Natalizumab Therapy In Patients Research Articles

Natalizumab therapy in patients with pediatric-onset multiple sclerosis in Greece: clinical and immunological insights of time-long administration and future directions-a single-center retrospective observational study.

Pediatric-onset multiple sclerosis (MS, POMS) accounts for 3-5% of all MS cases and is characterized by a highly inflammatory profile, often warranting treatment with high-efficacy agents. Our aim is to present real-world data of a series of 18 Hellenic POMS patients treated with natalizumab (NTZ) either as adolescents or as adults, after high disease activity has efficiently subsided. Clinical and imaging/laboratory data from 18 POMS patients who have received at least one NTZ infusion were selected in this single-center retrospective observational study. Human leukocyte antigen (HLA) genotyping was performed with standard low-resolution sequence-specific oligonucleotide techniques. Eighteen patients with a mean age of disease onset of 15.3 ± 2.4years were treated with NTZ with a mean of 51.7 ± 46.4 infusions, 6 as adolescents and 12 as adults. 22.2% were treatment naïve. At the end of the observational period, patients of both groups remained relapse-free, with no radiological activity and significantly reduced disability accumulation. No evidence of disease activity (NEDA)-3 status was achieved in 66.7% of all patients, 58.3% in the adult-treated, and 83.3% in the adolescent-treated POMS patients. NTZ was generally well tolerated. Only 5 adverse events were observed, in 3 patients who were carriers of the HLA-DRB1*15 (HLA-DRB1*15/HLA-DRB1*11 and HLA-DRB1*15/HLA-DRB1*13 genotypes), 1 homozygous for the HLA-DRB1*03 allele and 1 heterozygous for HLA-DRB1*04 and HLA-DRB1*16 alleles. NTZ is highly efficacious and mostly safe for POMS patients with high disease activity in all age groups. The role of immunogenetics in personalized patient evaluation and treatment needs to be further investigated.

A potential role for continuation of natalizumab therapy in patients with secondary progressive multiple sclerosis. (P5.358)

A potential role for continuation of natalizumab therapy in patients with secondary progressive multiple sclerosis. (P5.358)

Eligibility Criteria to Natalizumab Therapy in Patients with Relapsingremitting Multiple Sclerosis: A Real-life Study in an Italian Population-based Cohort

Background: Many patients with relapsing-remitting MS (RRMS) show a suboptimal response to first-line disease-modifying drugs. In these patients treatment with natalizumab is highly effective, however its use has been limited due to safety concerns. Objective: To evaluate the consistency between the eligibility to natalizumab according to Italian Drug Agency (AIFA), European Medicines Agency (EMA) and Food and Drug Administration (FDA) criteria, and its use in clinical practice. Methods: Medical records of 402 patients from four Italian MS Centres were reviewed to identify patients eligible to natalizumab according to AIFA, EMA, and FDA criteria and verify how many of them were currently treated or had been previously treated in practice. Results: Of 316 RRMS patients, 13.3% were currently or had been previously treated with natalizumab, while additional 7.0%, 14.2%, and 27.2% were not receiving the drug although they were eligible according to AIFA, EMA, and FDA criteria, respectively. Compared to patients treated with natalizumab, subject who were eligible but remained untreated were older and with shorter education. Conclusion: In a cohort of RRMS patients, 20.3%, 27.5%, and 40.5% were eligible to natalizumab according to AIFA, EMA, and FDA, respectively, although only part of them were actually treated.

Efficacy and side effects of natalizumab therapy in patients with multiple sclerosis.

Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08–3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.

Partial Recovery After Severe Immune Reconstitution Inflammatory Syndrome in a Multiple Sclerosis Patient with Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare and severe complication of natalizumab therapy in patients with multiple sclerosis and it may be accompanied by immune reconstitution inflammatory syndrome (IRIS). Here, we describe a case of abnormally severe IRIS, which occurred 2 months after natalizumab-associated PML in a 38-year-old woman affected by multiple sclerosis. The patient was John Cunningham virus-positive and was treated for 21 months when she developed PML. The subsequent IRIS diffusely afflicted the brain, producing edema and signs of intracranial hypertension, with a clinically severe form compromising the state of consciousness, requiring intensive care and high-dosage steroid treatment. Nevertheless, she survived and partially recovered. There is still difficulty in differentiating PML progression from IRIS onset and there is not a clear description in the literature about different clinical forms of IRIS, prognostic factors and guidelines to properly treat this complication in order to reduce the residual disability of the patient surviving this treatment complication.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.

Long-Term Decrease in VLA-4 Expression and Functional Impairment of Dendritic Cells during Natalizumab Therapy in Patients with Multiple Sclerosis

Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are central to the initiation and the regulation of immune processes in multiple sclerosis (MS). Natalizumab (NTZ) is a humanized monoclonal antibody approved for the treatment of MS that acts by blocking expression of VLA-4 integrins on the surface of leukocytes. We determined the proportions of circulating DC subsets and analyzed expression of VLA-4 expression in 6 relapsing-remitting MS patients treated with NTZ for 1 year. VLA-4 expression levels on pDCs and mDCs decreased significantly during follow-up. In vitro coculture of peripheral blood mononuclear cells and pDCs, with different doses of NTZ in healthy controls (HC) and MS patients showed dose-dependent down-regulation of VLA-4 expression levels in both MS patients and HC, and reduced functional ability to stimulate antigen-specific T-lymphocyte responses. The biological impact of NTZ may in part be attributable to inhibition of transmigration of circulating DCs into the central nervous system, but also to functional impairment of interactions between T cells and DC.

