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1.
Mult Scler Relat Disord ; 57: 103345, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1851824

ABSTRACT

COVID-19 pandemic represented a challenge in the management of treatments for Multiple Sclerosis (MS), such as Natalizumab (NTZ). NTZ interferes with the homing of lymphocytes into the central nervous system, reducing immune surveillance against opportunistic infection. Although NTZ efficacy starts to decline 8 weeks after the last infusion, increasing the risk of disease reactivation, evidence is lacking on the safety of reinfusion during active SARS-CoV-2 infection. We report clinical outcomes of 18 pwMS receiving NTZ retreatment during confirmed SARS-CoV-2 infection. No worsening of infection or recovery delay was observed. Our data supports the safety of NTZ redosing in these circumstances.


Subject(s)
COVID-19 , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Immunologic Factors/adverse effects , Multiple Sclerosis/drug therapy , Multiple Sclerosis/epidemiology , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Natalizumab/adverse effects , Pandemics , SARS-CoV-2
3.
Lancet Infect Dis ; 22(5): 611-621, 2022 05.
Article in English | MEDLINE | ID: covidwho-1735123

ABSTRACT

BACKGROUND: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040. FINDINGS: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed. INTERPRETATION: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. FUNDING: Merck & Co, National Cancer Institute, OncoImmune.


Subject(s)
COVID-19 , Adolescent , Adult , COVID-19/drug therapy , Double-Blind Method , Humans , Immunologic Factors/adverse effects , Oxygen , SARS-CoV-2 , Treatment Outcome
4.
Expert Opin Drug Saf ; 21(1): 1-8, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1735444

ABSTRACT

INTRODUCTION: Ustekinumab is a human IgG1 kappa monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23 and blocks the binding of these cytokines to the IL-12Rß1 chain of their receptors. Ustekinumab is approved for treating moderate-to-severe ulcerative colitis (UC). AREAS COVERED: We reviewed the mechanism of action, pharmacokinetics, efficacy, and safety of ustekinumab. Future challenges for optimizing UC treatment with ustekinumab are discussed. EXPERT OPINION: Ustekinumab has favorable clinical efficacy and safety profiles for moderately-to-severely active UC. Ustekinumab is the first biologic for targeting IL-12/IL-23 pathways. Therefore, ustekinumab can be a therapeutic option following the failure of other biologics, including anti-tumor necrosis factor-α antagonists and anti-α4ß7 integrin antagonists. However, the positioning of ustekinumab in the therapeutic strategy for UC remains unclear. The efficacy of combinations of ustekinumab and immunomodulators over ustekinumab monotherapy has not been supported in studies. Ustekinumab is a human immunoglobulin G monoclonal antibody with low immunogenicity. Therefore, ustekinumab monotherapy, which should be safe, could be sufficient for treating UC. Further studies are required to understand the efficacy and safety of ustekinumab in patients with UC, particularly in special situations, and to optimize UC treatment with ustekinumab.


Subject(s)
Colitis, Ulcerative/drug therapy , Immunologic Factors/administration & dosage , Ustekinumab/administration & dosage , Animals , Colitis, Ulcerative/immunology , Colitis, Ulcerative/physiopathology , Humans , Immunologic Factors/adverse effects , Interleukin-12/immunology , Interleukin-23/immunology , Severity of Illness Index , Ustekinumab/adverse effects
5.
J Pediatr Gastroenterol Nutr ; 70(6): 727-733, 2020 06.
Article in English | MEDLINE | ID: covidwho-1722710

