Tocilizumab: An Updated Review of Its Use in the Treatment of Rheumatoid Arthritis and Its Application for Other Immune-Mediated Diseases

2013 ◽  
Vol 5 ◽  
pp. CMT.S9282 ◽  
Author(s):  
Toshio Tanaka ◽  
Atsushi Ogata ◽  
Masashi Narazaki
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Responses ◽  
T Cell Subsets ◽  
Unknown Etiology ◽  
Autoantibody Production ◽  
Future Studies ◽  
Effector T Cell ◽  
Immune Mediated ◽  
Cell Source ◽  
Acute Phase Reactions

Interleukin-6 (IL-6), produced by a variety of cells, is a typical cytokine featuring redundancy and pleiotropic activity. IL-6 is promptly and transiently synthesized in response to infections or injuries, and participates in host defense by inducing immune responses, hematopoiesis, and acute-phase reactions. However, since its abnormal persistent production of mostly unknown etiology plays an important pathological role in the development of various immune-mediated diseases, a humanized anti-IL-6 receptor monoclonal antibody, tocilizumab, was developed and is now used as an innovative biologic for rheumatoid arthritis in more than 90 countries. Several factors strongly suggest that a IL-6 blockade strategy may have a broad application for the treatment of various immune-mediated diseases. These factors include favorable results of pilot or case studies with off-label use of tocilizumab, pathological analyses of the contribution of IL-6 to the development of immune-mediated diseases, and the potential capability of tocilizumab to both repair an imbalance of effector T cell subsets and to suppress pathologic autoantibody production. However, clinical trials to evaluate the efficacy and safety of tocilizumab for these diseases are essential. Furthermore, clarification of the cell source of IL-6 production and of the mechanisms through which dysregulated continuous IL-6 synthesis is induced constitutes an important issue for future studies into the pathogenesis of diseases.

scholarly journals THU0031 ABATACEPT ALTERS THE FREQUENCY OF IMMUNOREGULATORY AND EFFECTOR T CELL SUBPOPULATIONS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 229.2-229
Author(s):  
B. Dreo ◽  
B. Prietl ◽  
S. Kofler ◽  
H. Sourij ◽  
A. Lackner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
Effector T Cell ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

