Systemic Lupus Erythematosus (SLE) and lupus nephritis treatment is still based on non-specific immune suppression despite the first biological therapy for the disease having been approved more than ...a decade ago. Intense basic and translational research has uncovered a multitude of pathways that are actively being evaluated as treatment targets in SLE and lupus nephritis, with two new medications receiving FDA approval in the last 3 years. Herein we provide an overview of targeted therapies for SLE including medications targeting the B lymphocyte compartment, intracellular signaling, co-stimulation, and finally the interferons and other cytokines.
•Non-specific immune-suppression are still used for the treatment of Systemic Lupus Erythematosus and lupus nephritis.•Medications targeting B cells, Type I Interferons and Calcineurin have recently been approved for the treatment of SLE and LN.•Actively evaluated therapeutic targets include BLyS/APRIL, CD19/CD20, Jak, dendritic cells and co-stimulatory molecules.
Targeting cytokines to treat autoimmunity Kyttaris, Vasileios C.
Clinical immunology (Orlando, Fla.),
September 2019, 2019-09-00, 20190901, Volume:
206
Journal Article
Peer reviewed
Monoclonal antibodies, small molecules and soluble receptors that target cytokines have revolutionized the treatment of autoimmune and autoinflammatory diseases. The articles that are presented in ...this special issue of Clinical Immunology analyze the basic science, the clinical implications and the future directions of cytokine targeting in these diseases.
•TNF-α inhibition changed treatment landscape in multiple autoimmune diseases, like Rheumatoid Arthritis, Inflammatory Bowel Disease and Psoriatic Arthritis.•IL-1 inhibition, though moderately effective in Rheumatoid Arthritis, is fast becoming the treatment of choice in a variety of autoinflammatory diseases.•IL-2 can be used to both boost and inhibit the immune response.•Targeted therapies for severe Systemic Lupus Erythematosus and Antiphospholid Syndrome remain elusive.•IL-6 although efficacious in the treatment of Giant Cell Arteritis, does not fully suppress the inflammatory response within the vessel wall.
Rituximab (RTX) is a very effective treatment for autoimmune rheumatic diseases (AIRD), but it increases infection risk and impairs vaccine responses. Herein we evaluated the antibody response of ...RTX-treated patients to the supplemental COVID-19 vaccine. After the supplemental dose, 53.1% of patients had detectable antibody titers. Only 36% of patients who did not mount an antibody response after the original vaccine series did have detectable antibodies after the supplemental dose (seroconversion). Patients with undetectable CD20+ cell levels did not seroconvert while hypogammaglobulinemia was associated with a 15-times decrease in the likelihood of seroconversion. Although we noted 11 COVID-19 infections after the supplemental dose, no patients who received monoclonal antibodies pre-exposure prophylaxis had COVID-19 afterwards. We propose that patients receiving RTX should continue to be prioritized for prophylaxis measures and that vaccination should be timed after B cell recovery wherever possible.
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•A little more than half of Rituximab-treated patients mounted an antibody response after SARS-CoV-2 supplemental dose•Patients with hypogammaglobulinemia were significantly less likely than controls to respond to the COVID19 vaccine.•Patients with undetectable CD20+ cells did not develop an antibody response to the supplemental vaccine•Pre-exposure prophylaxis is very efficacious in preventing infections.
Objective
Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. The selective Gls1 inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl sulfide (BPTES) suppresses Th17 development and ...ameliorates experimental autoimmune encephalomyelitis (EAE). The present study was undertaken to investigate whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE), and the involved mechanisms.
Methods
MRL/lpr mice were treated with BPTES or vehicle control, and disease activity was examined. Then naive CD4+ T cells from patients with SLE were cultured under Th17‐polarizing conditions with BPTES or vehicle. Furthermore, using newly generated Gls1 conditional‐knockout mice, in vitro Th17 differentiation was examined, and EAE was induced in the mice. Glutaminolysis and glycolysis were measured with an extracellular flux analyzer. The expression of hypoxia‐inducible factor 1α (HIF‐1α) was examined by Western blotting.
Results
Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17‐dependent manner. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation (P < 0.05). Using the conditional‐knockout mice, we demonstrated that both in vitro Th17 differentiation (P < 0.05) and the development of EAE were dependent on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF‐1α protein, which induces glycolysis.
Conclusion
We demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17‐related autoimmune diseases. Mechanistically, we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing HIF‐1α protein in Th17 cells.
Purpose of Review
Undifferentiated connective tissue disease (UCTD) is characterized by the presence of clinical symptoms of a systemic autoimmune disease in addition to laboratory evidence of ...autoimmunity with the patients not fulfilling any of the widely used classification criteria for classic autoimmune diseases. The presence of UCTD as a separate entity versus an early stage of such diseases as systemic lupus erythematosus (SLE) or scleroderma has long been debated. Given the uncertainty regarding this condition, we performed a systematic review on the topic.