ABSTRACT

INTRODUCTION: With the current coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised about the risk to children with inflammatory bowel diseases (IBD). We aimed to collate global experience and provide provisional guidance for managing paediatric IBD (PIBD) in the era of COVID-19. METHODS: An electronic reporting system of children with IBD infected with SARS-CoV-2 has been circulated among 102 PIBD centres affiliated with the Porto and Interest-group of ESPGHAN. A survey has been completed by major PIBD centres in China and South-Korea to explore management during the pandemic. A third survey collected current practice of PIBD treatment. Finally, guidance points for practice have been formulated and voted upon by 37 PIBD authors and Porto group members. RESULTS: Eight PIBD children had COVID-19 globally, all with mild infection without needing hospitalization despite treatment with immunomodulators and/or biologics. No cases have been reported in China and South Korea but biologic treatment has been delayed in 79 children, of whom 17 (22%) had exacerbation of their IBD. Among the Porto group members, face-to-face appointments were often replaced by remote consultations but almost all did not change current IBD treatment. Ten guidance points for clinicians caring for PIBD patients in epidemic areas have been endorsed with consensus rate of 92% to 100%. CONCLUSIONS: Preliminary data for PIBD patients during COVID-19 outbreak are reassuring. Standard IBD treatments including biologics should continue at present through the pandemic, especially in children who generally have more severe IBD course on one hand, and milder SARS-CoV-2 infection on the other.


Subject(s)
Coronavirus Infections/therapy , Inflammatory Bowel Diseases/therapy , Pneumonia, Viral/therapy , Adolescent , Adult , Betacoronavirus , COVID-19 , Child , Consensus , Coronavirus Infections/chemically induced , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Health Care Surveys , Humans , Immunologic Factors/adverse effects , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/epidemiology , Pandemics , Pneumonia, Viral/chemically induced , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Severity of Illness Index
6.
Brain Behav Immun ; 87: 34-39, 2020 07.
Article in English | MEDLINE | ID: covidwho-1719335

ABSTRACT

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.


Subject(s)
Coronavirus Infections/psychology , Cytokine Release Syndrome/psychology , Mental Disorders/psychology , Nervous System Diseases/psychology , Pneumonia, Viral/psychology , Acute Disease , Anxiety/etiology , Anxiety/immunology , Anxiety/psychology , Bacterial Translocation , Betacoronavirus , COVID-19 , Chronic Disease , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Demyelinating Diseases/etiology , Demyelinating Diseases/immunology , Demyelinating Diseases/physiopathology , Demyelinating Diseases/psychology , Depression/etiology , Depression/immunology , Depression/psychology , Humans , Immunologic Factors/adverse effects , Mental Disorders/etiology , Mental Disorders/immunology , Mental Health , Nervous System Diseases/etiology , Nervous System Diseases/immunology , Nervous System Diseases/physiopathology , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/physiopathology , Neurodegenerative Diseases/psychology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy , Psychoneuroimmunology , Psychotic Disorders/etiology , Psychotic Disorders/immunology , Psychotic Disorders/psychology , Public Health , SARS-CoV-2 , Stress Disorders, Post-Traumatic/etiology , Stress Disorders, Post-Traumatic/immunology , Stress Disorders, Post-Traumatic/psychology
9.
Lancet Respir Med ; 9(5): 522-532, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537199

ABSTRACT

BACKGROUND: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. METHODS: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. FINDINGS: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference -1·7 [-9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [-6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI -7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. INTERPRETATION: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. FUNDING: Sanofi and Regeneron Pharmaceuticals.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Cytokine Release Syndrome , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Critical Care/methods , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Dose-Response Relationship, Drug , Drug Monitoring/methods , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , International Cooperation , Male , Middle Aged , Mortality , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Severity of Illness Index , Treatment Outcome
10.
Lancet Respir Med ; 9(5): 511-521, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537197

ABSTRACT

BACKGROUND: Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. METHODS: COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). FINDINGS: 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. INTERPRETATION: Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. FUNDING: Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Cytokine Release Syndrome , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Critical Care/methods , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Drug Monitoring/methods , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , India , Male , Middle Aged , Mortality , Respiration, Artificial/methods , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Severity of Illness Index , Treatment Outcome
11.
Int J Immunopathol Pharmacol ; 35: 20587384211059677, 2021.
Article in English | MEDLINE | ID: covidwho-1533223

