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BACKGROUND: The humanized monoclonal anti-CD20-antibody ofatumumab is highly effective in treating relapsing multiple sclerosis (MS). OBJECTIVE: This study aimed to investigate the immanent effect of ofatumumab on the peripheral immune system, particularly targeting B and T cells expressing CD20. METHODS: Blood samples of 53 MS patients receiving ofatumumab were collected prior to first application and after one week, two weeks and three months. Multicolor flow cytometry was used to phenotype peripheral blood mononuclear cells, and immunoglobulin (Ig) concentrations were measured by nephelometry. RESULTS: Among CD20+ lymphocytes, 13 % co-expressed CD3 (identifying them as CD3+CD20+ T lymphocytes), with a noticeable shift in the CD4/CD8-ratio towards CD8+ T cells. One week after administering ofatumumab, a significant reduction of CD20+ lymphocytes with complete depletion of CD3+CD20+ T lymphocytes was observed, persisting during the investigation period. During the treatment, IgM levels showed a slight but significant decrease, whereas IgA and IgG levels remained stable. CONCLUSION: Ofatumumab effectively depletes CD20+ lymphocytes already after the first administration. This depletion affects not only B cells, but also a small proportion of T cells (CD3+CD20+), affirming the hypothesis that the anti-inflammatory effects of CD20+ cell depletion might extend to the reduction of CD3+CD20+ T lymphocytes.
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Background: This study examines the humoral and cellular response in multiple sclerosis (MS) patients on anti-CD20 therapy before and after the 1st to 4th BNT162b2 mRNA SARS-CoV-2 vaccination and the relationship with breakthrough infection. Methods: Participants with McDonald 2017 MS that were treated with ocrelizumab were included. The study duration was throughout the COVID-19 pandemic until four months after fourth mRNA SARS-CoV-2 vaccination (BNT162b2). Longitudinal blood samples were analysed for: IgG antibodies of SARS-CoV-2 spike anti-receptor binding domain (anti-RBD), nucleocapsid IgG antibodies (anti-N) and activation induced marker expressing CD4+, CD8+ T-cells and concentration of ocrelizumab and anti-drug antibodies. Incidences of breakthrough infection were confirmed with SARS-CoV-2 PCR tests. Results: The rate of anti-RBD positive participants increased substantially between the third and fourth vaccination from 22.2% to 55.9% (median 54.7 BAU/mL; IQR: 14.5 - 221.2 BAU/mL and 607.7 BAU/mL; IQR: 29.4 - 784.6 BAU/mL, respectively). Within the same period 75% of participants experienced breakthrough infection. The fourth vaccination resulted in an additional increase in seropositive individuals (64.3%) (median 541.8 BAU/mL (IQR: 19.1-1007 BAU/mL). Breakthrough infection did not influence the cellular response without a significant change after the fourth vaccination. During the study period two participants had detectable anti-N, both after the fourth vaccination. No correlation was found between serum concentration of ocrelizumab and the humoral and cellular response. Discussion: Low levels or absence of specific anti-RBD following vaccination, with a significant increase after breakthrough infections and boosted by the fourth vaccination. T-cell reactivity remained sustained and unaffected by breakthrough infections.
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Anticuerpos Antivirales , Vacuna BNT162 , COVID-19 , Inmunidad Celular , Inmunidad Humoral , Esclerosis Múltiple , SARS-CoV-2 , Humanos , Masculino , COVID-19/inmunología , COVID-19/prevención & control , Femenino , SARS-CoV-2/inmunología , Vacuna BNT162/inmunología , Adulto , Persona de Mediana Edad , Estudios Longitudinales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Vacunas contra la COVID-19/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Glicoproteína de la Espiga del Coronavirus/inmunología , Antígenos CD20/inmunología , Vacunación , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Infección IrruptivaRESUMEN
The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine "take" in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients.