Recent Findings
UCTD can be subcategorized as evolving (eUCTD) or stable UCTD (sUCTD) based on its evolution towards a definable autoimmune syndrome. Analyzing the data from six UCTD cohorts published in the literature, we found that 28% of patients have an evolving course with the majority developing SLE or rheumatoid arthritis within 5–6 years of the UCTD diagnosis. From the remaining patients, 18% do achieve remission. Published treatment regimens were similar to other mild autoimmune diseases with low-dose prednisone, hydroxychloroquine, and NSAID. One-third of patients did need immune suppressive medications. Importantly, the reported outcomes were excellent with survival rates of more than 90% over 10 years. It has to be noted though that as data on patient related outcomes are not available to date, the exact impact of this condition on quality of life is unclear.
Summary
UCTD is a mild autoimmune condition with generally good outcomes. There is still great uncertainty though regarding diagnosis and management. Going forward, consistent classification criteria are needed to advance UCTD research and eventually provide authoritative guidance on the management of the condition.
T cells that express IL-17 infiltrate the kidneys of patients with systemic lupus erythematosus. A significant proportion of these cells are CD3(+)CD4(-)CD8(-) double-negative T cells. In this study, ...we show that double-negative T cells from MRL/lpr mice express high amounts of IL-17 and that as disease progressively worsens, the expression of IL-17 and of IL-23 receptor in lymphocytes from these mice increases. Lymph node cells from lupus-prone mice, but not control mice, treated in vitro with IL-23 induce nephritis when transferred to non-autoimmune, lymphocyte-deficient Rag-1(-/-) mice. Kidney specimens from these recipient mice show significant Ig and complement deposition. The data indicate that an aberrantly active IL-23/IL-17 axis contributes to the development of nephritis in lupus-prone mice.
Rituximab (RTX), an important therapeutic option for patients with rheumatic diseases, has been shown to reduce immune responses to various vaccines. We asked whether following SARS-CoV-2 ...vaccination, response rates in RTX treated patients are reduced and whether specific patient characteristics influence the responses. We recruited patients on chronic RTX therapy undergoing anti-SARS-CoV2 vaccination and measured the post-vaccination anti-spike IgG antibody levels. The median time from pre-vaccination RTX infusion to vaccination and from vaccination to the post-vaccination RTX infusion was 20.5 weeks and 7.2 weeks respectively. Only 36.5% of patients developed measurable titers of IgG anti-SARS-CoV-2 spike antibody after vaccination. Hypogammaglobulinemia (IgG and/or IgM) but not timing of vaccination, B cell numbers, or concomitant immune suppressive medications, correlated with sero-negativity (p = 0.004). Our results underscore the fact that even after B cell reconstitution, RTX induced chronic hypogammaglobulinemia significantly impairs the ability of the immune system to respond to SARS-CoV-2 vaccination.
•Rituximab therapy leads to impaired response to SARS-CoV2 vaccination in the majority of vaccinated patients with autoimmune rheumatic diseases.•Immunoglobulin levels are a major predictor of immunization response to SARS-CoV2 vaccination in rituximab treated patients.•Older individuals treated with Rituximab may be less likely to respond to SARS-CoV2 vaccination.•Responses to the SARS-CoV2 vaccination did not improve even after following published guidelines on timing vaccination post RTX infusion.
Novel Treatments in Lupus Vukelic, Milena; Li, Yi; Kyttaris, Vasileios C
Frontiers in immunology,
11/2018, Volume:
9
Journal Article
Peer reviewed
Open access
The standard treatment options for systemic lupus erythematosus (SLE) are focused on non-specific immunosuppression. Over the past few years, scientific studies and ongoing clinical trials have ...shifted the paradigm with rapid advances in developing biologics and small molecules. A number of monoclonal antibodies and small molecule inhibitors have been developed to target specific pathways involved in SLE. Many of these novel therapeutic agents are already being tested in clinical trials and they may 1 day reshape the landscape of SLE treatment. Herein we review potential future therapeutic options for SLE.
Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet ...the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.
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•Expanded CD8CD38high T cells in SLE patients identify patients with infections•CD8CD38high T cells express decreased amounts of cytotoxic molecules•CD38 decreases NAD+ and SIRT1 activity and releases the activity of EZH2•Inhibition of EZH2 restores the degranulation capacity of CD8CD38high T cells
Katsuyama et al. find that an expanded CD8CD38high T cell population in SLE patients is linked to infections. CD8CD38high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD+/Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE.
Significance IL-10 is an immune-regulatory cytokine with pro- and anti-inflammatory functions. Through its B cell-stimulating capacities, IL-10 contributes to the differentiation, activation and ...survival of B cells. Thus, it has been linked with autoimmune disorders, including systemic lupus erythematosus (SLE). Here, we demonstrate T cells as a source of increased IL-10 expression in SLE. Reduced DNA methylation of the IL10 gene allows for transcription-factor recruitment. Increased phosphorylation of the transcription factor Stat3 in SLE T cells results in epigenetic remodeling and trans -activation of IL10 , allowing for IL-10 expression. Thus, our observations offer molecular targets in the search for pathophysiologic mechanisms and target-directed treatment options in SLE.
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