B-cell Depletion Therapies Research Articles

B-cell Depletion Therapy in Pediatric Neuroinflammatory Disease.

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. 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.

A new perspective on therapies involving B-cell depletion in autoimmune diseases.

It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion.

Treatment Strategies for Anti-Synthetase Syndrome

Anti-aminoacyl tRNA synthetase (ARS) antibodies are the most frequent in idiopathic inflammatory myopathy, notably associated with anti-synthetase syndrome (ASyS), which is characterized by six clinical features: arthritis, myositis, interstitial lung disease (ILD), fever, Raynaud's phenomenon, and mechanical hands. Although patients with ASyS often respond well to initial glucocorticoid (GC) therapy, they tend to have a chronic, recurrent disease course. In anti-ARS-positive patients, the treatment goal involves suppressing disease recurrence and progression while achieving a minimal GC dose. In this regard, the administration and continuation of immunosuppressants, such as calcineurin inhibitors, have been suggested. B-cell depletion therapies are expected to be valuable in patients with refractory ASyS. Moreover, additional antifibrotic agents may be beneficial for patients with progressive fibrosing ILD.

Clinical manifestations and risk factors for COVID-19 and its severity in patients with hematological malignancies

BackgroundPatients with hematological malignancies (HM) were at a high risk of developing severe disease from coronavirus disease 2019 (COVID-19). We aimed to assess the clinical outcome of COVID-19 in hospitalized patients with HM. MethodsAdult patients with HM who were hospitalized with a laboratory-confirmed COVID-19 between May, 2021 and November, 2022 were retrospectively identified. Primary outcome was respiratory failure requiring mechanical ventilation or mortality within 60 days after hospitalization. We also analyzed associated factors for de-isolation (defined as defervescence with a consecutive serial cycle threshold value > 30) within 28 days. ResultsOf 152 eligible patients, 22 (14.5%) developed respiratory failure or mortality in 60 days. Factors associated with developing respiratory failure that required mechanical ventilation or mortality included receipt of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) (adjusted hazards ratio [aHR], 5.10; 95% confidence interval [CI], 1.64–15.85), type 2 diabetes mellitus (aHR, 2.47; 95% CI, 1.04–5.90), lymphopenia at admission (aHR, 6.85; 95% CI, 2.45–19.15), and receiving <2 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines (aHR, 3.00; 95% CI, 1.19–7.60). Ninety-nine (65.1%) patients were de-isolated in 28 days, against which two hazardous factors were identified: receipt of B-cell depletion therapies within one year prior to COVID-19 (aHR, 0.55, 95% CI, 0.35–0.87) and lymphopenia upon admission (aHR, 0.65; 95% CI, 0.43–1.00). ConclusionWe found a high rate of respiratory failure and mortality among patients with HM who contracted the SARS-CoV-2. Factors associated with developing respiratory failure or mortality in 60 days included receipt of allo-HSCT, type 2 diabetes mellitus and lymphopenia upon admission. Having received ≥2 doses of vaccination conferred protection against clinical progression.

Updated COVID-19 clearance time among patients with cancer in the Delta and Omicron waves.

COVID-19 infection delays therapy and in-person evaluation for oncology patients, but clinic clearance criteria are not clearly defined. We conducted a retrospective review of oncology patients with COVID-19 at a tertiary care center during the Delta and Omicron waves and compared clearance strategies. Median clearance by two consecutive negative tests was 32.0 days (Interquartile Range [IQR] 22.0-42.5, n = 153) and was prolonged in hematologic malignancy versus solid tumors (35.0 days for hematologic malignancy, 27.5 days for solid tumors, p = 0.01) and in patients receiving B-cell depletion versus other therapies. Median clearance by single negative test was reduced to 23.0 days (IQR 16.0-33.0), with recurrent positive rate 25.4% in hematologic malignancy versus 10.6% in solid tumors (p = 0.02). Clearance by a predefined waiting period required 41 days until an 80% negative rate. COVID-19 clearance remains prolonged in oncology patients. Single-negative test clearance can balance delays in care with risk of infection in patients with solid tumors.