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Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Linfoma , Rituximab , SARS-CoV-2 , Humanos , Rituximab/uso terapéutico , COVID-19/inmunología , COVID-19/prevención & control , Femenino , Masculino , Anciano , SARS-CoV-2/inmunología , Persona de Mediana Edad , Vacunas contra la COVID-19/inmunología , Linfoma/inmunología , Linfoma/tratamiento farmacológico , Linfoma/terapia , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Glicoproteína de la Espiga del Coronavirus/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Antígenos CD20/inmunología , Anciano de 80 o más Años , Vacunación , Vacunas de ARNmRESUMEN
PURPOSE OF REVIEW: B-cell depletion therapy, including anti-CD20 and anti-CD19 therapies, is increasingly used for a variety of autoimmune and conditions, including those affecting the central nervous system. However, B-cell depletion therapy use can be complicated by adverse effects associated with administration and immunosuppression. This review aims to summarize the application of anti-CD20 and anti-CD19 therapies for the pediatric neurologist and neuroimmunologist. RECENT FINDINGS: Most existing literature come from clinical trials with adult patients, although more recent studies are now capturing the effects of these therapies in children. The most common side effects include infusion related reactions and increased infection risk from immunosuppression. Several strategies can mitigate infusion related reactions. Increased infections due to persistent hypogammaglobulinemia can benefit from replacement immunoglobulin. B-cell depletion therapies can be safe and effective in pediatric patients. Anticipation and mitigation of common adverse effects through primary prevention strategies, close monitoring, and appropriate symptomatic management can improve safety and tolerability.
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BACKGROUND: Pediatric-onset multiple sclerosis (POMS) cases, defined as multiple sclerosis (MS) with onset before the age of 18, represent between 3 and 5 % of all MS patients. Anti-CD20 drugs mainly rituximab, ocrelizumab, and ofatumumab are being widely used in adult-onset MS. Their use in POMS is also being increasingly considered by experts. OBJECTIVE: to review the latest evidence on safety and efficacy of the use of anti-CD20 therapies in POMS. METHODS: An extensive search was performed in PubMed, Scopus, and Web of Science databases until the end of July 1st, 2024. Two independent reviewers screened the articles, and collected data. 832 studies were screened using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS: 12 studies on rituximab (328 patients) and 6 studies on ocrelizumab (106 patients) were synthesized. Using monoclonal antibodies in POMS patients has a noteworthy effect on reducing relapses and lesions and achieving no evidence of disease activity especially in highly active POMS patients. However, anti-CD20 therapies in MS are associated with potential adverse events (AEs). Additional data is required on the effect of anti-CD20 therapy on disability accrual. CONCLUSION: Although anti-CD20 therapy is associated with some AEs, it can be provided in several circumstances, especially to patients with highly active disease, or ones resistant to platform therapies.
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Epstein-Barr virus meningoencephalitis is a rare central nervous system infection that lacks standardized treatment. Immunocompetent and immunosuppressed individuals with this condition frequently have poor prognostic outcomes, making the need to identify therapeutic interventions high. Here, we report 2 pediatric cases of severe Epstein-Barr virus meningoencephalitis, both unresponsive to immunoglobulin and corticosteroid therapy, who demonstrated rapid clinical recovery following rituximab administration. Prognostic outcomes revealed marked improvements in symptoms, neurologic function, and quality of life. Rituximab may offer therapeutic potential in severe and refractory Epstein-Barr virus meningoencephalitis through the medication's target of Epstein-Barr virus harboring B cells. This report emphasizes the need for timely evaluation and consideration of rituximab therapy in immunocompetent pediatric patients with Epstein-Barr virus meningoencephalitis.
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Mycoplasma pneumoniae, a frequent respiratory pathogen, can cause neurological disease manifestations. We here present a case of M. pneumoniae as cause of meningitis and occurrence of an intracranial abscess as a complication of mastoiditis with septic cerebral venous sinus thrombosis in a patient with multiple sclerosis on anti-CD20 therapy.
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Myasthenia gravis (MG) is an autoimmune disease mediated by B cells and is associated with acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK) antibodies in the postsynaptic membrane at the neuromuscular junction. Anti-CD20 monoclonal antibodies, such as ofatumumab demonstrated promising disease control in MG patients. We presented the rare case of a 34-year-old female with acetylcholine receptor-positive myasthenia gravis (AChR-MG), concomitant with systemic lupus erythematosus (SLE) and metastatic thyroid carcinoma, who was treated with ofatumumab and exhibited improvements during follow-up.
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More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of anti-IL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective.