ABSTRACT

Oral booster-single strain probiotic bifidobacteria could be a potential strategy for SARS-CoV-2. This study aims to evaluate the role of oral probiotic Bifidobacterium on moderate/severe SARS-CoV-2 inpatients. In this single-center study, we analyzed data of 44 moderate/severe inpatients with diagnosed COVID-19 in Istanbul Maltepe University Medical Faculty Hospital, 2020 from 1 November 2020 to 15 December 2020. Clinical and medication features were compared and analyzed between patients with or without probiotic. In result, 19 of the 44 patients (43.18%) who were administrated with oral booster-single strain probiotic were discharged with the median inpatient day of 7.6 days which were significantly shorter than those of patients without probiotic. There were significant differences in inpatient days, radiological improvement at day 6 and week 3, and reduction in interleukin-6 levels in those receiving oral probiotic therapy. Although the mortality rate was 5% in the probiotic group, it was 25% in the non-probiotic group. Booster-single strain probiotic bifidobacteria could be an effective treatment strategy for moderate/severe SARS-CoV-2 inpatients to reduce the mortality and length of stay in hospital.


Subject(s)
Bifidobacterium , COVID-19 , Interleukin-6/blood , Probiotics , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , Female , Hospitalization/statistics & numerical data , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Length of Stay/statistics & numerical data , Male , Middle Aged , Mortality , Probiotics/administration & dosage , Probiotics/adverse effects , Retrospective Studies , SARS-CoV-2/drug effects , Severity of Illness Index , Treatment Outcome , Turkey/epidemiology
12.
Mult Scler Relat Disord ; 57: 103364, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1487906

ABSTRACT

BACKGROUND: Patients with multiple sclerosis (MS) who are treated with monoclonal antibodies frequently report an increase of MS-related symptoms prior to the next dose known as the wearing-off phenomenon. The objective of this study was to assess the prevalence and predicting factors of the wearing-off phenomenon in patients with MS using ocrelizumab. METHODS: This was a prospective cohort study in patients with MS receiving ocrelizumab ≥1 year. Most participants received B-cell guided personalized extended interval dosing to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic (cut-off ≥ 10 cells/µL). Participants completed questionnaires during ocrelizumab infusion and 2 weeks thereafter. Demographics, clinical and radiological characteristics, CD19 B-cell counts, and serum neurofilament light (sNfL) levels were collected. Data were analyzed using logistic regression analyses. RESULTS: Seventy-one (61%) out of 117 participants reported the wearing-off phenomenon during ocrelizumab treatment. The most frequently reported symptoms were fatigue, cognitive disability and sensory symptoms. Wearing-off symptoms started < 1 week (11%), 1-4 weeks (49%) or more than 4 weeks (37%) before ocrelizumab infusion. Fifty participants (43%) reported a current wearing-off phenomenon at the first questionnaire. Higher body mass index (threshold BMI ≥ 25) increased the odds of reporting a current wearing-off phenomenon (OR 2.70, 95% CI 1.26 to 5.80, p = .011). Infusion interval, EDSS score, MRI disease activity, clinical relapses, CD19 B-cell counts, and sNfL levels were no predictors. Disappearance of the wearing-off phenomenon occurred in the first week after ocrelizumab infusion in most participants. Participants with a current wearing-off phenomenon significantly improved in self-reported physical and psychological functioning after ocrelizumab infusion. Reporting the wearing-off phenomenon did not influence treatment satisfaction. Forty of 109 participants (37%) reported post-infusion symptoms, such as fatigue, flu-like symptoms or walking difficulties. These post-infusion symptoms started directly or in the first week after ocrelizumab infusion and disappeared within 2 weeks. CONCLUSIONS: The wearing-off phenomenon is reported by more than half of patients with MS using ocrelizumab. Only BMI was identified as a predicting factor. The wearing-off phenomenon was not elicited by extending infusion intervals or higher B-cell counts. The wearing-off phenomenon of ocrelizumab therefore does not seem to reflect suboptimal control of MS disease activity.


