recent experience with checkpoint inhibitors, guidance for MS drug discontinuation, and strategies to monitor and facilitate immune restoration.

[Increased disease activity in a case of multiple sclerosis after switching treatment from fingolimod to natalizumab].

A 42-year-old woman diagnosed with multiple sclerosis (MS) at the age of 37 was initially treated with interferon-ß IM. The frequency of clinical relapses was twice in 4 years. At the age of 41, due to difficulty in administering muscle injections, an oral medication fingolimod was started. However, it was discontinued after a month due to decreased lymphocyte count, following which natalizumab was administered. The number of relapses increased 3 times in eleven months, and the number of T2 lesions on the MRI increased from 12 to 23. Natalizumab was discontinued because the test for the anti-natalizumab antibody was positive. It was suspected that both, the rebound syndrome caused by fingolimod cessation and the drug neutralization by anti-natalizumab antibodies, were associated with the exacerbation of disease activity. Thus, careful attention should be paid to potential occurrence of these events post switching between disease-modifying drugs for treating MS with high activity.

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

Optimization of Receptor Occupancy Assays in Mass Cytometry: Standardization Across Channels with QSC Beads.

Receptor occupancy, the ratio between amount of drug bound and amount of total receptor on single cells, is a biomarker for treatment response to therapeutic monoclonal antibodies. Receptor occupancy is traditionally measured by flow cytometry. However, spectral overlap in flow cytometry limits the number of markers that can be measured simultaneously. This restricts receptor occupancy assays to the analysis of major cell types, although rare cell populations are of potential therapeutic relevance. We therefore developed a receptor occupancy assay suitable for mass cytometry. Measuring more markers than currently available in flow cytometry allows simultaneous receptor occupancy assessment and high-parameter immune phenotyping in whole blood, which should yield new insights into disease activity and therapeutic effects. However, varying sensitivity across the mass cytometer detection range may lead to misinterpretation of the receptor occupancy when drug and receptor are detected in different channels. In this report, we describe a method for optimization of mass cytometry receptor occupancy measurements by using antibody-binding quantum simply cellular (QSC) beads for standardization across channels with different sensitivities. We evaluated the method in a mass cytometry-based receptor occupancy assay for natalizumab, a therapeutic antibody used in multiple sclerosis treatment that binds to α4-integrin, which is expressed on leukocyte cell surfaces. Peripheral blood leukocytes from a treated patient were stained with a panel containing metal-conjugated antibodies for detection of natalizumab and α4-integrin. QSC beads with known antibody binding capacity were stained with the same metal-conjugated antibodies and were used to standardize the signal intensity in the leukocyte sample before calculating receptor occupancy. We found that QSC bead standardization across channels corrected for sensitivity differences for detection of drug and receptor and generated more accurate results than observed without standardization. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Prediction of natalizumab anti-drug antibodies persistency.

BACKGROUND: Anti-drug antibodies (ADA) against natalizumab develop early during treatment. ADA persistency is defined by two consecutive positive results as performed by the current qualitative ELISA assay (positive/negative). Very little is known about the magnitude of the natalizumab ADA response and persistency. DESIGN/METHODS: We developed a highly sensitive natalizumab ADA titration assay on the Meso Scale Discovery (MSD) platform and a pharmacokinetic (PK) assay. We included 43 patients with a positive ELISA-ADA result within 6 months of treatment initiation (baseline) of whom a follow-up serum sample was available 12-30 months after treatment start. MSD-ADA titres and drug levels were measured. RESULTS: Median MSD-ADA titre at baseline was 4881 and 303 at follow-up. A titre of >400 at baseline had a 94% sensitivity and 89% specificity to predict ADA persistency. Reversion to ADA negativity occurred in 10 patients with mean drug levels of 10.8 µg/mL. The median trough drug level in ADA-positive samples was 0 µg/mL. PK levels and ADA titres correlated strongly negatively ( r = -0.67). CONCLUSION: High baseline natalizumab ADA titres accurately predict persistency. Despite continuous treatment, the majority of patients with persistent ADA had no detectable drug levels indicating loss of efficacy in line with phase 3 study results.

Anti-JCV serology during natalizumab treatment: Review and meta-analysis of 17 independent patient cohorts analyzing anti-John Cunningham polyoma virus sero-conversion rates under natalizumab treatment and differences between technical and biological sero-converters.