Regulation of CD8 T cell by B-cells: A narrative review.

Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several in vivo studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.

Migratory Pneumonia in Prolonged SARS-CoV-2 Infection in Patients Treated With B-cell Depletion Therapies for B-cell Lymphoma.

To report the clinical and radiological characteristics of patients with underlying B-cell lymphoma and coronavirus disease 2019 (COVID-19) showing migratory airspace opacities on serial chest computed tomography (CT) with persistent COVID-19 symptoms. From January 2020 to June 2022, of the 56 patients with underlying hematologic malignancy who had undergone chest CT more than once at our hospital after acquiring COVID-19, seven adult patients (5 female; age range, 37-71 years; median age, 45 years) who showed migratory airspace opacities on chest CT were selected for the analysis of clinical and CT features. All patients had been diagnosed with B-cell lymphoma (three diffuse large B-cell lymphoma and four follicular lymphoma) and had received B-cell depleting chemotherapy, including rituximab, within three months prior to COVID-19 diagnosis. The patients underwent a median of 3 CT scans during the follow-up period (median 124 days). All patients showed multifocal patchy peripheral ground glass opacities (GGOs) with basal predominance in the baseline CTs. In all patients, follow-up CTs demonstrated clearing of previous airspace opacities with the development of new peripheral and peribronchial GGO and consolidation in different locations. Throughout the follow-up period, all patients demonstrated prolonged COVID-19 symptoms accompanied by positive polymerase chain reaction results from nasopharyngeal swabs, with cycle threshold values of less than 25. COVID-19 patients with B-cell lymphoma who had received B-cell depleting therapy and are experiencing prolonged SARS-CoV-2 infection and persistent symptoms may demonstrate migratory airspace opacities on serial CT, which could be interpreted as ongoing COVID-19 pneumonia.

SARS-CoV-2 infection in multiple sclerosis patients: interaction with treatments, adjuvant therapies, and vaccines against COVID-19.

The SARS-CoV-2 pandemic has raised particular concern for people with Multiple Sclerosis, as these people are believed to be at increased risk of infection, especially those being treated with disease-modifying therapies. Therefore, the objective of this review was to describe how COVID-19 affects people who suffer from Multiple Sclerosis, evaluating the risk they have of suffering an infection by this virus, according to the therapy to which they are subjected as well as the immune response of these patients both to infection and vaccines and the neurological consequences that the virus can have in the long term. The results regarding the increased risk of infection due to treatment are contradictory. B-cell depletion therapies may cause patients to have a lower probability of generating a detectable neutralizing antibody titer. However, more studies are needed to help understand how this virus works, paying special attention to long COVID and the neurological symptoms that it causes.

Evaluation of Humoral and Cellular Immune Responses to the SARS-CoV-2 Vaccine in Patients With Common Variable Immunodeficiency Phenotype and Patient Receiving B-Cell Depletion Therapy.

IntroductionSARS-CoV-2 vaccines’ effectiveness is not yet clearly known in immunocompromised patients. This study aims to assess the humoral and cellular specific immune response to SARS-CoV-2 vaccines and the predictors of poor response in patients with common variable immunodeficiency (CVID) phenotype and in patients treated with B-cell depletion therapies (BCDT), as well as the safety of these vaccines.MethodsFrom March to September 2021, we performed a prospective study of all adult patients who would receive the SARS-CoV-2 vaccination and were previously diagnosed with (i) a CVID syndrome (CVID phenotype group; n=28) or (ii) multiple sclerosis (MS) treated with B-cell depleting therapies three to six months before vaccination (BCD group; n=24). Participants with prior SARS-CoV-2 infection; or prior SARS-CoV-2 vaccine administration; or use of any immunosuppressant (except BCDT in MS group) were excluded. A group of subjects without any medical condition that confers immunosuppression and who met all study criteria was also assessed (control group; n=14). A chemiluminescence immunoassay was used to determine pre- and post-SARS-CoV-2 vaccine anti-S IgG antibodies. T-cell specific response was assessed by analysis of pre- and post-SARS-CoV-2 vaccination blood samples with an interferon-gamma release assay. The baseline blood sample also included several biochemical, haematological and immunological analyses.ResultsSARS-CoV-2 vaccines are safe in immunocompromised patients, although their effectiveness was lower than in healthy individuals. CVID phenotype patients showed impaired humoral (29%) and cellular (29%) response, while BCD patients fundamentally presented humoral failure (54%). Low IgA values, low CD19+ peripheral B cells, low switched memory B cells, and a low CD4+/CD8+ ratio were predictors of inadequate specific antibody response in CVID phenotype patients. No factor was found to predict poor cellular response in CVID phenotype patients, nor a defective humoral or cellular response in BCD patients.ConclusionThe effectiveness of SARS-CoV-2 vaccines in CVID phenotype and BCD patients is lower than in healthy individuals. Knowledge of predictive factors of humoral and cellular response failure in immunocompromised patients could be very useful in clinical practice, and thus, studies in this regard are clearly needed.