Subject(s)
COVID-19 , Multiple Sclerosis , Antibodies, Monoclonal, Humanized , Humans , Immunologic Factors/adverse effects , Multiple Sclerosis/drug therapy , Pandemics , Prospective Studies , SARS-CoV-2
13.
Hum Vaccin Immunother ; 17(11): 4345-4362, 2021 Nov 02.
Article in English | MEDLINE | ID: covidwho-1475712

ABSTRACT

Traditionally, the management of active relapsing remitting MS was based on the, so-called, maintenance therapy, which is characterized by continuous treatment with particular disease modifying therapy (DMT), and a return of disease activity when the drug is discontinued. Another approach is characterized by a short treatment course of a DMT, which is hypothesized to act as an immune reconstitution therapy (IRT), with the potential to protect against relapses for years after a short course of treatment. Introduction of monoclonal antibodies in the treatment of MS has revolutionized MS treatment in the last decade. However, given the increasingly complex landscape of DMTs approved for MS, people with MS and neurologists are constantly faced with the question which DMT is the most appropriate for the given patient, a question we still do not have an answer to. In this product review, we will discuss the first DMT that acts as IRT, an anti-CD52 monoclonal antibody alemtuzumab and an anti CD20 monoclonal antibody, ocrelizumab that has the potential to act as an IRT, but is administered continuously. Special emphasis will be given on safety in the context of COVID-19 pandemics and vaccination strategies.


Subject(s)
COVID-19 , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Alemtuzumab/adverse effects , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Humans , Immunologic Factors/adverse effects , Multiple Sclerosis/drug therapy , Multiple Sclerosis, Relapsing-Remitting/drug therapy , SARS-CoV-2
15.
JAMA Neurol ; 78(12): 1510-1514, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1432341

ABSTRACT

Importance: B-cell-depleting therapies may affect the development of a protective immune response following vaccination. Understanding the ability to develop vaccine-specific immunity to COVID-19 in patients with multiple sclerosis (MS) treated with B-cell-depleting therapy is of importance for clinical decisions. Objective: To assess SARS-CoV-2 vaccine-specific humoral and cellular responses in patients treated with ocrelizumab compared with healthy controls. Design, Setting, and Participants: This single-center study performed at Hadassah Medical Center in Jerusalem, Israel, included patients with MS treated with ocrelizumab, healthy controls, and untreated patients with MS. Vaccination occurred between December 2020 and April 2021. Participants donated blood 2 to 4 and 2 to 8 weeks after the second vaccine dose for antibody and T-cell assessments, respectively. Exposures: All participants received 2 doses of BNT162b2 vaccine (Pfizer/BioNTech) and completed the study. Main Outcomes and Measures: Proportion of patients treated with ocrelizumab with SARS-CoV-2-specific serology and/or T-cell responses following vaccination. All participants underwent SARS-CoV-2 antibody testing; 29 patients treated with ocrelizumab and 15 healthy controls had evaluation of SARS-CoV-2-specific T-cell responses. Results: Of 112 participants, 49 (43.8%) had MS and were treated with ocrelizumab (33 [67.3%] female; mean [SD] age, 47.9 [13.3] years), 23 (20.5%) had MS and were not treated with disease-modifying therapies (18 [78.3%] female; mean [SD] age, 49 [13.4] years), and 40 (35.7%) were healthy controls (25 [62.5%] female; mean [SD] age, 45.3 [16] years). Twenty-six of 29 patients (89.7%) treated with ocrelizumab and 15 of 15 healthy controls (100%) had SARS-CoV-2-specific T cells following vaccination at similar levels (mean [SD], 15.4 [7.6] and 14.3 [6.3] spot-forming cells, respectively). Mean antibody titers and positive serology rate were lower in the group of patients treated with ocrelizumab (mean [SD] antibody titers and positive serology rate, 26.2 [49.2] and 376.5 [907.6] AU/mL; 10 of 40 [25%] and 20 of 49 [40.8%] for S1/S2 and receptor-binding domain, respectively) compared with healthy controls (mean [SD] antibody titers and positive serology rate, 283 [100] and 12 712 [9114] AU/mL; 100% S1/S2 and receptor-binding domain) and untreated patients (mean [SD] antibody titers and positive serology rate, 288.3 [113.8] and 10 877 [9476] AU/mL; 100% S1/S2 and receptor-binding domain), with positive association to time from ocrelizumab infusion (S1/S2: r = 0.7, P < .001; receptor-binding domain: r = 0.4, P = .04). Conclusion and Relevance: In this study, patients with MS who were treated with ocrelizumab generated comparable SARS-CoV-2-specific T-cell responses with healthy controls and had lower antibody response following vaccination. Given the potential role of T cells in protection from severe disease, this is reassuring and will help physicians develop consensus guidelines regarding MS treatment in the era of the COVID-19 pandemic.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , COVID-19 Vaccines/immunology , Immunity, Humoral/immunology , Immunologic Factors/adverse effects , Multiple Sclerosis/immunology , T-Lymphocytes/immunology , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Immunologic Factors/therapeutic use , Lymphocyte Count , Male , Middle Aged , Multiple Sclerosis/drug therapy
16.
Curr Opin Allergy Clin Immunol ; 21(6): 597-601, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1429314