Efficacy of Natalizumab Therapy in Patients of African Descent With Relapsing Multiple Sclerosis

Patients with multiple sclerosis (MS) who are of African descent experience a more aggressive disease course than patients who are of white race/ethnicity. In phase 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]), natalizumab use significantly improved clinical and magnetic resonance imaging outcomes over 2 years in patients with relapsing MS. Because patients of African descent may be less responsive to interferon beta treatment than patients of white race/ethnicity, the efficacy of natalizumab therapy in this population is clinically important. To evaluate the efficacy of natalizumab use in patients of African descent with relapsing MS. Post hoc analysis. Academic research. Patients of African descent with relapsing MS who received natalizumab or placebo in the phase 3 AFFIRM study and those who received natalizumab plus intramuscular interferon beta-1a or placebo plus intramuscular interferon beta-1a in the phase 3 SENTINEL study. Efficacy of natalizumab use in patients of African descent with relapsing MS who participated in the AFFIRM or SENTINEL trial. Forty-nine patients of African descent participated in AFFIRM (n = 10) or SENTINEL (n = 39). Demographic and baseline disease characteristics were similar between patients treated with natalizumab (n = 21) or placebo (n = 28). Natalizumab therapy significantly reduced the annualized MS relapse rate by 60% (0.21 vs 0.53 in the placebo group, P = .02). Compared with placebo use, natalizumab therapy also significantly reduced the accumulation of lesions observed on magnetic resonance imaging over 2 years: the mean number of gadolinium-enhancing lesions was reduced by 79% (0.19 vs 0.91, P = .03), and the mean number of new or enlarged T2-weighted lesions was reduced by 90% (0.88 vs 8.52, P = .008). Natalizumab therapy significantly improved the relapse rate and accumulation of brain lesions in patients of African descent with relapsing MS.

CD49d blockade by natalizumab therapy in patients with multiple sclerosis increases immature B-lymphocytes

CD49d blockade by natalizumab therapy in patients with multiple sclerosis increases immature B-lymphocytes

The MS nurse's role in managing natalizumab therapy in patients with relapsing-remitting MS

In this article, an overview of current pharmacological therapies used in the treatment of relapsing-remitting multiple sclerosis (MS) will be provided. MS is the most common neurological disease affecting young adults in the Western world. While there is no cure, recent advancements in drug therapy may alter the long-term outcome of this disease, offering more hope to individuals living with MS. This article will focus on natalizumab (Tysabri), a monoclonal antibody (mAb) that significantly reduces relapses and disease progression in relapsing-remitting MS. However, it has been associated with increased risk of a potentially fatal brain infection, progressive multifocal leukoencephalopathy (PML). The MS nurse's role in educating, administering and monitoring patients on this drug will be considered. In the future, mAb therapy will alter the way in which MS is treated, and therefore the skills and knowledge of the MS nurse will have to continually evolve in order to care for patients on this therapy and administer these drugs safely.

Observations during an elective interruption of natalizumab treatment: a post-marketing study

In this prospective post-marketing study, 21 patients with multiple sclerosis treated with natalizumab for 24 consecutive months elected a trial of treatment interruption (90–180 days). During a mean duration of treatment interruption of 111.5 days 4 patients (19.0%) experienced a relapse and 9 out of 19 (47.4%) had MRI activity. Number of contrast-enhancing lesions at baseline was lower than during treatment interruption, but the difference was not significant. These findings suggest that disease activity may return after the last infusion of natalizumab. Patients should have regular MRI assessment during treatment interruption to rapidly identify any return of disease activity. The aim of this study was to determine the optimal duration for temporary interruption of natalizumab therapy in patients who have received continuous therapy with natalizumab for 24 months.

Natalizumab update

The pharmacology, pharmacokinetics, indications, clinical efficacy, adverse effects, drug interactions, and dosage and administration of natalizumab are reviewed. Natalizumab, the first commercially available selective adhesion-molecule inhibitor, is approved as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis (MS). Natalizumab exerts its immunologic effects by targeting the alpha4 integrin receptor, the site responsible for the migration of leukocytes from the blood into inflamed tissues. Because of the increased risk of progressive multifocal leukoencephalopathy (PML), natalizumab is generally recommended for patients who have had an inadequate response to or are intolerant of alternative MS therapies. Data evaluating the efficacy and safety of natalizumab for the treatment of MS are available from published Phase II and III trials. The most common adverse effects reported include headache, fatigue, urinary-tract infection, depression, arthralgia, and lower respiratory-tract infection. The recommended dosage of natalizumab for the treatment of relapsing forms of MS is 300 mg administered by i.v. infusion over one hour once every four weeks. Natalizumab is available only through a risk-minimization program run by the manufacturer. Natalizumab offers an effective treatment option for patients with MS who have had an inadequate response to or are intolerant of alternative MS therapies. Because of its potential to increase the risk of PML, the risks and benefits should be carefully weighed before initiating natalizumab therapy in patients with MS. Natalizumab should not be used to treat Crohn's disease or any other unapproved indication until more postmarketing safety data are available.