Desensitization Therapy Among Highly Sensitized LVAD Patients

<h3>Purpose</h3> Among patients listed for heart transplantation (HT), human leukocyte antigen (HLA) sensitization is a major risk factor for prolonged wait-list time, wait-list mortality, and delisting. Desensitization therapies (Dx) like immunoglobulins (Ig), plasmapheresis and direct immunomodulators (IM)s such as B-cell depletion therapies (BCDT) or proteosome inhibitors (PI) have been used to reduce levels of sensitization. Specifically, for left ventricular assist device (LVAD) patients, however, Dx may pose unique problems: plasmapheresis removes coagulation factors and can increase bleeding risk, and IMs may worsen the risk of LVAD associated infections. We sought to assess safety and efficacy of Dx among LVAD patients. <h3>Methods</h3> LVAD patients undergoing Dx including plasmapheresis, Ig, Rituximab (BCDT) or Bortezomib (PI) were analyzed. Data on major coagulopathic and infectious complications while on LVAD support, changes in HLA antibodies and rates of HT were collected. Wilcoxon matched-pairs signed-ranks test was performed to compare changes in HLA antibody profiles following Dx. <h3>Results</h3> Between March 2016 and June 2021, 14 waitlisted LVAD patients underwent Dx [age: 52 years (inter-quartile range (IQR): 44, 60), 78% female, 43% Black, 64% HeartWare and 36% HeartMate III]. DTs were initiated 282 days (IQR: 129, 429) post LVAD implantation, with the majority receiving plasmapheresis (86%), Ig (86%) and bortezomib (93%). Two patients developed de-novo LVAD infections, and 2 suffered neurological events (1 hemorrhagic stroke and 1 transient ischemic event); no episodes of de-novo mucosal bleeding or hemolysis were noted. Eleven (78.6%) patients underwent HT, 2 remain waitlisted and 1 was delisted (myocardial recovery). Figure shows changes in antibody profiles with Dx. <h3>Conclusion</h3> In our cohort of highly sensitized LVAD patients, Dx were largely safe, significantly reduced class I panel reactive antibodies, and resulted in successful HT for most patients; future large scale trial data is necessary to validate our findings.

Real-world data about the side effects of SARS-CoV-2 vaccinations can be obtained only from representative samples undergoing comprehensive investigations

We read with interest the article by Lotan et al. about a study of the side effects to SARS-CoV-2 vaccinations in 438 patients with rare neuro-immunological disorders, such as neuromyelitis optica (NMO), myelin oligodendrocyte glycoprotein (MOG) antibody disease, transverse myelitis, optic neuritis, or acute, disseminated encephalomyelitis (ADEM) (Lotan et al., 2021). It was concluded that the safety profile of COVID-19 vaccines in patients with rare neuro-immunological diseases seems favourable and that the rate of adverse events may be lower in patients receiving immunotherapies, particularly B-cell depletion therapies (Lotan et al., 2021).

B cell depletion therapies in autoimmune disease: advances and mechanistic insights.

