Treatment Of Autoimmune Diseases Research Articles

A novel dosing approach for rituximab in glomerular diseases based on a population pharmacokinetic analysis

ObjectivesRituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. MethodsWe compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients’ characteristics, rituximab levels and anti-rituximab antibodies. ResultsThe analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. ConclusionIn order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.

Optimal Weight-based Dosing of Intravenous Immunoglobulin (IVIG) among Overweight and Obese Patients

Background: Intravenous immunoglobulin (IVIG), as an expensive medication under a national shortage, has been widely used for the treatment of several autoimmune diseases and immunodeficiency syndromes. Although conducting studies on therapeutic indications of IVIG has increased significantly, a limited number of researches have investigated individualized dosing in terms of the drug, disease state, and some patient-specific factors like obesity. Objective: The objective of the review was to describe the impact of various weight-based dosing regimens on the pharmacokinetics parameters, efficacy, safety, and cost of IVIG and to choose the best dosing approach for obese patients. Methods and Results: Thirteen of the total 128 manuscripts collected, reviewed, and analyzed were found from Scopus, PubMed, and Google scholar. Discussion: The evidence suggests that obesity may have an impact on IVIG pharmacokinetics, safety, and efficacy. Conclusion: The logical approach is to initial the dose based on the ideal or adjusted body weight and then modify the maintenance dose according to the patient's clinical response.

Discovery of GLPG3667, a Selective ATP Competitive Tyrosine Kinase 2 Inhibitor for the Treatment of Autoimmune Diseases.

Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).

Methotrexate Induced Oral Mucositis and Bone Marrow Suppression in Psoriatic Patient

Methotrexate is an antimetabolite which binds to the dihydrofolate reductase enzyme and used in the treatment of malignant disorders and autoimmune diseases. Myelosuppression is a serious complication of methotrexate toxicity. The following case describes a case of 67 year old male patient diagnosed with psoriasis and wrongly taken methotrexate 7.5 mg daily for 3 days and twice daily for 4 days. He presented with oral mucositis and his lab reports showed myelosuppression. Our case emphasizes the significance of effective patient counselling to ensure the understanding of prescription and to prevent drug toxicity. The key learning points of our case report include the importance of adhering to prescribed medication regimens, awareness of MTX toxicity, early initiation of folinic acid as an antidote, vigilant monitoring of toxicity, and effective patient education on proper medication use. Adherence to established MTX therapy guidelines in dermatological conditions is crucial to minimize the risk of patient.

TIGIT Stimulation Suppresses Autoimmune Uveitis by Inhibiting Th17 Cell Infiltration.

T cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint molecule that suppresses T cell activation and promotes an immunosuppressive environment to suppress autoimmune diseases. However, the impact of a TIGIT agonist as a treatment for ocular autoimmune disease has not been investigated. We examined TIGIT expression on Th17 and Treg cells, the role of TIGIT on experimental autoimmune uveitis (EAU) and Th17 cells, and the impact of Treg generation following TIGIT stimulation. TIGIT stimulation at the onset of clinical symptoms reduced the severity of uveitis and suppressed infiltration of Th17 cells into the eye. Further, Tregs from mice treated with the TIGIT agonist were capable of suppressing EAU in recipient mice. This report demonstrates that stimulation of TIGIT at onset of disease suppresses symptoms and allows for induction of regulatory immunity that provides resistance to uveitis.

Natural IgG protects against early dissemination of vesicular stomatitis virus

Neonatal Fc receptor (FcRn) recycles immunoglobulin G, and inhibition of FcRn is used clinically for treatment of autoimmune diseases. In this work, using the vesicular stomatitis virus (VSV) mouse infection model system, we determined the role of FcRn during virus infection. While induction of neutralizing antibodies and long-term protection of these antibodies was hardly affected in FcRn deficient mice, FcRn deficiency limited the amount of natural IgG (VSV-specific) antibodies. Lack of natural antibodies (nAbs) limited early control of VSV in macrophages, accelerated propagation of virus in several organs, led to the spread of VSV to the neural tissue resulting in fatal outcomes. Adoptive transfer of natural IgG into FcRn deficient mice limited early propagation of VSV in FcRn deficient mice and enhanced survival of FcRn knockout mice. In line with this, vaccination of FcRn mice with very low dose of VSV prior to infection similarly prevented death after infection. In conclusion we determined the importance of nAbs during VSV infection. Lack of FcRn limited nAbs and thereby enhanced the susceptibility to virus infection.

