Clinical use of Jak 1 inhibitors for rheumatoid arthritis.
Ontology highlight
ABSTRACT:
SUBMITTER: Nash P
PROVIDER: S-EPMC8098107 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Clinical use of Jak 1 inhibitors for rheumatoid arthritis.
Rheumatology (Oxford, England) 20210501 Suppl 2
The uptake of Jak inhibitors in the RA space has been among the most rapid in rheumatology, based on the results of comprehensive clinical trial programmes of five agents. Newer generations of Jak inhibitors, like upadacitinib and filgotinib, target Jak 1 selectively with the aim of maximizing efficacy and to improve safety. This article will review the clinical significance of evidence on: (i) Jak 1 selectivity; (ii) efficacy from the SELECT and FINCH clinical trial programmes including patient ...[more]
Similar Datasets
Project description:Janus kinase (JAK) Inhibitors are the latest drug class of disease-modifying medication to emerge for the treatment of rheumatoid arthritis (RA). They are a small molecule-targeted treatment and are the first oral option to compare favourably to existing biologic disease-modifying anti-rheumatic drugs (DMARDs). Tofacitinib, baricitinib and upadacitinib are the first 3 JAK inhibitors to become commercially available in the field and are the core focus of this review. To date, they have demonstrated comparable efficacy to tumour necrosis factor (TNF) inhibitors in terms of American College of Rheumatology (ACR) response rates and disease activity (DAS28) scores with similar cost to the benchmark adalimumab. This narrative review article aims to synthesise and distil the key available trial data on JAK inhibitor efficacy and safety, along with their place in the ACR and European League Against Rheumatism (EULAR) guidelines for RA. The novel mechanism of action of the JAK/STAT pathway is highlighted along with the potential effects of modulating each pathway. The rapid onset of action, role in attenuation of central pain processing and effect on structural damage and radiographic progression are also all examined in detail. We also explore the latest meta-analyses and comparative performance of each of the 3 available JAKs in an effort to determine which is most efficacious and which has the most favourable safety profile. Post marketing concerns regarding thromboembolism risk and herpes zoster infection are also discussed. Additionally, we review the cost-benefit analyses of the available JAK inhibitors and address some of the pharmacoeconomic considerations for real-world practice in the UK and US by detailing the raw acquisition cost and the value they provide in comparison to the benchmark biologic adalimumab and the anchor DMARD methotrexate.
| S-EPMC7500842 | biostudies-literature
Project description:Background: More and more trials have been conducted. We aimed to assess the efficacy and safety of different JAKinibs in RA. Methods: A systematic search of randomized controlled trials (RCTs) with JAKinib treatment in RA published in the Medline, Embase, and Cochrane databases up to May 2021 was performed. Results: 37 trials involving 15,174 patients were identified. Pooled analysis revealed that JAKinibs were associated with significant therapeutic improvement in RA patients as determined by ACR20 (RR = 2.03, 95% CI: 1.85 to 2.28) and HAQ-DI (MD = −0.31, 95% CI: −0.33 to −0.28) over placebo. Compared to placebo, JAKinib treatment was also associated with more adverse events (RR = 1.10, p < 0.001; RR = 1.29, p < 0.001; RR = 1.59, p = 0.02). Baricitinib and upadacitinib were related to more frequent adverse events (RR = 1.10; 95% CI: 1.01, 1.21; RR = 1.19; 95% CI: 1.11, 1.28) and infection (RR = 1.22; 95% CI: 1.09, 1.37; RR = 1.38; 95% CI: 1.22, 1.56), whereas only baricitinib was associated with more herpes zoster (RR = 3.15; 95% CI: 1.19, 8.33). Conclusions: JAKinibs were superior to placebo for improving signs, symptoms, and health-related quality of life in RA patients at short term, whereas the overall risk of adverse events and infections were greater with baricitinib and upadacitinib, and a higher risk of herpes zoster was only associated with baricitinib. More trials are needed to investigate the long-term safety.
| S-EPMC9369647 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease associated by inflammation of the synovial tissue and autoantibody production. Oxidative stress and free radicals are known to be indirectly implicated in joint damage and cartilage destruction in RA. Several studies describe the presence of mitochondrial dysfunction in RA, but few of them follow the dynamics in energy parameters after therapy. The aim of our investigation is to evaluate the direct effect of JAK inhibitors on cellular metabolism (and under induced oxidative stress) in RA patients. Ten newly diagnosed RA patients were included in the study. Peripheral blood mononuclear cells (PBMCs) and plasma were isolated before and 6 months after therapy with JAK inhibitors. A real-time metabolic analysis was performed to assess mitochondrial function and cell metabolism in PBMCs. Sonographic examination, DAS28 and conventional clinical laboratory parameters were determined also prior and post therapy. A significant decrease in proton leak after therapy with JAK inhibitors was found. The increased production of ATP indicates improvement of cellular bioenergetics status. These findings could be related to the catalytic action of JAK inhibitors on oxidative phosphorylation which corresponds to the amelioration of clinical and ultra-sonographic parameters after treatment. Our study is the first to establish the dynamics of mitochondrial parameters in PBMCs from RA patients before and after in vivo therapy with JAK inhibitors.