Background:Under physiological conditions, T regulatory cells (Tregs) are responsible for the downregulation of the immune response. In autoimmune diseases, such as rheumatoid arthritis (RA), auto-inflammation is driven by an imbalance of activation and downregulation of immunological pathways. Thus, treatment plans for autoimmune diseases often involve the enhancement of immunoregulatory pathways by administering inhibitors of costimulation, i.e. CTLA-4-Ig (abatacept, ABA). ABA binds specifically to CD80 and CD86 on antigen presenting cells (APC). Consequently, T cell activation via the CD28 receptor is blocked. Previous studies have demonstrated surprising effects of abatacept on Tregs, specifically decreased frequency of these cells but enhancement in their function1. Whether these alterations can only be found in patients with ABA treatment, or whether they are also present in patients receiving other anti-inflammatory drugs is currently unknown.Objectives:The aim of our research was to delineate the impact of ABA on the different subsets of effector and regulatory T cells in RA and compare these findings with patients receiving tocilizumab (TCZ) or rituximab (RTX).Methods:Peripheral blood samples from 56 RA patients (median ± SE; age: 60.5 ± 1.3 years, female ratio: 0.7, disease duration: 17.9 ± 2.1 years; respectively) were drawn over a sampling period of 2 years. Freshly isolated PBMCs of RA patients were stained with fluorochrome-labelled antibodies and T cell subsets were identified by flow cytometric means. CD3+CD4+T cells were further classified using different T cell markers (CD25, CD127, CD39, CD95). All cytometric measurements were performed using a standardized BD LSR-Fortessa platform. RA patients were compared according to their treatment with ABA, TCZ or RTX.Results:Eighteen out of 56 RA patients (32%) received ABA, 25 patients (45%) received TCZ and 13 patients (23%) were under CD20+ cell depletion therapy with RTX. RA patients receiving ABA displayed a significant decrease in CD3+CD4+CD25+CD127dimTregs (3.7% ± 0.4) compared to patients with TCZ (5.4% ± 0.4, p = 0.041) and patients under RTX treatment (7.52% ± 0.93, p = 0.026). CD39+Tregs were significantly higher in RA patients treated with TCZ (49.5% + 3.2, p = 0.000) or RTX (50.5% ± 5.3, p = 0.026) compared to patients receiving ABA (24.5% ± 3.1). In addition, the frequency of CD95+Tregs was significantly reduced in ABA patients compared to RTX patients (59.6% ± 3.1 vs.76.7% ± 3.6, p = 0.014; respectively). Interestingly, T cells displaying an effector T cell phenotype (CD3+CD4+CD25+/-CD127+) were increased in ABA treated patients compared to RTX treated patients (59.6% ± 3.1 and 76.7% ± 3.6, p = 0.002). Since none of our patients were a non-responder or had high disease activity, we could not analyse whether these changes are associated with treatment outcome.Conclusion:Our data demonstrate that blockage of T cell stimulation via ABA leads to characteristic alterations in different regulatory and effector T cells not seen in patients treated with TCZ or RTX. Further studies must clarify whether the analysis of regulatory and effector T cell subpopulations before treatment initiation can be used as biomarker for treatment response.References:[1]Álvarez-Quiroga C, Abud-Mendoza C, Doníz-Padilla L, et al. CTLA-4-Ig therapy diminishes the frequency but enhances the function of treg cells in patients with rheumatoid arthritis.J Clin Immunol. 2011;31(4):588-595.doi:10.1007/s10875-011-9527-5Acknowledgments:Work done in “CBmed” was funded by the Austrian Federal Government within the COMET K1 Centre Program, Land Steiermark and Land Wien.Disclosure of Interests:None declared

scholarly journals Mining the human tonsillar microbiota as autoimmune modulator

2019 ◽  
Author(s):  
Jing Li ◽  
Shenghui Li ◽  
Jiayang Jin ◽  
Ruochun Guo ◽  
Xiaolin Sun ◽  
...  
Keyword(s):  
Autoimmune Disorder ◽  
T Cell Subsets ◽  
Immune Homeostasis ◽  
Antibacterial Peptides ◽  
Streptococcus Salivarius ◽  
Active Components ◽  
Autoantibody Production ◽  
Palatine Tonsils ◽  
Effector T Cell ◽  
First Time

AbstractPalatine tonsils are important lymphoid organs featuring constant cross-talks between the commensal microorganisms and immune system, and have been implicated as critical autoimmunity origins for immune-related diseases, including rheumatoid arthritis (RA), a common autoimmune disorder. However, there was no evidence to show link between tonsillar microbiota and RA. Here, we identified a significant dysbiosis of RA tonsillar microbiota, with loss of Streptococcus salivarius and its functional molecules salivaricins (a type of antibacterial peptides). Consistent with the niche-preference, S. salivarius and salivaricins administrated intranasally or intraorally conferred prophylactic and therapeutic efficacies against experimental arthritis. Moreover, we demonstrated, for the first time, that S. salivarius and salivaricins exerted immunosuppressive capacities via inhibiting CD4+effector T cell subsets and autoantibody production in mice and human. These results uncover a communication between tonsillar microbiota and host autoimmunity, and identify the active components from tonsillar microbes in modulating immune homeostasis.One sentence summaryTonsillar microbiota regulate host autoimmunity via antibacterial peptides

scholarly journals JAK Inhibitors and Modulation of B Cell Immune Responses in Rheumatoid Arthritis

2021 ◽  
Vol 7 ◽  
Author(s):  
Rita A. Moura ◽  
João Eurico Fonseca
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Janus Kinase ◽  
Sustained Remission ◽  
Close Monitoring ◽  
Jak Inhibitors ◽  
Autoantibody Production ◽  
Cell Functions

Rheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disease that can lead to joint destruction, functional disability and substantial comorbidity due to the involvement of multiple organs and systems. B cells have several important roles in RA pathogenesis, namely through autoantibody production, antigen presentation, T cell activation, cytokine release and ectopic lymphoid neogenesis. The success of B cell depletion therapy with rituximab, a monoclonal antibody directed against CD20 expressed by B cells, has further supported B cell intervention in RA development. Despite the efficacy of synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs) in the treatment of RA, few patients reach sustained remission and refractory disease is a concern that needs critical evaluation and close monitoring. Janus kinase (JAK) inhibitors or JAKi are a new class of oral medications recently approved for the treatment of RA. JAK inhibitors suppress the activity of one or more of the JAK family of tyrosine kinases, thus interfering with the JAK-Signal Transducer and Activator of Transcription (STAT) signaling pathway. To date, there are five JAK inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib) approved in the USA, Europe and/ or Japan for RA treatment. Evidence from the literature indicates that JAK inhibitors interfere with B cell functions. In this review, the main results obtained in clinical trials, pharmacokinetic, in vitro and in vivo studies concerning the effects of JAK inhibitors on B cell immune responses in RA are summarized.

scholarly journals NOVEL NANO THERAPEUTIC MATERIALS FOR THE EFFECTIVE TREATMENT OF RHEUMATOID ARTHRITIS-RECENT INSIGHTS

2021 ◽  
pp. 31-40
Author(s):  
NARESH KUMAR AHUJA ◽  
JITENDRA SINGH RAJAWAT
Keyword(s):  
Rheumatoid Arthritis ◽  
Critical Role ◽  
Lipid Nanoparticles ◽  
Unknown Etiology ◽  
Good Growth ◽  
Synovial Joint ◽  
Cardiovascular Risks ◽  
Tissue Destruction ◽  
Inflammatory Infiltration ◽  
Autoantibody Production

Recent advances in science and technology and greatly modified the way we stumble on, deal with and prevent special diseases in all components of human lifestyles. Rheumatoid arthritis (RA) is the most not unusual complex multifactorial joint related autoimmune, chronic, severe systemic inflammatory ailment with unknown etiology completed with increased cardiovascular risks. It is regularly associated with critical synovial joint inflammation, autoantibody production, cartilage/bone tissue destruction, cardiovascular, pulmonary, skeletal disorders and massive inflammatory infiltration which might in the end motive extreme disability, huge complications, premature mortality and decreased life quality. Pro-inflammatory cytokines like IL-1, IL-6, IL-8 and IL-10 were dependable for the induction of inflammation in RA patients. It has a global occurrence of around 1% with the incidence among women being 2-3 times extra in men. Preclinical RA, genetic variables, and environmental factors have all been linked to the disease's etiology. Because there is no known cure for RA, the primary goal of treatment is to achieve the shortest possible illness duration and, if possible, rehabilitation. Current clinical remedies of RA display numerous drawbacks which include excessive doses, common administration, speedy metabolism, bad absorption, low responsiveness, higher cost and serious side consequences. These obstacles have inspired extremely good growth of the studies and to enhance those obstacles, nanoparticles that are able to encapsulating and protecting tablets from degradation earlier than they reach the target site in vivo, might also function drug delivery structures. Bioavailability and therapeutic bioactivity can be improved, and limited emphasis on damaged joints can be allowed. The current study provides a platform for different lipid nanoparticle methods for RA therapy, using the newly developing field of lipid nanoparticles to improve a targeted theranostic device for RA treatment. This review aims to present the most recent major application of lipid nanoparticles as a biocompatible and biodegradable transport device for improving RA concentration on over free drugs by presenting tissue-specific concentrated on of ligand-controlled drug release by modulating nanoparticle composition. Additionally, we also discuss the pivotal demanding situations to be addressed, as well as destiny views. Therefore, it is feasible to claim that nanoparticles will, within the near future, play a critical role in advanced treatment and affected person-particular cures for human diseases which include RA.