BACKGROUND: Anti-John Cunningham virus (JCV) serology has been studied with varying results concerning longitudinal changes. OBJECTIVES AND METHODS: Results from 17 published natalizumab-treated multiple sclerosis (MS) patient cohorts were analyzed with common parameters and subsequently verified in two large independent cohorts with 722 and 499 patients from Germany and the United States. RESULTS: Published studies and the verification showed (1) a mean of 10.80% sero-negative patients presented with sero-status change to positivity per year; (2) patients, who sero-convert to index values <0.9, convert from near the threshold and have a high probability of reverting with time; (3) patients, who convert to index values >0.9, start with low index values; (4) while JCV sero-positive patients with low index values sometimes revert to sero-negativity, patients with high index values almost never revert; and (5) the conversion rate of natalizumab-treated patients is three to four times higher than the biological conversion by age. CONCLUSION: JCV sero-conversion was comparable using standardized parameters and indicates influence of natalizumab on JCV immune control. Converters to low index values are probably consistently infected with JCV with varying low levels of activity, in line with their low risk to develop progressive multifocal leukoencephalopathy (PML). Patients with high index values rarely revert back to sero-negativity.

Natalizumab in the treatment of Crohn's disease patients.

INTRODUCTION: Amongst the available therapies for moderate to severe Crohn's disease (CD) patients who are refractory to conventional therapy, anti-TNF blockers are the most effective biological treatment option. However, many patients experience a primary or secondary non-response to anti-TNF therapy, creating the need for alternative biological drugs that target different mechanisms of action and inflammatory pathways. Natalizumab, the first non-anti-TNF biological drug to be approved for treatment of CD patients, is a recombinant humanized antibody that targets the α4-subunit of both α4ß1 and α4ß7 integrins, thus preventing activated leukocyte homing to the intestinal mucosa. Areas covered: This article summarizes the pathophysiological background and the efficacy and safety data of natalizumab, as well as the regulatory issues surrounding it. Expert opinion: Natalizumab represents an effective therapy for refractory CD patients. However, the rare but serious event of progressive multifocal leukoencephalopathy occurrence has compromised its widespread use. The subsequent advent of more specific anti-integrin drugs (i.e. vedolizumab) that carry a more favorable safety profile further reduces the clinical indications for natalizumab. The regulatory process for natalizumab distribution and monitoring in the US may provide a forum for discussion on how to optimally manage use of drugs that offer clinical benefits to patients, while minimizing associated risks.

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results.

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNß) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNß preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNß-1a subcutaneous (s.c.) and IFNß-1b s.c. in favor of the least immunogenic preparation IFNß-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNß-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNß-1a i.m. (1.41 and 2.27 years), IFNß-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNß-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNß ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis.

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNß)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNß-1a subcutaneous and IFNß-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNß-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFNß therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNß in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNß. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

Natalizumab modulates the humoral response against HERV-Wenv73-88 in a follow-up study of Multiple Sclerosis patients.

Multiple Sclerosis (MS) is a heterogeneous disorder of the central nervous system (CNS) that begins as an inflammatory autoimmune disorder mediated by auto-reactive lymphocyte followed by microglial activation and chronic degeneration. The etiology of Multiple Sclerosis (MS) is unknown but several data support the hypothesis of possible infectious agents which may act as a trigger for the pathogenic cascade. Human endogenous retrovirus (HERV-W/MSRV), Epstein Barr Virus (EBV) and Mycobacterium avium ss. paratuberculosis (MAP) have been associated to Multiple Sclerosis. In this study, we evaluated the humoral response against different peptides: the human endogenous retrovirus HERV-Wenv73-88, MAP106c121-132 from MAP, EBNA1 400-413 from EBV and the homologous human peptide MBP85-98 in a cohort of MS patients treated with natalizumab. Results showed a statistically significant difference in the response against the HERV-W peptide in MS patients after two years of natalizumab treatment.

Smokers run increased risk of developing anti-natalizumab antibodies.

BACKGROUND: Smoking may contribute to the induction of neutralizing antibodies to interferon ß-1a. OBJECTIVE: In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis. METHODS: This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals. RESULTS: Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2-4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5-5.1). INTERPRETATIONS: The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.