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Absceso , Autoanticuerpos , Humanos , Femenino , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Adolescente , Absceso/inmunología , Subunidad p40 de la Interleucina-12/inmunología , Recurrencia , Osteomielitis/inmunologíaRESUMEN
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by inflammation and autoimmune responses. This review explores the participation of T cells, particularly certain CD3+CD20+ T cells, in the clinical manifestations of MS and highlights their presence in diagnosed patients. These T cells show aberrant expression of CD20, normally considered a B-cell marker. In this review, relevant journal articles available in PubMed and CINAHL were identified by employing diverse search terms, such as MS, CD3+CD20+ T cells, the incidence and significance of CD3+CD20+ T cells in MS patients, and the impact of rituximab treatment. The search was limited to articles published in the ten-year period from 2014 to 2024. The results of this review suggest that most scholars agree on the presence of CD3+CD20+ T cells in cerebrospinal fluid. Emerging concepts relate to the fundamental role of CD20-expressing T cells in determining the target and efficacy of MS therapeutics and the presence of T cells in the cerebrospinal fluid of MS patients. The results clearly show that CD20+ T cells indicate disease chronicity and high disease activity.
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Antígenos CD20 , Complejo CD3 , Esclerosis Múltiple , Rituximab , Linfocitos T , Humanos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Antígenos CD20/metabolismo , Antígenos CD20/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Complejo CD3/metabolismo , Complejo CD3/inmunología , Rituximab/uso terapéuticoRESUMEN
T cells play critical roles in adipose tissue (AT) inflammation. The role of CD20+T cell in AT dysfunction and their contributing to insulin resistance (IR) and type 2 diabetes progression, is not known. The aim was to characterize CD20+T cells in omental (OAT), subcutaneous (SAT) and peripheral blood (PB) from subjects with obesity (OB, n = 42), by flow cytometry. Eight subjects were evaluated before (T1) and 12 months post (T2) bariatric/metabolic surgery (BMS). PB from subjects without obesity (nOB, n = 12) was also collected. Higher percentage of CD20+T cells was observed in OAT, compared to PB or SAT, in OB-T1. CD20 expression by PB CD4+T cells was inversely correlated with adiposity markers, while follicular-like CD20+T cells were positively correlated with impaired glucose tolerance (increased HbA1c). Notably, among OB-T1, IR establishment was marked by a lower percentage and absolute number of PB CD20+T cells, compared nOB. Obesity was associated with higher percentage of activated CD20+T cells; however, OAT-infiltrated CD20+T cells from OB-T1 with diabetes displayed the lowest activation. CD20+T cells infiltrating OAT from OB-T1 displayed a phenotype towards IFN-γ-producing Th1 and Tc1 cells. After BMS, the percentage of PB CD4+CD20+T cells increased, with reduced Th1 and increased Th17 phenotype. Whereas in OAT the percentage of CD20+T cells with Th1/17 and Tc1/17 phenotypes increased. Interestingly, OAT from OB pre/post BMS maintained higher frequency of effector memory CD20+T cells. In conclusion, CD20+T cells may play a prominent role in obesity-related AT inflammation.
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Tejido Adiposo , Antígenos CD20 , Cirugía Bariátrica , Obesidad , Humanos , Masculino , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/cirugía , Femenino , Persona de Mediana Edad , Antígenos CD20/metabolismo , Adulto , Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Inmunofenotipificación , Linfocitos T/inmunología , Linfocitos T/metabolismo , BiomarcadoresRESUMEN
Background: CD20 is a membrane protein extensively expressed on the surface of B cells at various stages of development and differentiation. Herein, we conducted a bibliometrics analysis of the literature on CD20-targeting antibody therapy in lymphoma. Methods: A total of 6663 articles were downloaded from the web of science core collection (WOSCC) from 1999 to July 23, 2022. Bibliometric.com was used for citation and annual publications analysis. VOSviewer was used to map countries/institutions/authors/journals nodes and links, extract hotspot keywords, and analyze the time trend of keywords. Citespace was employed to recognize the turning points based on the centrality value of countries, define the topic distribution of academics according to the map of dual-map overlay of journals, and characterize the emerging topics or landmark articles in a field based on references citation bursts. Results: All articles were cited 225,032 times, averaging 33.77. The number of articles increased from 1999 to 2002, while the growth rate entered the platform after 2002. The USA was the most publication country, and China was the largest emerging country. Hotspots in this field still focus on the efficacy of rituximab in treating non-Hodgkin's lymphoma and the pathogenesis of lymphoma Application of generation CD-20 antibodies or molecule inhibitors in clinical research and cellular therapy/immunotherapy, such as CAR-T and PDL1/PD1 were the emerging research topics. Conclusion: This study provides essential information and the tendency of the CD20-targeting antibody therapy in lymphoma by using bibliometric and visual methods, which would provide helpful references for clinical experiments and basic scientific research.