Secukinumab: A Breakthrough in the Treatment of Autoimmune Disease

Secukinumab is a significant advancement in the treatment of autoimmune disease, particularly psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis. By targeting interleukin-17A(IL-17A), it offers a focused approach to mitigating inflammation. This article provides a comprehensive overview of Secukinumab, exploring its mechanism of action, clinical efficacy, safety profile, administration, and ongoing research aimed at expanding its therapeutic scope.

Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Hydroxychloroquine and Chloroquine-Induced Cardiac Arrhythmias and Sudden Cardiac Death in Patients with Systemic Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis

Hydroxychloroquine (HCQ) and chloroquine (CQ) are foundational treatments for several systemic autoimmune rheumatic diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Concerns regarding the risk of cardiac arrhythmia and death have been raised, yet the burden of HCQ and CQ-related cardiac toxicities remains unclear. A systematic literature search was conducted in the MEDLINE and Embase databases for articles published between the earliest date and April 2023 reporting cardiac conduction abnormalities in patients with systemic autoimmune rheumatic diseases taking HCQ or CQ. Meta-analysis was performed to calculate the difference in mean QTc and odds ratio of prolonged QTc in those taking HCQ or CQ versus not. Of 2673 unique records, 34 met the inclusion criteria, including 70,609 subjects. Thirty-three studies reported outcomes in HCQ and 9 in CQ. Five studies reported outcomes in RA, 11 in SLE, and 18 in populations with mixed rheumatic diseases. Eleven studies reported mean QTc and OR for prolonged QTc for meta-analysis, all reporting outcomes in HCQ. There was a significant increase in mean QTc among HCQ users in patients with RA (10.29 ms, p = 0.458). There was no difference in mean QTc between HCQ and non-HCQ users in other systemic autoimmune rheumatic diseases. When rheumatic diseases were pooled, HCQ users were more likely to have prolonged QTc (odds ratio 1.57, 95%CI: 1.19, 2.08). QTc prolongation was more likely in patients with systemic autoimmune rheumatic diseases. Clinicians should be aware of potential adverse cardiac events of HCQ and consider QTc monitoring.

Heterogeneity and plasticity of tissue-resident memory T cells in skin diseases and homeostasis: a review.

Skin tissue-resident memory T (Trm) cells are produced by antigenic stimulation and remain in the skin for a long time without entering the peripheral circulation. In the healthy state Trm cells can play a patrolling and surveillance role, but in the disease state Trm cells differentiate into various phenotypes associated with different diseases, exhibit different localizations, and consequently have local protective or pathogenic roles, such as disease recurrence in vitiligo and maintenance of immune homeostasis in melanoma. The most common surface marker of Trm cells is CD69/CD103. However, the plasticity of tissue-resident memory T cells after colonization remains somewhat uncertain. This ambiguity is largely due to the variation in the functionality and ultimate destination of Trm cells produced from memory cells differentiated from diverse precursors. Notably, the presence of Trm cells is not stationary across numerous non-lymphoid tissues, most notably in the skin. These cells may reenter the blood and distant tissue sites during the recall response, revealing the recycling and migration potential of the Trm cell progeny. This review focuses on the origin and function of skin Trm cells, and provides new insights into the role of skin Trm cells in the treatment of autoimmune skin diseases, infectious skin diseases, and tumors.

The Metabolism and Disposition of Brepocitinib in Humans and Characterization of the Formation Mechanism of an Aminopyridine Metabolite.