ABSTRACT

PURPOSE OF REVIEW: As of June 2021, coronavirus disease 2019 (COVID-19) exceeded 180 million reported cases and was responsible for almost 4 million deaths globally. Asthma affects approximately 262 million people worldwide and is an important cause of morbidity and mortality. Presently, it appears asthma is neither associated with an increased risk of contracting COVID-19 nor with a risk of severe COVID-19 or COVID-19 related death. Regarding the severe asthma patients on biologics, questions remain. The purpose of this review is to discuss the evidence regarding the relationship between asthma, biologics and COVID-19. RECENT FINDINGS: The available evidence does not suggest that severe asthmatics on treatment with biologics have a higher risk of severe acute respiratory syndrome coronavirus 2 infection compared to the general population. It does not appear that they have a higher risk of severe disease or COVID-19 related death either. SUMMARY: This review suggests that treatment with biologics for severe asthma is safe and should be maintained during the COVID-19 pandemic. However, more studies are needed to address this question and the role of biological therapy on different asthma phenotypes.


Subject(s)
Asthma/drug therapy , Biological Products/adverse effects , COVID-19/immunology , Immunologic Factors/adverse effects , SARS-CoV-2/immunology , Asthma/diagnosis , Asthma/immunology , Biological Products/administration & dosage , COVID-19/diagnosis , COVID-19/mortality , Humans , Immunologic Factors/administration & dosage , Risk Assessment/statistics & numerical data , Risk Factors , Severity of Illness Index
18.
J Neurol Sci ; 429: 117622, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1364275

ABSTRACT

Natalizumab effectively prevents disease activity in relapsing-remitting multiple sclerosis, but many treated patients report subjective wearing-off symptoms at the end of the 4-week interval between infusions. Extended interval dosing (EID) is a promising strategy to mitigate the risk of natalizumab-associated progressive multifocal leukoencephalopathy, but it is unknown whether EID affects wearing-off symptoms. In this observational study, we evaluated if prevalence or intensity of wearing-off symptoms changed when natalizumab dosing intervals were extended from 4 to 6 weeks in 30 treated patients during the outbreak of COVID-19 in Norway. New or increased wearing-off symptoms during EID were reported by 50%. Symptom increase was more frequent among patients with pre-existing wearing-off symptoms during standard dosing compared to patients without such pre-existing symptoms [p = 0.0005]. Our observations support the need to study the effect of EID on wearing-off symptoms in randomized controlled trials.


Subject(s)
COVID-19 , Leukoencephalopathy, Progressive Multifocal , Multiple Sclerosis, Relapsing-Remitting , Humans , Immunologic Factors/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Natalizumab/adverse effects , Pandemics , SARS-CoV-2
19.
Neurol Neuroimmunol Neuroinflamm ; 8(5)2021 09.
Article in English | MEDLINE | ID: covidwho-1339394