| S-EPMC10766792 | biostudies-literature
Project description:Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.
| S-EPMC6390879 | biostudies-literature
Project description:IntroductionJanus kinase (JAK) inhibitors are a class of targeted therapies for rheumatoid arthritis (RA) with established clinical efficacy. However, little is known about their efficacy compared with each other. This network meta-analysis (NMA) estimated the comparative efficacy of JAK inhibitors currently approved for RA.MethodsA targeted literature review was conducted for phase III randomized controlled trials (RCTs) evaluating the efficacy of three approved JAK inhibitors (tofacitinib, baricitinib, and upadacitinib) as monotherapy or combination therapy among patients with moderate-to-severe RA who had inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARD-IR). Using Bayesian NMA, American College of Rheumatology (ACR) 20/50/70 responses and clinical remission (defined as DAS28-CRP < 2.6) were evaluated separately at 12 and 24 weeks.ResultsEleven RCTs were identified and included in the NMA. All JAK inhibitors demonstrated significantly better efficacy than csDMARD. Among combination therapies, upadacitinib 15 mg had the highest 12-week ACR50 responses (median [95% credible interval]: 43.4% [33.4%, 54.5%]), followed by tofacitinib 5 mg (38.7% [28.6%, 49.8%]), baricitinib 2 mg (37.1% [25.0%, 50.6%]), and baricitinib 4 mg (36.7%, [27.2%, 47.0%]). Similar results were observed for ACR20/70 and at week 24. Upadacitinib 15 mg + csDMARD was also found to have the highest clinical remission rates at week 12 (29.8% [16.9%, 47.0%]), followed by tofacitinib 5 mg (24.3%, [12.7%, 40.2%]), baricitinib 4 mg (22.8%, [11.8%, 37.5%]), and baricitinib 2 mg (20.1%, [8.6%, 37.4%]). Similar results were seen at week 24. Among monotherapies, upadacitinib had a higher ACR50 response (38.5% [25.3%, 53.2%]) than tofacitinib (30.4% [18.3%, 45.5%]). The differences in efficacy measures were not statistically significant between the JAK inhibitors.ConclusionsThe NMA found that upadacitinib 15 mg once daily had numerically higher efficacy in terms of ACR response and clinical remission among approved JAK combination therapies and monotherapies for csDMARD-IR patients with RA.
| S-EPMC7467453 | biostudies-literature
Project description:BackgroundTo compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea.MethodsUsing 2009-2019 Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating a JAKi or TNFi. The primary outcomes were herpes zoster (HZ), serious bacterial (SBI), and opportunistic infections (OI). Propensity-score fine-stratification (PSS) and weighting were applied to adjust for > 70 baseline covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing JAKi versus TNFi users.ResultsWe included 2963 JAKi initiators PSS-weighted on 5169 TNFi initiators. During a follow-up of 1.16 years, the most frequent type of infections was HZ with incidence rate (IR) per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively. The IR of SBI was 1.39 and 1.32, respectively. The OI was rare with a majority being tuberculosis and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively. The PSS-weighted HR (95% CI) for individual types of infections was 2.37 (2.00-2.80) for HZ, 1.04 (0.71-1.52) for SBI, and 0.25 (0.09-0.73) for OI.ConclusionsThis population-based cohort study on RA patients treated with JAKi or TNFi in Korea showed an exceptionally high IR of HZ in both treatment groups compared to that from Western countries, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of SBI was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators.