scholarly journals Interleukin 6 and Rheumatoid Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Yuji Yoshida ◽  
Toshio Tanaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Interleukin 6 ◽  
Infectious Agents ◽  
First Line ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Immune Mediated ◽  
The World ◽  
Acute Phase Reactions ◽  
Immunological Abnormalities

Interleukin-6 (IL-6) is a representative cytokine featuring pleiotropic activity and redundancy. A transient synthesis of IL-6 contributes to host defense against infectious agents and tissue injuries by inducing acute phase reactions and immunological and hematopoietic responses. However, uncontrolled persistent production of IL-6 may lead to the development of several immune-mediated diseases. Rheumatoid arthritis (RA) is a chronic disease with joint and systemic inflammation resulting from immunological abnormalities and it has been found that IL-6 plays a key role in the development of this disease. Clinical trials in various parts of the world of tocilizumab, a humanized anti-IL-6 receptor antibody, have proved its efficacy and tolerable safety either as monotherapy or in combination with disease-modifying antirheumatic drugs. As a result, it is currently used as a first-line biologic for the treatment of moderate-to-severe RA in more than 100 countries. Clarification of the mechanism(s) through which tocilizumab exerts its effect on RA and of the reason(s) why IL-6 is continuously produced in RA can be expected to lead to the best use of this agent for RA patients and aid in investigations into the pathogenesis of RA.

Autoimmune Mechanisms Involved in the Pathogenesis of Rheumatoid Arthritis

1996 ◽  
Vol 10 (1) ◽  
pp. 47-51 ◽  
Author(s):  
R.C. Williams
Keyword(s):  
Rheumatoid Arthritis ◽  
Progressive Disease ◽  
Plasma Cells ◽  
Disease Process ◽  
Underlying Disease ◽  
Autoantibody Production ◽  
Rheumatoid Nodules ◽  
Immune Mediated ◽  
Lymphocytic Infiltrates ◽  
Insight Into

Rheumatoid arthritis (RA) was one of the first systemic disorders to be considered an autoimmune disease. Two major aspects of RA suggest a fundamental immune-mediated derangement in the disease: (1) presence of often massive lymphocytic infiltrates and activated CD4(+) T cells within the inflamed hypertrophied synovium, and (2) production of large amounts of rheumatoid factor (RF) by B-cells and plasma cells in the involved synovium itself. The actual tissue damage to joints and extra-articular structures affected by the disease comes from the rheumatoid inflammatory pannus or granulomatous collections of cells called rheumatoid nodules. RF production has long been studied as a prime example of apparent autoantibody production in association with the basic underlying disease process. RA patients who belong to subtype HLA DR4, Dw4 (DR B1 or 0401, Dw14 (0404/0408), or Dw15 (0405/0410) are most likely to be seropositive for RF and to have severe progressive disease. RFs are felt to represent an autoantibody associated with RA, since they show principal specificity for structures on the Cγ3 and C γ2 (Fc) domains of IgG. Recent work by our group has defined a number of solvent-exposed linear RF-reactive epitopes on Cγ3 and Cγ2 using a strategy of overlapping 7-mers of primary sequence. RFs also have been demonstrated to react with two different regions, SKDWSFY and LSQPKIVKWDR, on β2-microglobulin (β 2m). Many of the RF-reactive sites on Cγ2 and C γ3 as well as on β2m show common immunodominant valines, leucines, tryptophanes, arginines, lysines, and glutamines, thus comprising common reactive residues. In the future, this approach may provide more direct insight into the specificities of other autoantibodies.

scholarly journals Rheumatoid Arthritis-Associated Mechanisms of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans

2019 ◽  
Vol 8 (9) ◽  
pp. 1309 ◽  
Author(s):  
Eduardo Gómez-Bañuelos ◽  
Amarshi Mukherjee ◽  
Erika Darrah ◽  
Felipe Andrade
Keyword(s):  
Rheumatoid Arthritis ◽  
Autoimmune Disease ◽  
Porphyromonas Gingivalis ◽  
Aggregatibacter Actinomycetemcomitans ◽  
Unknown Etiology ◽  
Preventive Interventions ◽  
Periodontal Pathogens ◽  
Periodontal Bacteria ◽  
Immune Mediated

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology characterized by immune-mediated damage of synovial joints and antibodies to citrullinated antigens. Periodontal disease, a bacterial-induced inflammatory disease of the periodontium, is commonly observed in RA and has implicated periodontal pathogens as potential triggers of the disease. In particular, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans have gained interest as microbial candidates involved in RA pathogenesis by inducing the production of citrullinated antigens. Here, we will discuss the clinical and mechanistic evidence surrounding the role of these periodontal bacteria in RA pathogenesis, which highlights a key area for the treatment and preventive interventions in RA.

scholarly journals Immunopathogenic Mechanisms and Novel Immune-Modulated Therapies in Rheumatoid Arthritis

2019 ◽  
Vol 20 (6) ◽  
pp. 1332 ◽  
Author(s):  
Shyi-Jou Chen ◽  
Gu-Jiun Lin ◽  
Jing-Wun Chen ◽  
Kai-Chen Wang ◽  
Chiung-Hsi Tien ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Unknown Etiology ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Disease Outcomes ◽  
Immune Mediated ◽  
Clinical Impairment ◽  
Inflammatory Autoimmune Disease ◽  
Near Future ◽  
Better Than

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anticitrullinated peptide antibodies. The orchestra of the inflammatory process among various immune cells, cytokines, chemokines, proteases, matrix metalloproteinases (MMPs), and reactive oxidative stress play critical immunopathologic roles in the inflammatory cascade of the joint environment, leading to clinical impairment and RA. With the growing understanding of the immunopathogenic mechanisms, increasingly novel marked and potential biologic agents have merged for the treatment of RA in recent years. In this review, we focus on the current understanding of pathogenic mechanisms, highlight novel biologic disease-modifying antirheumatic drugs (DMRADs), targeted synthetic DMRADs, and immune-modulating agents, and identify the applicable immune-mediated therapeutic strategies of the near future. In conclusion, new therapeutic approaches are emerging through a better understanding of the immunopathophysiology of RA, which is improving disease outcomes better than ever.

Immuno-biological Assessments of Temporomandibular Joint Disease in Patients with Immune-mediated Rheumatic Conditions. A cross sectional study of 273 cases

2018 ◽  
Vol 68 (12) ◽  
pp. 2987-2991
Author(s):  
Cristina Iordache ◽  
Bogdan Vascu ◽  
Eugen Ancuta ◽  
Rodica Chirieac ◽  
Cristina Pomirleanu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Psoriatic Arthritis ◽  
Temporomandibular Joint ◽  
Final Analysis ◽  
Cross Sectional Study ◽  
Joint Disease ◽  
Sectional Study ◽  
Cross Sectional ◽  
Immune Parameters ◽  
Immune Mediated

Temporomandibular joint (TMJ) is commonly involved in various immune-mediated rheumatic disorders accounting for significant disability and impaired quality of life. The aim of our study was to assess inflammatory and immune parameters in patients with TMJ arthritis related to rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) and to identify potential relation with severity and dysfunction of TMJ pathology. We performed a cross-sectional study in a cohort of 433 consecutive RA, 32 JIA, 258 AS, and 103 PsA. Only patients presenting with clinically significant TMJ involvement (273) related to their rheumatic condition were included in the final analysis. TMJ involvement is traditionally described in chronic inflammatory rheumatic disorders, particularly in patients with higher levels of inflammation as detected in rheumatoid arthritis and psoriatic arthritis. Disease activity and severity, as well as biological and positive serological assessments (rheumatoid factor, anti-cyclic citrullinated peptide, IL-1) remain significant determinants of the severity of TMJ arthritis.

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