ABSTRACT

BACKGROUND AND OBJECTIVES: We sought to define the risk of severe coronavirus disease 2019 (COVID-19) infection requiring hospitalization in patients with CNS demyelinating diseases such as MS and the factors that increase the risk for severe infection to guide decisions regarding patient care during the COVID-19 pandemic. METHODS: A pilot cohort of 91 patients with confirmed or suspected COVID-19 infection from the Northeastern United States was analyzed to characterize patient risk factors and factors associated with an increased severity of COVID-19 infection. Univariate analysis of variance was performed using the Mann-Whitney U test or analysis of variance for continuous variables and the χ2 or Fisher exact test for nominal variables. Univariate and stepwise multivariate logistic regression identified clinical characteristics or symptoms associated with hospitalization. RESULTS: Our cohort demonstrated a 27.5% hospitalization rate and a 4.4% case fatality rate. Performance on Timed 25-Foot Walk before COVID-19 infection, age, number of comorbidities, and presenting symptoms of nausea/vomiting and neurologic symptoms (e.g., paresthesia or weakness) were independent risk factors for hospitalization, whereas headache predicted a milder course without hospitalization. An absolute lymphocyte count was lower in hospitalized patients during COVID-19 infection. Use of disease-modifying therapy did not increase the risk of hospitalization but was associated with an increased need for respiratory support. DISCUSSION: The case fatality and hospitalization rates in our cohort were similar to those found in MS and general population COVID-19 cohorts within the region. Hospitalization was associated with increased disability, age, and comorbidities but not disease-modifying therapy use.


Subject(s)
COVID-19 , Demyelinating Autoimmune Diseases, CNS , Hospitalization/statistics & numerical data , Immunologic Factors/therapeutic use , Registries/statistics & numerical data , Respiration, Artificial/statistics & numerical data , Adult , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/therapy , Cohort Studies , Comorbidity , Demyelinating Autoimmune Diseases, CNS/drug therapy , Demyelinating Autoimmune Diseases, CNS/epidemiology , Female , Humans , Immunologic Factors/adverse effects , Male , Middle Aged , Mortality , New England/epidemiology , Pilot Projects , Risk Factors , Severity of Illness Index
20.
Immunopharmacol Immunotoxicol ; 43(5): 507-518, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1319088

ABSTRACT

BACKGROUND: Rituximab is a FDA-approved monoclonal antibody for adults with moderate to severe potentially life-threatening pemphigus vulgaris. Recent studies have focused on assessments of efficacy and safety of low-dose rituximab (<2 gram in each cycle). METHOD: Databases were searched from 2010 to 2020 (last update: 1 June 2020). RESULT: Nine studies were entered; including180 cases (92: women, 88: men, age range: 9-83 years). The dosages of each Rituximab cycle varied between ultra-low-dose (≤500 mg for a cycle, either multiple infusions or a single infusion), low-dose (2 × 375 mg/m2 or 2 × 500 mg) and modified-dose (3 × 375 mg/m2 or 3 × 500 mg). The efficacy and safety of Rituximab in the studies are known by the recovery time, relapse time, and side events. According to the studies, 2 × 500 can lead to complete remission in a broad range, from 35 to 82%. These differences might be explained by different end-points and variable cumulative corticosteroid dosage after RTX administration. Although the studies showed that low dose RTX is efficient, there are some controversies regarding the choosing low-dose for severe patients. CONCLUSION: Considering the effectiveness of low-dose, intermediate dose, and ultra-low-dose protocols of Rituximab in inducing remission in pemphigus disease and considering factors such as cost of therapy, and the need to induce a minimum of immunosuppression for a minimum duration in the COVID-19 pandemic, suggested to use low-dose Rituximab protocol (2 infusions of 500 mg Rituximab: interval of 2 weeks) to induce the remission in mild-to-moderate pemphigus patients.


Subject(s)
COVID-19/immunology , Immunocompromised Host , Immunologic Factors/administration & dosage , Pemphigus/drug therapy , Rituximab/administration & dosage , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/virology , Child , Female , Humans , Immunologic Factors/adverse effects , Male , Middle Aged , Pemphigus/diagnosis , Pemphigus/immunology , Remission Induction , Risk Factors , Rituximab/adverse effects , SARS-CoV-2/immunology , Treatment Outcome , Young Adult
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