<s><s></s></s> Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of 14C-brepocitinib (~300 nCi). The average mass balance recovery was 96.7% {plus minus} 6.3% with the majority of dose (88.0% {plus minus} 8.0%) recovered in urine and 8.7% {plus minus} 2.1% of the dose in recovered in feces. Absorption of brepocitinib was rapid, with maximal plasma concentrations of total radioactivity and brepocitinib achieved within 0.5 hours after dosing. Circulating radioactivity consisted primarily of brepocitinib (47.8%) and metabolite M1 (37.1%) derived from hydroxylation at the C5' position of the pyrazole ring. Fractional contributions to metabolism via cytochrome P450 (CYP) enzymes were determined to be 0.77 for CYP3A4/5 and 0.14 for CYP1A2 based on phenotyping studies in HLM. However, additional clinical studies are required to understand the potential contribution of CYP1A1. Approximately 83% of the dose was eliminated as N-methylpyrazolyl oxidative metabolites, with 52.1% of the dose excreted as M1 alone. Notably, M1 was not observed as a circulating metabolite in earlier metabolic profiling of human plasma from a multiple ascending study with unlabeled brepocitinib. Mechanistic studies revealed M1 was highly unstable in human plasma and phosphate buffer, undergoing chemical oxidation leading to loss of the 5-hydroxy-1-methylpyrazole moiety and formation of aminopyrimidine cleavage product M2. Time dependent inhibition and trapping studies with M1 yielded insights into the mechanism of this unusual and unexpected instability. Significance Statement This work describes the mass balance and metabolic profile of brepocitinib in human, a JAK1/TYK2 inhibitor being developed for treatment of autoimmune diseases.

Pharmacology of drugs used in autoimmune dermatopathies in cats and dogs: A narrative review.

Immunosuppressive drugs are the mainstay of treatment for many feline and canine autoimmune skin diseases, either as monotherapy or in combination with other drugs. Treatment with these drugs is often lifelong and may have long-term consequences on the affected animal's overall quality-of-life. Clinicians need to understand the pharmacology of immunosuppressants in planning and executing the treatment regimen for the best possible clinical outcome, as well as reducing the risk of adverse effects. This review paper will focus on the mechanism of action, pharmacokinetics and pharmacodynamics, clinical uses and adverse effects of immunosuppressive drugs used to treat autoimmune dermatoses in cats and dogs. These include glucocorticoids, ciclosporin A, azathioprine, chlorambucil, mycophenolate mofetil, oclacitinib and Bruton's tyrosine kinase inhibitors.

CPT-11 mitigates autoimmune diseases by suppressing effector T cells without affecting long-term anti-tumor immunity

The incidence of autoimmune diseases has significantly increased over the past 20 years. Excessive host immunoreactions and disordered immunoregulation are at the core of the pathogenesis of autoimmune diseases. The traditional anti-tumor chemotherapy drug CPT-11 is associated with leukopenia. Considering that CPT-11 induces leukopenia, we believe that it is a promising drug for the control of autoimmune diseases. Here, we show that CPT-11 suppresses T cell proliferation and pro-inflammatory cytokine production in healthy C57BL/6 mice and in complete Freund’s adjuvant-challenged mice. We found that CPT-11 effectively inhibited T cell proliferation and Th1 and Th17 cell differentiation by inhibiting glycolysis in T cells. We also assessed CPT-11 efficacy in treating autoimmune diseases in models of experimental autoimmune encephalomyelitis and psoriasis. Finally, we proved that treatment of autoimmune diseases with CPT-11 did not suppress long-term immune surveillance for cancer. Taken together, these results show that CPT-11 is a promising immunosuppressive drug for autoimmune disease treatment.

Highlight of 2023: CAR Tcells driving precision therapy for autoimmune disease.

CAR Tcell therapy is showing remarkable results in autoimmune disease with treatment-refractory patients showing durable drug-free remission. Here, we highlight five key papers from 2023 that are driving the development of CAR Tcells to improve precision, safety, efficacy and accessibility for the treatment of autoantibody-associated autoimmune diseases.

Innovative Diagnosis and Therapeutic Modalities: Engineered Exosomes in Autoimmune Disease.