In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology. This has been fuelled in part by the clinical success of B cell depletion therapies (BCDTs). Originally conceived as a method of eliminating cancerous B cells, BCDTs such as those targeting CD20, CD19 and BAFF are now used to treat autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. The use of BCDTs in autoimmune disease has led to some surprises. For example, although antibody-secreting plasma cells are thought to have a negative pathogenic role in autoimmune disease, BCDT, even when it controls the disease, has limited impact on these cells and on antibody levels. In this Review, we update our understanding of B cell biology, review the results of clinical trials using BCDT in autoimmune indications, discuss hypotheses for the mechanism of action of BCDT and speculate on evolving strategies for targeting B cells beyond depletion.

Progress with the use of monoclonal antibodies for the treatment of systemic lupus erythematosus.

In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advances in our understanding of the complexity of SLE immunopathogenesis have led to the testing of several biologic agents in clinical trials. Monoclonal therapies currently emerging or under development include B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anticytokine therapies. Issues remain, however, regarding clinical trial design and outcome measures in SLE which need to be addressed to optimize translation of these promising therapies into clinical practice.

Anti-CD20 antibody in primary Sjögren's syndrome management.

Primary Sjogren's Syndrome (pSS) is a systemic inflammatory autoimmune of unknown aetiology affecting exocrine glands, particularly the lacrimal and salivary glands. Growing evidence that B-cell depletion therapies are remarkably efficacious in the disorder indicate a major role for B-cell in the immunopathogenesis of pSS. B cell-targeted therapies have raised new therapy promise for they interact with B-cell homeostasis. Anti-CD20 therapy is the unique effective non-symptomatic therapy used in pSS. Growing data suggest Rituximab a promising candidate for pSS therapy. We performed a search for publications on Rituximab in the treatment of pSS to explicate pathogenetic function of B cells and assesse the efficacy in glandular symptoms, systemic manifestations and laboratory parameters in pSS patients. However, the efficiency on glandular manifestations is rather disappointing and controversial. Whether pSS patients with a reasonable residual salivary flow and/or with shorter disease duration will benefit most from Rituximab treatment still remains unclear. Fatigue is the symptom that responds best to Rituximab therapy compared with other systematical involvements. The efficiency in laboratory parameters is unsatisfactory.

Hepatic Manifestations in Juvenile Systemic Lupus Erythematosus

Juvenile systemic lupus erythematosus (JSLE) is a chronic autoimmune disease characterized by multisystem involvement and diverse clinical and serological manifestations. Clinically significant hepatic disease is generally regarded as unusual in JSLE, but many studies have showed that hepatic disease may be more common in SLE than was usually thought. Hepatic disease does not cause significant morbidity and mortality, but subclinical liver involvement is common. One of the hepatic disorders associated with JSLE is autoimmune hepatitis (AIH). The precise etiology of AIH and JSLE remains unknown, however both AIH and JSLE are associated with antinuclear antibody (ANA) and multisystem disease manifestations. A shared immunologic response and genetic predisposition were suggested. Recently, new approaches for treatment of SLE and recent patents that could develop into novel therapeutic agents in clinical management of SLE have been proposed. An array of promising new therapies is currently emerging or being developed including B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and present review, we will also report the case of a 12-year old girl who developed JSLE four years after her preliminary diagnosis with AIH.

Umbilical cord-derived stromal cell therapy for rheumatoid arthritis: what does the future hold?

Limitations of the current therapies for rheumatoid arthritis Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease characterized by progressive cartilage loss and bone destruction with progressive functional decline. It is thought to be an autoimmune disease with aberrant Band T-cell function eventually culminating in an increased local production of inflammatory mediators and cytokines in particular, such as TNF-a, IL-1b, IL-6 and others. Collectively these cytokines orchestrate the molecular cascades that are activated in osteoclasts, fibroblasts and immune cells that culminate in joint destruction. An appreciation of these pathways has lead to the development of anticytokine therapies, costimulatory pathway blockade therapy and B-cell depletion therapies, which have dramatically improved patient outcomes. Despite these therapeutic advances, it is clear that a significant burden of RA inflammatory disease activity remains suboptimally treated. First, many patients are intolerant to the current therapies. Second, there is the issue of toxicity of existing therapies including the risks of serious infections or other noninfectious immunological perturbations that restrict therapy use. Third, many patients who benefit from the existing therapies only have a partial response and continue to experience significant joint pains owing to joint damage and functional loss. Finally, there is a small hard core of cases that have a fairly resistant inflammatory course where newer approaches are needed. Multipotential stromal cells, also called mesenchymal stem cells (MSCs) were originally studied for their tissue regenerative capabilities. The immunomodulatory capacity of allogeneic MSCs was first documented in a pioneering paper by Le Blanc et al. who showed

