scholarly journals Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in RA Patients?

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Przemyslaw J. Kotyla
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Metabolism ◽  
Theoretical Background ◽  
Janus Kinase ◽  
Biologically Active ◽  
System Functioning ◽  
And Function

The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response. JAK kinase blockade offers a unique opportunity to block most of the key cytokines enabling the deep interaction into immune system functioning. Following discovery first Jakinibs were intensively studied in various forms of autoimmune diseases, including rheumatoid arthritis, and finally two Jakinibs tofacitinib and Baricitinib have been approved for the treatment of rheumatoid arthritis. Some clinical data indicated that under special circumstances Jakinibs may be even superior to biologics in the treatment of RA; however this suggestion should be verified in large clinical and observational studies.

scholarly journals Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview

2021 ◽  
Vol 10 (6) ◽  
pp. 1241
Author(s):  
Yoshiya Tanaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Damage ◽  
Kinase Inhibitors ◽  
Joint Destruction ◽  
Joint Damage ◽  
Nuclear Factor Κb ◽  
Cartilage Destruction ◽  
Janus Kinase ◽  
Systemic Autoimmune Disease ◽  
And Cartilage

In rheumatoid arthritis, a representative systemic autoimmune disease, immune abnormality and accompanying persistent synovitis cause bone and cartilage destruction and systemic osteoporosis. Biologics targeting tumor necrosis factor, which plays a central role in the inflammatory process, and Janus kinase inhibitors have been introduced in the treatment of rheumatoid arthritis, making clinical remission a realistic treatment goal. These drugs can prevent structural damage to bone and cartilage. In addition, osteoporosis, caused by factors such as menopause, aging, immobility, and glucocorticoid use, can be treated with bisphosphonates and the anti-receptor activator of the nuclear factor-κB ligand antibody. An imbalance in the immune system in rheumatoid arthritis induces an imbalance in bone metabolism. However, osteoporosis and bone and cartilage destruction occur through totally different mechanisms. Understanding the mechanisms underlying osteoporosis and joint destruction in rheumatoid arthritis leads to improved care and the development of new treatments.

scholarly journals Fc-gamma receptors and S100A8/A9 cause bone erosion during rheumatoid arthritis. Do they act as partners in crime?

Rheumatology ◽  
2019 ◽  
Vol 58 (8) ◽  
pp. 1331-1343 ◽  
Author(s):  
Irene Di Ceglie ◽  
Nik N L Kruisbergen ◽  
Martijn H J van den Bosch ◽  
Peter L E M van Lent
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Disease Progression ◽  
Immune Cells ◽  
Bone Erosion ◽  
Fcγ Receptor ◽  
Receptor Signalling ◽  
Radiographic Disease ◽  
Osteoclast Function ◽  
And Function

AbstractBone erosion is one of the central hallmarks of RA and is caused by excessive differentiation and activation of osteoclasts. Presence of autoantibodies in seropositive arthritis is associated with radiographic disease progression. ICs, formed by autoantibodies and their antigens, activate Fcγ-receptor signalling in immune cells, and as such stimulate inflammation-mediated bone erosion. Interestingly, ICs can also directly activate osteoclasts by binding to FcγRs on their surface. Next to autoantibodies, high levels of alarmins, among which is S100A8/A9, are typical for RA and they can further activate the immune system but also directly promote osteoclast function. Therefore, IC-activated FcγRs and S100A8/A9 might act as partners in crime to stimulate inflammation and osteoclasts differentiation and function, thereby stimulating bone erosion. This review discusses the separate roles of ICs, FcγRs and alarmins in bone erosion and sheds new light on the possible interplay between them, which could fuel bone erosion.

scholarly journals Placebo Response in Rheumatoid Arthritis Clinical Trials

2019 ◽  
Vol 47 (1) ◽  
pp. 28-34 ◽  
Author(s):  
Katie Bechman ◽  
Mark Yates ◽  
Sam Norton ◽  
Andrew P. Cope ◽  
James B. Galloway
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Placebo Response ◽  
Janus Kinase ◽  
Controlled Trials ◽  
American College Of Rheumatology ◽  
Factor Therapy ◽  
Expectation Bias ◽  
Over Time

Objective.Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization.Methods.The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)–naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time.Results.There were 32 trials in total: anti–tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09–0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04–0.31, p = 0.01) that remained significant after controlling for potential confounders.Conclusion.There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.

scholarly journals Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Javier Traba ◽  
Michael N. Sack ◽  
Thomas A. Waldmann ◽  
Olga M. Anton
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Immune Surveillance ◽  
Antitumor Effects ◽  
Cancer Management ◽  
Immunosuppressive Tumor Microenvironment ◽  
And Function ◽  
Main Effects

Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management.

scholarly journals Monitoring the transition of patients on biologics in rheumatoid arthritis: Consensus guidance for pharmacists

2021 ◽  
Vol 19 (3) ◽  
pp. 2377
Author(s):  
Denis Choquette ◽  
Jonathan Chan ◽  
Mohammad Bardi ◽  
Carolyn Whiskin ◽  
Gabriel Torani ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Best Practices ◽  
Kinase Inhibitors ◽  
Unmet Need ◽  
Nominal Group Technique ◽  
Janus Kinase ◽  
Nominal Group ◽  
Nocebo Effect ◽  
Patient Journey ◽  
Janus Kinase Inhibitors

