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Inflammatory Bowel Disease
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Natalizumab: This is a humanized IgG4 monoclonal antibody approved for treatment of CD. Data regarding safety in pregnancy is limited, but the Natalizumab Pregnancy Exposure Registry does not demonstrate an association with adverse pregnancy outcomes [95]. As with all biologics, there is a theoretical concern with the effect of the drug on the neonatal immune system and response to vaccines. A neonatology or pediatric consultation should be obtained to discuss the vaccination plan. Data is limited but natalizumab appears to be compatible with breastfeeding [86].
Progressive multifocal leukoencephalopathy
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Eric M. L. Williamson, Joseph R. Berger
The relative risk of some of the aforementioned disorders versus that which comes from the immune-suppressing agents used to treat them can be difficult to sort out. With respect to risk clearly attributable to biological agents rather than underlying illness, natalizumab has been associated with more PML cases than any other therapy. The monoclonal antibody natalizumab is a combined α4β1 and α4β7 integrin inhibitor that has proven substantial therapeutic efficacy in multiple sclerosis and inflammatory bowel disorders. The α4β1 integrin inhibition prevents the entry of inflammatory cells into the CNS and it is this activity that is believed to be responsible for the increased risk of PML seen with this agent by means of decreased immune surveillance. As of 2017, nearly 800 confirmed cases of natalizumab-associated PML have been recognized [178]. Further estimates of incidence by treatment duration and increased risk when the therapy is used after other immunosuppressive therapy have been frequently cited. Of note, the incidence in some cohorts of patients treated with natalizumab is higher than the incidence of PML in any other patient population, including patients with AIDS [179,180].
Organ-specific autoimmune diseases
Published in Gabriel Virella, Medical Immunology, 2019
Gabriel Virella, George C. Tsokos
Recently, several new pharmacological agents have been found to be useful in the treatment of MS. Teriflunomide, a pyrimidine synthesis inhibitor, has been found in phase III trials to be equivalent to IFNβ. Dimethyl fumarate has a comparable clinical effect that correlates inversely with lymphocyte counts and has been approved by the U.S. Food and Drug Administration (FDA). Fingolimod, a sphingosine-1-phosphate-1 receptor antagonist, inhibits the egression of lymphocytes from lymph nodes to the bloodstream. It has been shown to have a good clinical effect and has also been approved by the FDA. Natalizumab is a humanized monoclonal antibody that recognizes the adhesion molecule α4 integrin and blocks its interaction with the vascular cell adhesion molecule 1. Natalizumab has great clinical efficacy. A downside is there is a substantial risk for the development of progressive multifocal leukoencephalopathy caused by activation of the JC virus. Other monoclonal antibodies shown to be clinically valuable and used to treat MS are the B cell–depleting antibodies (rituximab and ocrelizumab).
Use of medications during pregnancy and breastfeeding for Crohn’s disease and ulcerative colitis
Published in Expert Opinion on Drug Safety, 2021
Robyn Laube, Sudarshan Paramsothy, Rupert W Leong
Like IgG1 antibodies, IgG4 undergoes active transport across the placenta at a rate exponentially increasing in the second half of gestation [169,218]. Animal studies have reported hematologic abnormalities in infants exposed to high dose natalizumab in utero, including splenomegaly and thymic atrophy [219]. Most human data originates from women with multiple sclerosis, which has also reported self-limiting neonatal anemia and thrombocytopenia after natalizumab exposure during the third trimester [220,221]. Although a large observational study of 376 women taking natalizumab during pregnancy reported an increased rate of major congenital abnormalities (5.05% vs. 2.67% in the control database), the absence of a pattern of defects argued against a drug effect [222]. Other human studies have not reported an increased risk of congenital malformations, premature birth, LBW or infant infections [193,223]. Therefore, natalizumab is thought to be safe to continue during pregnancy if clinically indicated. Administering the final dose 4–6 weeks prior to the expected date of delivery may be prudent to reduce infant drug levels and transient hematologic abnormalities [38].
How not to discover a drug - integrins
Published in Expert Opinion on Drug Discovery, 2021
While a promising therapy for both MS and Crohn’s there was a serious safety concern with natalizumab. It was associated with reactivation of JC virus infection leading to Progressive Multifocal Leukoencephalopathy (PML) [140] due to lysis of neurons and permanent destruction of the myelin sheath. In patients that are JC virus positive the incidence of PML is 1% with a 25% mortality rate and 30% of survivors will have severe neurological complications [141]. This was to be a major blow for natalizumab. While it was an effective disease-modifying therapy its safety profile was of concern. Although it was not withdrawn from the market it is only prescribed under a risk evaluation and mitigation strategy (REMS). With the advent of newer disease modifying therapies such as fingolimod and dimethyl fumarate it is no longer a frontline treatment. PML is not unique to natalizumab with a number of other immune suppressants associated with PML however, the incidence is much higher with natalizumab.
Matching-adjusted indirect treatment comparison of siponimod and other disease modifying treatments in secondary progressive multiple sclerosis
Published in Current Medical Research and Opinion, 2020
Imtiaz A. Samjoo, Evelyn Worthington, Anja Haltner, Chris Cameron, Richard Nicholas, Nicolas Rouyrre, Frank Dahlke, Nicholas Adlard
Scenario analysis. Natalizumab was evaluated in ASCEND, a randomized, double-blind, placebo-controlled, parallel group trial for the treatment of patients with SPMS. Natalizumab was administered intravenously over 96 weeks. The overall study designs of EXPAND and ASCEND were similar despite differences in study duration and route of treatment administration. Study eligibility criteria were similar between both studies; however, age and recently documented progression differed. The key difference was in the assessment of disability progression. In ASCEND, time to CDP-6 was a composite outcome; it was not possible to account for this composite using IPD from EXPAND. Therefore, in order to draw an indirect comparison between EXPAND and ASCEND for CDP-6, the proportion of patients who experienced CDP-6 by or at 96 weeks in each trial was assessed. The proportion of patients who experienced CDP-6 at 96 weeks was determined from the EXPAND IPD. EXPAND patients censored (i.e. missing or lost to follow-up) at or before 96 weeks were imputed using the conservative assumption that all censored patients had experienced CDP-6. Finally, time to CDP-3 was not reported in ASCEND. Patient characteristics between the two trials were broadly similar but differences were noted in the proportion of patients with an expanded disability status scale (EDSS) score greater than 6.0, the duration of SPMS, the proportion of patients with Gd + lesions on T1-weighted images, and the timed 25-foot walk (T25FW) test.