scholarly journals JAK2 mutation may predict response and guide first line treatment in rheumatoid arthritis

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Yasmin Adel ◽  
Mohamed Sabry ◽  
Amr Mohamed El-Sabbagh ◽  
Yousra Sadeq
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitors ◽  
Poor Response ◽  
Janus Kinase ◽  
Response Criteria ◽  
First Line ◽  
Jak2 Mutation ◽  
Early Introduction ◽  
Link Type ◽  
Tnf Α

Abstract Background JAK (Janus kinase) inhibitors work by inhibiting the activity of one or more of the enzyme Janus kinase with a therapeutic application for treatment of cancer and inflammatory disorders such as rheumatoid arthritis (RA). We aimed to study impact of JAK2 mutation in serum of rheumatoid arthritis patients on response to first line with conventional synthetic disease-modifying anti-rheumatic drug (csDMARDS) at 3rd month by evaluating DAS28 and ACR response criteria. The study included 85 newly diagnosed rheumatoid arthritis patients and 50 matched controls. Basal JAK2 mutation assessed by PCR in blood samples, TNF-α and IL 6 were measured by ELISA in serum of patient and control groups. All patients started therapy with csDMARDs. Response assessment at 3rd month was evaluated by DAS28 and ACR response criteria. JAK2 mutation was correlated with different clinical and laboratory parameters of patients. Results Seventeen females (83.5%) and 14 males (16.5%) with age mean ± SD (years); (48.7 ± 7.2). Pretreatment JAK2 mutation, TNF-α and IL 6 were significantly high in patients. JAK2 mutation was detected in 45 (52.9%) patients while 40 (47.1%) patients were JAK2 non-mutant. Mutant JAK2 was significantly linked to severity of disease evaluated by DAS28; 14 (70%) of patients with DAS28 (≤ 2.6) were non-mutant JAK2 vs sex (30%) patients mutant JAK2 while 19 (73.1%) of patients with DAS28 (> 5.1) were mutant JAK2 vs 7 (26.9%) patients non-mutant JAK2 (P 0.02). JAK2 mutation found to be significantly correlated with ACR 20, 50, and 70 response criteria; 68.2% of patients with non-mutant JAK2 showed ACR 70 vs 31.8% in mutant group, 52% of patients with non-mutant JAK2 showed ACR 50 vs 48% in mutant group while 31.6% of patients with non-mutant JAK2 showed ACR 20 vs 68.4% in mutant group (P 0.02). JAK2 mutation were more presented in young age patients (mean ± SD; 47.1 ± 7.2 vs 50.4 ± 6.9 in mutant vs non-mutant JAK2 patients, respectively with P 0.03). JAK2 mutation was associated with high pretreatment TNFα and IL6 level in serum. Mean ± SD of TNFα; 49.4 ± 41.9 in mutant vs 26 ± 24.4 pg/ml in non-mutant group, with P (0.003) while mean ± SD of IL6; 83.5 ± 56.8 in mutant vs 47 ± 46.9 pg/ml in non-mutant group, with P (0.002). Conclusions Adult RA with pretreatment JAK2 mutation significantly showed high disease activity and high pretreatment TNFα and IL6 levels. Patients with JAK2 mutation found to be linked to poor response to 1st line csDMARDs including MTX so they could get more benefit with early introduction of JAK inhibitors as first line monotherapy or when combined with csDMARDS especially those with moderate to severe active RA. Trial registration Institutional Research Board (IRB)-Faculty of Medicine: IRB Proposal Code: R.20.11.1075-2020/11/16. Clinicaltrials.gov registration date: 8/12/2020, code: NCT04667988.

scholarly journals Conventional Disease-Modifying Antirheumatic Drugs for the Treatment of Rheumatoid Arthritis

2021 ◽  
Vol 1 (5) ◽  
Author(s):  
Shannon Hill ◽  
Nina Frey
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
First Line ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
First Line Therapy ◽  
Line Therapy ◽  
Disease Modifying ◽  
Evidence Based Guidelines

Nine evidence-based guidelines were identified that recommend the use of conventional synthetic disease-modifying antirheumatic drugs as a first-line therapy for patients with rheumatoid arthritis prior to using biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors. Methotrexate monotherapy was the most commonly recommended conventional synthetic disease-modifying antirheumatic drug recommended as first-line therapy by the included guidelines. Eight of the included guidelines recommend combination therapy using multiple conventional synthetic disease-modifying antirheumatic drugs if monotherapy is ineffective and 4 included guidelines recommend the use of glucocorticoids in combination with conventional synthetic disease-modifying antirheumatic drugs.

scholarly journals AHR-dependent genes and response to MTX therapy in rheumatoid arthritis patients

2021 ◽  
Author(s):  
Anna Wajda ◽  
Ewa Walczuk ◽  
Barbara Stypińska ◽  
Jakub Lach ◽  
Danat Yermakovich ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Poor Response ◽  
Evolutionary Analysis ◽  
First Line ◽  
Aryl Hydrocarbon ◽  
First Line Therapy ◽  
Genes Expression ◽  
Ahr Gene