Background: Recent approvals for novel agents such as the small molecule Janus kinase inhibitors (JAKi), combined with the advent of biosimilars has widened the gamut of available therapeutic options in the treatment of rheumatoid arthritis (RA). This combined with the introduction of mandatory non- medical switches to biosimilars in some jurisdictions by both public and private payors has led to a significant increase in the volume of therapeutic changes for patients. Pharmacists are well positioned to ensure effective and safe transitions, however there is a significant unmet need for objective and subjective clinical guidance around therapy as well disease state monitoring in RA that facilitates best practices throughout the patient journey. Objective: In this paper we aim to create a consensus derived monitoring algorithm for pharmacists to facilitate best practices throughout therapeutic transitions from originator biologic to other originator biologics, biosimilars, and Janus kinase inhibitors in RA. Methods: The Nominal Group Technique (NGT) was used to understand if consensus could be found among the participants. Clinically relevant questions were developed to capture solutions to the identified unmet need. The faculty considered the questions as individuals, and privately generated answers/ideas. After discussion and consideration, the participants ranked the ideas and established a consensus. Results: Based on the outcome of the consensus discussions, an algorithm was created to help guide pharmacists through therapeutic transitions in RA. The tool covers important topics such as pre-transition considerations, avoiding the nocebo effect for biosimilars, specific considerations for each drug or class, monitoring efficacy, and when to refer. Conclusions: New classes of anti-rheumatic drugs including JAKi, along with the introduction of biosimilars are presenting more opportunity for therapeutic changes and monitoring in patients with RA. We hope our evidence-based consensus derived guidance tool will assist frontline pharmacists in supporting their patients to a successful therapeutic transition in RA.

scholarly journals Drug retention of 7 biologics and tofacitinib in biologics-naïve and biologics-switched patients with rheumatoid arthritis -The ANSWER cohort study-

2020 ◽  
Author(s):  
Kosuke Ebina ◽  
Toru Hirano ◽  
Yuichi Maeda ◽  
Wataru Yamamoto ◽  
Motomu Hashimoto ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Duration ◽  
Kinase Inhibitors ◽  
Proportional Hazards ◽  
Certolizumab Pegol ◽  
Cox Proportional Hazards ◽  
Janus Kinase ◽  
Retention Rates ◽  
Naive Group ◽  
Drug Retention

Abstract Background: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of 7 biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib (TOF), one of the janus kinase inhibitors, in bDMARDs-naïve and bDMARDs-switched patients with rheumatoid arthritis (RA).Methods: This study assessed 3,897 patients and 4,415 treatment courses with bDMARDs and TOF from 2001 to 2019 (2,737 bDMARDs-naïve patients and 1,678 bDMARDs-switched patients [59.5% switched to their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate 4.3; concomitant prednisolone [PSL] dose 6.1 mg/day [42.4%], and methotrexate [MTX] dose 8.5 mg/week [60.9%]). Treatment courses included abatacept (ABT; n=663), adalimumab (ADA; n=536), certolizumab pegol (CZP; n=226), etanercept (ETN; n=856), golimumab (GLM; n=458), infliximab (IFX; n=724), tocilizumab (TCZ; n=851), and TOF (n=101/only bDMARDs-switched cases). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX, starting date, and number of switched bDMARDs) using Cox proportional hazards modeling.Results: Adjusted drug retention rates for each discontinuation reason were as follows: lack of effectiveness in the bDMARDs-naïve group (from 70.8% [CZP] to 85.1% [ABT]; P=0.001 between agents) and the bDMARDs-switched group (from 52.8% [CZP] to 78.7% [TCZ]; P<0.001 between agents). Toxic adverse events in the bDMARDs-naïve group (from 86.9% [IFX] to 96.3% [ABT]; P<0.001 between agents) and the bDMARDs-switched group (from 81.1% [ADA] to 95.4% [ETN]; P=0.01 between agents). Finally, overall retention rates excluding discontinuation for non-toxic reasons or remission ranged from 64.2% (IFX) to 82.0% (ABT) (P<0.001 between agents) in the bDMARDs-naïve group and from 44.2% (ADA) to 66.8% (TCZ) (P<0.001 between agents) in the bDMARDs-switched group. Conclusions: Remarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.

Design, Synthesis, Cytotoxic Activity and Apoptosis-inducing Action of Novel Cinnoline Derivatives as Anticancer Agents

2018 ◽  
Vol 18 (8) ◽  
pp. 1208-1217 ◽  
Author(s):  
Manal M. Kandeel ◽  
Aliaa M. Kamal ◽  
Bassem H. Naguib ◽  
Marwa S.A. Hassan
Keyword(s):  
Tyrosine Kinase ◽  
Cytotoxic Activity ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Topoisomerase I ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Normal Breast ◽  
Biologically Active

Aims: Tyrosine kinases and topoisomerase I are common target enzymes for the majority of the anticancer agents. In contrast to quinazolines and quinolines, kinase inhibitors and topoisomerase inhibitors incorporating cinnoline scaffold are relatively infrequent. Thus the aim of this work was to replace the former scaffolds with the latter one. Eighteen novel cinnoline derivatives were designed, synthesized and characterized using both microanalytical and spectral data. Methods: The cytotoxic activity of the new compounds was screened in vitro against both human breast cancer cells and normal breast cells. Results: The enzymatic inhibition activity of promising candidates against both epidermal growth factor receptor tyrosine kinase and topoisomerase I was accomplished. Conclusions: Cell cycle profiles were observed at IC50 doses of representative biologically active compounds. Compound 7 represented a new scaffold incorporating triazepinocinnoline ring system and showed outstanding cytotoxic activity against MCF-7 (0.049 µM), tyrosine kinase inhibition (0.22 µM), apoptosis percentage and the highest selectivity index.

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