Autoimmune diseases refer to a group of conditions where the immune system produces an immune response against self-antigens, resulting in tissue damage. These diseases have profound impacts on the health of patients. In recent years, with the rapid development in the field of biomedicine, engineered exosomes have emerged as a noteworthy class of biogenic nanoparticles. By precisely manipulating the cargo and surface markers of exosomes, engineered exosomes have gained enhanced anti-inflammatory, immunomodulatory, and tissue reparative abilities, providing new prospects for the treatment of autoimmune diseases. Engineered exosomes not only facilitate the efficient delivery of bioactive molecules including nucleic acids, proteins, and cytokines, but also possess the capability to modulate immune cell functions, suppress inflammation, and restore immune homeostasis. This review mainly focuses on the applications of engineered exosomes in several typical autoimmune diseases. Additionally, this article comprehensively summarizes the current approaches for modification and engineering of exosomes and outlines their prospects in clinical applications. In conclusion, engineered exosomes, as an innovative therapeutic approach, hold promise for the management of autoimmune diseases. However, while significant progress has been made, further rigorous research is still needed to address the challenges that engineered exosomes may encounter in the therapeutic intervention process, in order to facilitate their successful translation into clinical practice and ultimately benefit a broader population of patients.

Macrophage-Derived Nanosponges Adsorb Cytokines and Modulate Macrophage Polarization for Renal Cell Carcinoma Immunotherapy.

Renal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8+ T cells and is highly sensitive to immunotherapy. However, tumor-associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage-derived nanosponges are fabricated by M2 macrophage membrane-coated poly（lactic-co-glycolic acid）（PLGA）, which could chemotaxis to the CXC and CC chemokine subfamily-enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad-spectrum immunosuppressive cytokines such as colony stimulating factor-1(CSF-1), transforming growth factor-β（TGF-β）, and Lnterleukin-10（IL-10）, thereby reversing the polarization of M2-TAMs toward the pro-inflammatory M1 phenotype, and enhancing the anti-tumor effect of CD8+ T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE-PEG-M2pep is conjugated on the surface of macrophage-derived nanosponges for specific recognition of M2-TAMs, and the toll like receptors 7/8（TLR7/8） agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases.

Crosstalking with dendritic cells: a path to engineer advanced T Cell immunotherapy

Crosstalk between dendritic cells and T cells plays a crucial role in modulating immune responses in natural and pathological conditions. DC-T cell crosstalk is achieved through contact-dependent (i.e., immunological synapse) and contact-independent mechanisms (i.e., cytokines). Activated DCs upregulate co-stimulatory signals and secrete proinflammatory cytokines to orchestrate T cell activation and differentiation. Conversely, activated T helper cells “license” DCs towards maturation, while regulatory T cells (Tregs) silence DCs to elicit tolerogenic immunity. Strategies to efficiently modulate the DC-T cell crosstalk can be harnessed to promote immune activation for cancer immunotherapy or immune tolerance for the treatment of autoimmune diseases. Here, we review the natural crosstalk mechanisms between DC and T cells. We highlight bioengineering approaches to modulate DC-T cell crosstalk, including conventional vaccines, synthetic vaccines, and DC-mimics, and key seminal studies leveraging these approaches to steer immune response for the treatment of cancer and autoimmune diseases.

Toll-like receptors in health and disease.

Toll-like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation-related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR-related diseases.

Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors.

Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.

Frequency of infections during rituximab treatment of autoimmune blistering diseases.

This study investigates the frequency of infections in autoimmune blistering disease (AIBD) patients treated with rituximab and evaluates the difference in infectious complications in patients on concomitant antibiotic and/or antiviral prophylaxis. The study retrospectively reviewed 43 AIBD patients who received rituximab over a five-year interval. The patients were categorized based on prophylaxis type (antibiotic, antiviral, or both) and concomitant immunosuppression status, which we defined as treatment with an immunosuppressive medication during the time frame they were given Rituximab. Our findings suggest that concomitant immunosuppression alongside rituximab did not significantly increase the risk of developing infectious complications compared to rituximab monotherapy. Results revealed that 34.4% of patients with concomitant immunosuppression had a secondary bacterial infection, defined as bacterial complications requiring hospitalization, consistent with prior studies. Moreover, antibiotic prophylaxis did not significantly reduce infection risk in patients on rituximab, with 45.1% of these patients experiencing bacterial complications. There was an absence of pneumocystis pneumonia in the study population. Despite the small sample size and limited timeline, this study suggests that antibiotic prophylaxis may not significantly mitigate the risk of infections in AIBD patients receiving rituximab, and the risk of infection with concomitant immunosuppression with rituximab requires additional investigation for definitive causal risk.