AbstractMethotrexate (MTX) is the first-line therapy for rheumatoid arthritis. Nevertheless, MTX resistance is quite a common issue in clinical practice. There are some premises that aryl hydrocarbon receptor (AhR) gene battery may take part in MTX metabolism. In the present retrospective study, we analyzed genes expression of AHR genes battery associated with MTX metabolism in whole blood of RA patients with good and poor response to MTX treatment. Additionally, sequencing, genotyping and bioinformatics analysis of AHR repressor gene (AHRR) c.565C > G (rs2292596) and c.1933G > C (rs34453673) have been performed. Theoretically, both changes may have an impact on H3K36me3 and H3K27me3. Evolutionary analysis revealed that rs2292596 may be possibly damaging. Allele G in rs2292596 and DAS28 seems to be associated with a higher risk of poor response to MTX treatment in RA. RA patients with poor response to MTX treatment revealed upregulated AhR and SLC19A1 mRNA level. Treatment with IL-6 inhibitor may be helpful to overcome the low-dose MTX resistance. Analysis of gene expression revealed possible another cause of poor response to MTX treatment which is different from that observed in the case of acute lymphoblastic leukemia.

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 Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment

2018 ◽  
Vol 46 (1) ◽  
pp. 7-18 ◽  
Author(s):  
Josef S. Smolen ◽  
Mark C. Genovese ◽  
Tsutomu Takeuchi ◽  
David L. Hyslop ◽  
William L. Macias ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Safety Profile ◽  
Active Rheumatoid Arthritis ◽  
Prolonged Exposure ◽  
Janus Kinase ◽  
Phase Iii ◽  
Integrated Analysis ◽  
Drug Discontinuation ◽  
Adverse Cardiovascular Event ◽  
Link Type

Objective.Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib’s safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)].Methods.The “all-bari-RA” group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 (“placebo-4 mg” dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data (“2 mg-4 mg–extended”). The uncommon events description used the non-controlled all-bari-RA.Results.There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure.Conclusion.In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers:NCT01185353,NCT00902486,NCT01469013,NCT01710358,NCT01721044,NCT01721057,NCT01711359, andNCT01885078atclinicaltrials.gov.

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 Safety and Efficacy of Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis in Open-label, Longterm Extension Studies

2014 ◽  
Vol 41 (5) ◽  
pp. 837-852 ◽  
Author(s):  
Jürgen Wollenhaupt ◽  
Joel Silverfield ◽  
Eun Bong Lee ◽  
Jeffrey R. Curtis ◽  
Susan P. Wood ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Incidence Rate ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Janus Kinase ◽  
Upper Respiratory Tract ◽  
Open Label ◽  
Safety And Efficacy ◽  
Mean Values ◽  
Link Type

Objective.To describe the longterm safety and efficacy profile of tofacitinib in patients with moderate to severe active rheumatoid arthritis (RA).Methods.Data were pooled from 2 open-label studies (NCT00413699, NCT00661661) involving patients who had participated in qualifying phase I, II, or III index studies of tofacitinib. Safety data included over 60 months of observation; efficacy data are reported up to Month 48. Treatment was initiated with tofacitinib 5 or 10 mg twice daily. Primary endpoints were adverse events (AE) and laboratory safety data. Secondary endpoints included American College of Rheumatology (ACR) response rates, and Disease Activity Score (28 joints) (DAS28)-4[erythrocyte sedimentation rate (ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) assessments.Results.Overall, 4102 patients were treated for 5963 patient-years; mean (maximum) treatment duration was 531 (1844) days; 20.8% of patients discontinued treatment over 60 months. The most common AE were nasopharyngitis (12.7%) and upper respiratory tract infection (10.5%). Serious AE were reported in 15.4% of patients with an exposure-estimated incidence rate of 11.1 events/100 patient-years. Serious infections were reported in 4.5% of patients with an exposure-estimated incidence rate of 3.1 events/100 patient-years (95% CI: 2.66–3.55). Mean values for laboratory variables were stable over time and consistent with phase II and III studies. Persistent efficacy was demonstrated through Month 48, as measured by ACR response rate (ACR20/50/70) DAS28-4-ESR, and HAQ-DI. Safety and efficacy were similar for patients receiving tofacitinib as monotherapy or with background nonbiologic disease-modifying antirheumatic drugs.Conclusion.Tofacitinib demonstrated consistent safety and persistent efficacy over 48 months in patients with RA.

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 The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

2014 ◽  
Vol 74 (6) ◽  
pp. 1311-1316 ◽  
Author(s):  
D L Boyle ◽  
K Soma ◽  
J Hodge ◽  
A Kavanaugh ◽  
D Mandel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Double Blind ◽  
Link Type ◽  
Stat3 Phosphorylation ◽  
Registration Number ◽  
Clinical Responses ◽  
Regulated Gene Expression

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.ConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599.

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