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Introduction: B-cell lymphocytes have been demonstrated to play a key role in the pathogenesis underlying membranous nephropathy (MN). The aim of this study was to evaluate the therapeutic efficacy and safety of Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody in individuals with MN. Methods: We retrospectively analyzed data from 59 consecutive patients with primary MN who provided consent to receive Obinutuzumab and were followed for at least 6 months. The primary outcomes were complete (proteinuria <0.3 g/d) or partial (proteinuria <3.5 g/d with ≥ 50% reduction) remission of proteinuria. Results: Twenty patients received Obinutuzumab as initial therapy, and 39 patients were previously treated with at least 1 immunosuppressant (second-line therapy). Fifty patients (84.7%) achieved complete remission (CR) or partial remission (PR) of proteinuria during the median follow-up of 9.4 months. The likelihood of remission was significantly higher when Obinutuzumab was used as initial therapy than as second-line therapy after adjusting for the baseline estimated glomerular filtration rate (eGFR), 24-hour urinary protein levels, and anti-phospholipase A2 receptor (PLA2R) status (adjusted hazard ratio [HR], 4.5; 95% confidence interval [CI]: 2.1-9.5, P < 0.001). Circulating CD19+ B-cell count decreased to <5 cells/µl in all patients within 2 weeks after infusion. Serum anti-PLA2R concentrations decreased to <14 relative units (RU)/ml in 43 of 48 patients with PLA2R-related MN. After Obinutuzumab administration, a significant reduction in 24-hour urine protein and increase in serum albumin were observed. No serious adverse events were observed. Conclusion: Obinutuzumab may represent a promising and well-tolerated therapeutic option for individuals with primary MN. The potential of Obinutuzumab was highlighted as an initial therapy for primary MN.
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Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton's tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.
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Anticuerpos Neutralizantes , Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Linfoma , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Anticuerpos Neutralizantes/uso terapéutico , Persona de Mediana Edad , Femenino , Antivirales/uso terapéutico , SARS-CoV-2/inmunología , Linfoma/tratamiento farmacológico , Linfoma/complicaciones , COVID-19/inmunología , COVID-19/complicaciones , Ritonavir/uso terapéutico , Anciano , Estudios Prospectivos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Resultado del Tratamiento , Combinación de Medicamentos , Recurrencia , Lopinavir/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéuticoRESUMEN
OBJECTIVE: The aim of this study is to assess the efficacy and safety of divozilimab in patients who have received post-marketing treatment and participants of clinical trials BCD-132-2 and BCD-132-4 were conducted at the IHB RAS. Additionally, we will present a case report of divozilimab therapy in a patient with highly active multiple sclerosis (MS). MATERIAL AND METHODS: The study included 27 patients with MS. We assessed the dynamics of neurological status, magnetic resonance imaging (MRI) findings, and disability level during divozilimab treatment. We also analyzed the incidence and severity of adverse events (AE), including infusion reactions. RESULTS: During treatment with divozilimab, no exacerbations or radiological disease activity were observed after the first six months. Complete clinical remission was achieved in 25 patients. All 12 patients who received the drug as part of post-marketing use met the NEDA-3 criteria, and five of them showed improvement. Most AE were mild, none exceeding grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE). Laboratory parameter changes were also mild and did not exceed I-II grade according to CTCAE. There were no instances of therapy discontinuation due to intolerance. CONCLUSION: The data from post-registration use of divozilimab confirm the results of clinical trials, showing high efficacy of the drug with a predictable and favorable safety profile.