Novel therapeutic agents in clinical development for systemic lupus erythematosus

Conventional immunosuppressive therapies have radically transformed patient survival in systemic lupus erythematosus (SLE), but their use is associated with considerable toxicity and a substantial proportion of patients remain refractory to treatment. A more comprehensive understanding of the complexity of SLE immunopathogenesis has evolved over the past decade and has led to the testing of several biologic agents in clinical trials. There is a clear need for new therapeutic agents that overcome these issues, and biologic agents offer exciting prospects as future SLE therapies.An array of promising new therapies are currently emerging or are under development including B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anti-cytokine therapies, such as monoclonal antibodies against interleukin-6 and interferon-α.

New helping friends for B cells

Over the past decade, a growing recognition of the importance of neutralizing antibodies in host defense combined with the success of B-cell depletion therapies in treating auto-immune disorders has led to an increased focus on better understanding the pathways underpinning B-cell antibody production. In general, B cells require cognate interaction with T helper cells in the germinal center of lymphoid follicles to generate protective antibodies. However, recent evidence shows that B cells receive additional help from invariant natural killer T cells, dendritic cells, and various granulocytes, including neutrophils, eosinophils, and basophils. These innate immune cells enhance T-cell-dependent antibody responses by delivering B-cell helper signals both in the germinal center and at postgerminal center lymphoid sites such as the bone marrow. In addition to enhancing and complementing the B-cell helper activity of canonical T cells, invariant natural killer T cells, dendritic cells, and granulocytes can deliver T cell-independent B-cell helper signals at the mucosal interface and in the marginal zone of the spleen to initiate rapid innate-like antibody responses. Here, we discuss recent advances in the role of adaptive and innate B-cell helper signals in antibody diversification and production.

Human “Orchestrator” CD11b+ B1 Cells Spontaneously Secrete Interleukin-10 and Regulate T-Cell Activity

Immune regulation produced by B cells has been attributed to production and secretion of interleukin (IL)-10, which is a characteristic of mouse B1 cells. In view of the widespread clinical use of B-cell depletion therapies in autoimmune and malignant diseases, it is important to monitor the function and fate of regulatory B cells. However, there is no consensus regarding the phenotypic identity of human IL-10(+) B cells. Here we show that human CD11b(+) B1 cells, one of two recently described subpopulations of B1 cells, spontaneously produce IL-10 and suppress T-cell activation. In view of the capacity of these B cells to either stimulate T-cell proliferation or suppress T-cell activation, CD11b(+) B1 cells are considered to be capable of orchestrating elements of immune responsiveness and thus are termed "orchestrator B1 cells," or "B1orc," whereas CD11b(-) B1 cells that primarily secrete antibody are termed "secretor B1 cells," or "B1sec."

Long-lived autoreactive plasma cells drive persistent autoimmune inflammation

Aberrant production of autoantibodies by inappropriately self-reactive plasma cells is an inherent characteristic of autoimmune diseases. Several therapeutic strategies aim to deplete the plasma cell pool, or to prevent maturation of B cells into plasma cells. However, accepted views of B-cell biology are changing; recent findings show that long-lived plasma cells refractory to immunosuppressants and B-cell depletion therapies contribute to the maintenance of humoral memory and, in autoimmunity, to autoreactive memory. As a consequence of their longevity and persistence, long-lived plasma cells can support chronic inflammatory processes in autoimmune diseases by continuously secreting pathogenic antibodies, and they can contribute to flares of symptoms. As long-lived plasma cells are not sufficiently eliminated by current therapies, these findings are extremely relevant to the development of novel concepts for the treatment of autoimmune diseases. Thus, long-lived plasma cells appear to be a promising new therapeutic target.