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Neurodegener Dis Manag ; 11(5): 387-409, 2021 10.
Article in English | MEDLINE | ID: covidwho-1394696


Teriflunomide, a once daily, oral disease-modifying therapy, has demonstrated consistent efficacy, safety and tolerability in patients with relapsing forms of multiple sclerosis (MS) and with a first clinical episode suggestive of MS treated up to 12 years. This review is an update to a previous version that examined data from the teriflunomide core clinical development program and extension studies. Data have since become available from active comparator trials with other disease-modifying therapies, treatment-related changes in brain volume (analyzed using structural image evaluation using normalization of atrophy) and real-world evidence including patient-reported outcomes. Initial data on the potential antiviral effects of teriflunomide in patients with MS, including case reports of patients infected with the 2019 novel coronavirus (SARS-CoV-2), are also presented.

Lay abstract Teriflunomide, a treatment taken orally once a day, has shown consistent effectiveness and safety in patients with relapsing forms of multiple sclerosis (MS). This review is an update to a previous version that summarized the trials from when teriflunomide was in clinical development for MS. Some of the newer studies described here compared teriflunomide with other MS treatments. Studies have shown positive effects of teriflunomide on brain volume; teriflunomide may also be effective against some viruses. People taking teriflunomide generally report stable cognition and quality of life, with no worsening of fatigue or disability. In the EU, teriflunomide has been recently approved for use in pediatric patients 10 years of age and above.

Crotonates/therapeutic use , Hydroxybutyrates/therapeutic use , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Nitriles/therapeutic use , Toluidines/therapeutic use , Brain/diagnostic imaging , Brain/pathology , Humans , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Organ Size
Eur J Pharmacol ; 906: 174233, 2021 Sep 05.
Article in English | MEDLINE | ID: covidwho-1260717


Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis), leflunomide was found to target pathways enriched in COVID-19. In vitro, both leflunomide (EC50 41.49 ± 8.8 µmol/L) and teriflunomide (EC50 26 µmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.

Antiviral Agents/pharmacology , COVID-19/drug therapy , Crotonates/pharmacology , Enzyme Inhibitors/pharmacology , Hydroxybutyrates/pharmacology , Leflunomide/pharmacology , Nitriles/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Toluidines/pharmacology , Animals , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Crotonates/adverse effects , Crotonates/therapeutic use , Drug Repositioning , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic use , Humans , Hydroxybutyrates/adverse effects , Hydroxybutyrates/therapeutic use , Leflunomide/adverse effects , Leflunomide/therapeutic use , Nitriles/adverse effects , Nitriles/therapeutic use , Toluidines/adverse effects , Toluidines/therapeutic use
CNS Drugs ; 35(3): 317-330, 2021 03.
Article in English | MEDLINE | ID: covidwho-1141535


BACKGROUND: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS). OBJECTIVE: The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies. METHODS: The IBM® Explorys electronic health record database of > 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19. COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity). As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen's Global Safety Database. RESULTS: 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p < 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p < 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine. CONCLUSIONS: Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach.

COVID-19/epidemiology , Hospitalization/statistics & numerical data , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis/drug therapy , Adolescent , Adult , African Americans/statistics & numerical data , Aged , Aged, 80 and over , Alemtuzumab/therapeutic use , Azathioprine/therapeutic use , COVID-19/mortality , Cladribine/therapeutic use , Comorbidity , Crotonates/therapeutic use , Cyclophosphamide/therapeutic use , Cyclosporine/therapeutic use , Databases, Factual , Dimethyl Fumarate/therapeutic use , Female , Fingolimod Hydrochloride/therapeutic use , Humans , Hydroxybutyrates , Immunologic Factors/therapeutic use , Incidence , Interferon-beta/therapeutic use , Logistic Models , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/epidemiology , Male , Methotrexate/therapeutic use , Middle Aged , Mitoxantrone/therapeutic use , Multiple Sclerosis/epidemiology , Mycophenolic Acid/therapeutic use , Natalizumab/therapeutic use , Nitriles , Obesity/epidemiology , Risk Factors , Rituximab/therapeutic use , SARS-CoV-2 , Toluidines/therapeutic use , United States/epidemiology , Young Adult
J Neurol ; 267(10): 2790-2796, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-506032


The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection. The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS. These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

Coronavirus Infections/complications , Crotonates/therapeutic use , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis/complications , Multiple Sclerosis/drug therapy , Pneumonia, Viral/complications , Toluidines/therapeutic use , Adult , Aged , Betacoronavirus , COVID-19 , Female , Humans , Hydroxybutyrates , Male , Middle Aged , Nitriles , Pandemics , SARS-CoV-2
Mult Scler Relat Disord ; 43: 102195, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-245403


OBJECTIVE: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease. METHODS: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models. RESULTS: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005). CONCLUSIONS: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Coronavirus Infections/immunology , Immunocompromised Host/immunology , Immunologic Factors/therapeutic use , Multiple Sclerosis/drug therapy , Pneumonia, Viral/immunology , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , B-Lymphocytes/immunology , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Cough , Cross-Sectional Studies , Crotonates/therapeutic use , Dimethyl Fumarate/therapeutic use , Disease Susceptibility , Dyspnea , Epidemics , Female , Fever , Fingolimod Hydrochloride/therapeutic use , Glatiramer Acetate/therapeutic use , Hospitalization/statistics & numerical data , Humans , Hydroxybutyrates , Intensive Care Units/statistics & numerical data , Interferons/therapeutic use , Iran/epidemiology , Lung/diagnostic imaging , Lymphocyte Depletion , Male , Multiple Sclerosis/complications , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis, Chronic Progressive/epidemiology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Natalizumab/therapeutic use , Nitriles , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Rituximab/therapeutic use , SARS-CoV-2 , Severity of Illness Index , Toluidines/therapeutic use , Tomography, X-Ray Computed
Mult Scler Relat Disord ; 43: 102174, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-232477


BACKGROUND: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS. OBJECTIVE: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis. OBSERVATIONS: Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm and vascular pathology appears to contribute to the damage in ARDS. IMPLICATIONS: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic.

Betacoronavirus/immunology , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Immunosuppressive Agents/therapeutic use , Lymphopenia/immunology , Multiple Sclerosis/therapy , Pneumonia, Viral/immunology , Alemtuzumab/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Viral/immunology , COVID-19 , Cladribine/therapeutic use , Crotonates/therapeutic use , Deprescriptions , Dimethyl Fumarate/therapeutic use , Fingolimod Hydrochloride/therapeutic use , Glatiramer Acetate/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Humans , Hydroxybutyrates , Immune Evasion/immunology , Immunity, Innate/immunology , Immunologic Factors/therapeutic use , Interferon-beta/therapeutic use , Macrophages/immunology , Monocytes/immunology , Natalizumab/therapeutic use , Nitriles , Pandemics , Respiratory Distress Syndrome/immunology , SARS-CoV-2 , Toluidines/therapeutic use