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Esclerosis Múltiple , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen por Resonancia Magnética , Esclerosis Múltiple/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with multiple sclerosis (MS) treated with anti-CD20 therapies such as rituximab may have increased risk of severe COVID-19 disease. Vaccination induces protective immunity, but humoral vaccine response is known to be attenuated in rituximab-treated MS-patients-patients, which has indicated a need for real world data on severe morbidity and mortality from COVID-19 after vaccination. METHODS: Rituximab-treated patients treated at Haukeland University Hospital were identified through the National MS Registry and invited to participate in the study by giving a consent and providing a blood sample 3 weeks or later after ordinary COVID-19- vaccination, i.e. 2 doses given with a standard interval of 3 weeks. Blood samples were analysed with Enzyme-Linked Immunosorbent assay (ELISA) to evaluate humoral vaccine response with screening test against receptor-binding domain (RBD) and confirmatory Spike IgG-specific ELISA. A haemagglutination test (HAT) was performed as a marker of neutralizing antibodies. Patient serum concentration of rituximab were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Registry data from the Norwegian MS registry and information on hospitalization from patient records were collected and linked to laboratory results. RESULTS: 111 patients were included in the study. A total of 7 (6.3%) were hospitalized due to COVID-19 disease during the observation period. No patient was admitted to ICU and there were no deaths. 34.2% did not have detectable titre of SARS CoV-2 Spike IgG antibodies, 72.1% did not have a detectable titre of SARS CoV-2 RBD antibodies, and 88.2% did not have a detectable HAT titre. There was a correlation between hospitalisation and the absence of SARS CoV-2 Spike IgG antibody titre, and between hospitalisation and MS disease duration, as well as between spike IgG antibody titre and CD19 B-cell count, time since last rituximab infusion, cumulative rituximab treatment time and total IgG level in the patients. CONCLUSION: A substantial proportion of rituximab-treated MS-patients-patients did not have detectable humoral vaccine responses after 2 doses of COVID-19 vaccination. Despite this, the cumulative percentage of patients hospitalized with COVID-19 disease throughout the observation period of 22 months was low, and no patients required ICU treatment. The results support that vaccinated MS-patients treated with rituximab have a protective effect against serious Covid-19 infection.
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Vacunas contra la COVID-19 , COVID-19 , Hospitalización , Factores Inmunológicos , Esclerosis Múltiple , Rituximab , Humanos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Rituximab/farmacología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/sangre , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacología , Hospitalización/estadística & datos numéricos , SARS-CoV-2/inmunología , Anticuerpos Antivirales/sangre , Sistema de Registros , Inmunidad Humoral/efectos de los fármacos , Inmunidad Humoral/inmunología , Noruega/epidemiologíaRESUMEN
BACKGROUND: The global impact of the coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality. Immunocompromised patients, particularly those treated for B-cell lymphoma, have shown an increased risk of persistent infection with SARS-CoV-2 and severe outcomes and mortality. Multi-mutational SARS-CoV-2 variants can arise during the course of such persistent cases of COVID-19. No optimal, decisive strategy is currently available for patients with persistent infection that allows clinicians to sustain viral clearance, determine optimal timing to stop treatment, and prevent virus reactivation. We introduced a novel treatment combining antivirals, neutralizing antibodies, and genomic analysis with frequent monitoring of spike-specific antibody and viral load for immunocompromised patients with persistent COVID-19 infection. The aim of this retrospective study was to report and evaluate the efficacy of our novel treatment for immunocompromised B-cell lymphoma patients with persistent COVID-19 infection. METHODS: This retrospective descriptive analysis had no controls. Patients with B-cell lymphoma previously receiving immunotherapy including anti-CD20 antibodies, diagnosed as having COVID-19 infection, and treated in our hospital after January 2022 were included. We selected anti-SARS-CoV-2 monoclonal antibodies according to subvariants. Every 5 days, viral load was tested by RT-PCR, with antivirals continued until viral shedding was confirmed. Primary outcome was virus elimination. Independent predictors of prolonged viral shedding time were determined by multivariate Cox regression. RESULTS: Forty-four patients were included in this study. Thirty-five patients received rituximab, 19 obinutuzumab, and 26 bendamustine. Median treatment duration was 10 (IQR, 10-20) days; 22 patients received combination antiviral therapy. COVID-19 was severe in 16 patients, and critical in 2. All patients survived, with viral shedding confirmed at median 28 (IQR, 19-38) days. Bendamustine use or within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma significantly prolonged time to viral shedding. CONCLUSIONS: Among 44 consecutive patients treated, anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antiviral drugs, switching, and combination therapy resulted in virus elimination and 100% survival. Bendamustine use, within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma were the significant independent predictors of prolonged viral shedding time.