| S-EPMC10369724 | biostudies-literature
Project description:ObjectivesThis study aimed to identify characteristics of patients with rheumatoid arthritis (RA) with an inadequate response to Janus kinase inhibitors (JAKi-IR) and evaluate the efficacy and safety of subsequent treatments.MethodsThis study included 434 patients with RA who started JAKi treatment. JAKi-IR patients were those who switched to another drug due to inadequate response or did not reach low disease activity within 26 weeks of beginning JAKi. The efficacy and safety of switched biological disease-modifying anti-rheumatic drugs (bDMARDs) or cycled targeted synthetic disease-modifying anti-rheumatic drugs were analysed 26 weeks after switching treatment in JAKi-IR patients.ResultsPatients with JAKi-IR RA accounted for 31.8% (n=138/434). Multiple logistic regression identified factors contributing to JAKi-IR, such as the prior use of multiple ineffective bDMARDs and suboptimal JAKi dosing. There were no differences in patient background when comparing patients with RA with JAKi-IR who cycled to another JAKi (n=31) versus those who switched to bDMARDs (n=45). Among those cycling to another JAKi, the Clinical Disease Activity Index (CDAI) scores improved by week 26, with higher remission rates, while retention and adverse events remained similar. Trajectory analysis identified three CDAI response patterns, with the 'treatment response' group showing rapid and sustained improvement when cycling to another JAKi. Multiple logistic regression in this group identified another JAKi cycle as the critical factor for the treatment response.ConclusionsCycling JAKis is more effective than switching to bDMARDs in JAKi-IR RA, with no differences in safety or retention. This study suggests that cycling to another JAKi may be appropriate for patients with RA with JAKi-IR.
| S-EPMC11759213 | biostudies-literature
Project description:ObjectiveRheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, characterized by significant individual variations in treatment response. Predicting treatment response remains a formidable challenge. This study aims to identify predictors within the synovium associated with the response to JAK inhibitor therapy in RA patients, employing a retrospective approach.MethodsA retrospective analysis was conducted on 27 RA patients who underwent synovial biopsy and received JAK inhibitor therapy for at least three months at our center, from January to November 2023. These patients had comprehensive clinical records. Based on their response to JAK inhibitor therapy, as measured by the ACR20 criteria, they were categorized into non-responder and responder groups. We compared clinical data (including sex, age, disease duration), laboratory findings (RF, ACPA, ESR, CRP, etc.), DAS28-CRP scores, and synovial pathology features-such as synovial lining hyperplasia, neovascularization, stromal activation, inflammatory infiltration, and the expression of CD3, CD20, CD68, and CD138 markers in the synovium-between the two groups.ResultsThe rate of non-responder to JAKi was found to be 33.3% (nine cases out of a total of 27 patients). Non-responders, when compared to responders, exhibited longer disease duration, more pronounced synovial neovascularization alongside reduced infiltration of labeled CD20+ and CD138+ cells in the synovium. Multivariate regression analysis identified synovial neovascularization and disease duration as independent predictors of a poor response to JAK inhibitor treatment.ConclusionsThe presence of vascular phenotype with low inflammation within the synovium of RA patients is an indicator of poor response to JAK inhibitor therapy, highlighting its potential as a predictive marker for treatment outcomes.
| S-EPMC11610464 | biostudies-literature
Project description:BackgroundBaricitinib (BARI) or Tofacitinib (TOFA) were the first Janus Kinase Inhibitors (JAKi) to be marketed in rheumatoid arthritis (RA). Concerns regarding venous thromboembolism (VTE) risk have emerged during the past years. The aim of the study was to compare the baseline characteristics of patients initiating BARI or TOFA in RA before versus after European Medicine Agency (EMA)'s VTE warnings and to compare real-world persistence with these two drugs.MethodsIn this multicentric cohort study, RA patients initiating BARI or TOFA were included from October 2017, date of BARI marketing authorization in France, to September 2020. Baseline characteristics regarding VTE risk were compared (before vs. after May 2019) by using pre-specified statistical tests. Comparison of persistence was assessed by using propensity-score methods.Results232 patients were included; 155 with BARI and 77 with TOFA. Baseline characteristics of patients regarding VTE risk factors were not statistically different when Janus Kinase inhibitor (JAKi) was initiated before vs. after EMA's warnings although a trend towards a lower proportion of VTE history was observed. Five VTE events occurred, four with BARI, one with TOFA. Cumulative persistence rate at 2 years was similar between BARI and TOFA: HR 0.96; 95% Cl: 0.52 to 1.74; p = 0.89.ConclusionsOur study did not show a significant change in patients characteristics starting a JAKi after the EMA's warnings, probably due to a lack of power. Though, the lower proportion of VTE history in patients after May 2019 suggests that rheumatologists have taken into account the potential VTE risk. These results need to be confirmed by further evidence.
| S-EPMC9820905 | biostudies-literature
Project description:Background/aimsWe aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease- modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs.MethodsA quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)-28- erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs).ResultsAmong 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups.ConclusionOur interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.
| S-EPMC10338257 | biostudies-literature