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Antivirales , COVID-19 , Linfoma de Células B , SARS-CoV-2 , Carga Viral , Esparcimiento de Virus , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Esparcimiento de Virus/efectos de los fármacos , SARS-CoV-2/inmunología , SARS-CoV-2/efectos de los fármacos , COVID-19/virología , COVID-19/inmunología , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Anciano , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/virología , Linfoma de Células B/inmunología , Factores de Riesgo , Carga Viral/efectos de los fármacos , Tratamiento Farmacológico de COVID-19 , Huésped Inmunocomprometido , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anciano de 80 o más AñosRESUMEN
Anti-factor VIII (FVIII) antibody development poses a significant challenge in hemophilia A (HA) patients receiving FVIII protein replacement therapy. There is an urgent need for novel therapeutic strategies to inhibit the production of anti-FVIII inhibitory antibodies (inhibitors) in HA. This study aimed to investigate a combination monoclonal antibody (mAb) therapy targeting CXCL13 and CD20 on the development of anti-FVIII antibodies in a HA murine model, along with the underlying mechanisms involved. Specifically, mAbs targeting mouse CD20 (18B12) with an IgG2a backbone and mouse CXCL13 (2C4) with an IgG1 backbone were synthesized. HA mice with FVIII inhibitors were established, and the results revealed that the combination therapy of anti-mCD20 with α-mCXCL13 significantly suppressed anti-FVIII antibody development and induced FVIII tolerance. Furthermore, this combination therapy led to a marked reduction of peripheral and splenic follicular helper T cells and an enhancement of regulatory T cell induction, along with sustained depletion of bone marrow and splenic plasma cells in HA mice with preexisting FVIII immunity. Thus, the concurrence of blockage of CD20 and neutralization of CXCL13 hold promise as a therapeutic strategy for HA patients with inhibitors.
Asunto(s)
Anticuerpos Monoclonales , Quimiocina CXCL13 , Factor VIII , Hemofilia A , Animales , Hemofilia A/tratamiento farmacológico , Hemofilia A/inmunología , Factor VIII/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/inmunología , Ratones , Quimiocina CXCL13/inmunología , Quimiocina CXCL13/metabolismo , Humanos , Antígenos CD20/inmunología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , MasculinoRESUMEN
INTRODUCTION: Ofatumumab (Kesimpta®) is a subcutaneous CD20-targeting antibody approved in Germany in 2021 for the treatment of relapsing multiple sclerosis (RMS). After careful instruction, patients can administer the treatment themselves. We previously reported data of 101 patients (Klimas et al. in Nervenarzt 94:923-933, 2023). The objective of this longitudinal study is to explore the tolerability and acceptability of ofatumumab from a patient perspective over a follow up period of 6 months. METHODS: In this prospective observational real-world study, we report follow up data of 81 patients. We evaluated sociodemographic data, disease duration, duration and side effects of ofatumumab use, expanded disability status scale (EDSS), Beck Depression Inventory II (BDI-II), Short-Form 36 (SF-36), Fatigue Scale of Motor and Cognitive Functions (FSMC), and modified Multiple Sclerosis Functional Composite Test (MSFC). In addition, we asked for subjective treatment outcomes, such as impact on quality of life, walking distance, concentration, mood, medication adherence, fatigue and the subjective course of MS on a numerical rating scale (1 = very negative; 5 = very positive). Furthermore, treatment discontinuations were recorded. RESULTS: The average duration of ofatumumab treatment was 10 months. In comparison to previous published data of our cohort, patients reported a significant increase in headache (10% up to 26%, p = 0.004) and limb pain (5% up to 26%, p < 0.001) as persistent side effects after the injections. More patients reported a very positive effect (p < 0.0001) on quality of life. 4 confirmed relapses occurred but no EDSS worsening, and no treatment discontinuations were documented during the observation period. DISCUSSION: As previously described, our prospective study indicates that patients have a good tolerability of ofatumumab, precisely because of the mild and few side effects at the first administration. However, the longer the observation period, the more headaches and limb pain occurred after the injections. Despite this, patients' subjective quality of life improved. There were no discontinuations during the follow-up period, with the limitation of a high loss to follow-up.