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Selectivity of Janus Kinase Inhibitors in Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases: Is Expectation the Root of All Headache?

ABSTRACT: Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors to the nucleus. Recently developed JAK inhibitors (JAKinibs) inhibit JAKs non-selectively or selectively and down-regulate the effects of corresponding ligands (i.e. cytokines and growth factors). JAKinibs are efficacious against rheumatoid arthritis and other immune-mediated inflammatory diseases and are being increasingly prescribed clinically. Regarding safety, JAKinib use is associated with common or unique changes in laboratory parameters; however, incidence rates of serious adverse drug reactions (ADRs) associated with these changes are low. Opportunistic and other infections, including tuberculosis, are the most critical ADRs of treatment with JAKinibs, and screening and monitoring of patients should be carefully performed. Incidence rates of herpes zoster (HZ) in patients receiving JAKinibs are high in Japan and Korea, and modestly high in other countries. Filgotinib may not be associated with an elevated risk for HZ, but long-term safety data are lacking. Data from clinical development programmes and post-marketing surveillance have indicated no increased risk for malignancy or serious cardiac events; however, long-term observational studies are necessary. Despite the non-elevated risk of gastrointestinal perforations, patients with older age and/or a history of diverticulitis or receiving non-steroidal anti-inflammatory drugs should be carefully evaluated to determine the risk-benefit balance. The incidence rates of venous thromboembolism with all approved doses are similar to that expected in the population, although there are discrepancies in the placebo-controlled portion of the baricitinib clinical development programmes. Regulatory agencies in the USA and Europe suggested a higher risk for thrombotic events in patients receiving JAKinibs. Pharmacokinetic studies demonstrated that dose adjustment should be considered for JAKinib use in patients with moderate-to-severe renal or hepatic dysfunction, depending on the metabolism of each drug. Long-term observational studies enrolling patients with diverse clinical backgrounds are required to strike a risk-benefit balance in clinical settings.

SUBMITTER: Harigai M

PROVIDER: S-EPMC7395017 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Selectivity of Janus Kinase Inhibitors in Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases: Is Expectation the Root of All Headache?

Harigai Masayoshi M Honda Suguru S

Drugs 20200801 12

Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors to the nucleus. Recently developed JAK inhibitors (JAKinibs) inhibit JAKs non-selectively or selectively and down-regulate the effects of corresponding ligands (i.e. cytokines and growth factors). JAKinibs are efficacious against rheumatoid arthritis and other immune-mediated inflammatory diseases and are being increasingly presc ...[more]

PMID: 32681420

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Project description:Background: Janus kinase (JAK) inhibitors have emerged as a progressively utilized therapeutic approach for the management of rheumatoid arthritis (RA). However, the complete determination of their cardiovascular safety remains inconclusive. Hence, the primary objective of this network meta-analysis is to meticulously assess and juxtapose the cardiovascular risks linked to distinct JAK inhibitors employed in RA patients. Methods: A systematic review and network meta-analysis were meticulously conducted, encompassing a collection of randomized controlled trials (RCTs) that focused on investigating the incidence of major adverse cardiovascular events (MACE) and all-cause mortality associated with Janus kinase (JAK) inhibitors administered to patients with rheumatoid arthritis (RA). Extensive exploration was performed across multiple electronic databases, incorporating studies published until March 2023. To be included in this analysis, the RCTs were required to involve adult participants diagnosed with RA who received treatment with JAK inhibitors. To ensure accuracy, two authors independently undertook the selection of eligible RCTs and meticulously extracted aggregate data. In order to examine the outcomes of MACE and all-cause mortality, a frequentist graph theoretical approach within network meta-analyses was employed, utilizing random-effects models. Third study has been registered on PROSPERO under the reference CRD42022384611. Findings: A specific selection encompassing a total of 14 meticulously chosen randomized controlled trials was undertaken, wherein 13,524 patients were assigned randomly to distinct treatment interventions. The analysis revealed no notable disparity in the occurrence of major adverse cardiovascular events (MACE) between the interventions and the placebo group. However, in comparison to adalimumab, the employment of JAK inhibitors exhibited an association with higher rates of all-cause mortality [odds ratio (OR): 1.7, 95% confidence interval (CI): 1.02-2.81]. This observed increase in risk primarily stemmed from the usage of tofacitinib (OR: 1.9, 95% CI: 1.12-3.23). None of the other JAK inhibitors exhibited a statistically significant variance in all-cause mortality when compared to adalimumab. Interpretation: Our study suggests that JAK inhibitors may not increase the risk of MACE in RA patients but may be associated with a higher risk of all-cause mortality compared to adalimumab, primarily due to tofacitinib use. Rheumatologists should carefully consider the cardiovascular risks when prescribing JAK inhibitors, particularly tofacitinib, for RA patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384611, CRD42022384611.

Project description:Introduction: Janus kinase inhibitors (JAK-i), a class of targeted synthetic disease-modifying antirheumatic drugs (tDMARDs), are suggested as second or third-line therapies in rheumatoid arthritis (RA). Synthesized cost-effective evidence would aid in informed decision-making given the similar clinical effectiveness of JAKi, but incongruent cost-effectiveness reports. Methods: Literature search was conducted in PubMed, Embase, Scopus, and Tufts Medical Centers’ cost-effective analysis registry. We pooled the incremental net benefit (INB) with 95% confidence interval (CI) using random-effects model and the heterogeneity was assessed using Cochrane-Q test and I2 statistic. Modified economic evaluation bias checklist was used to assess the quality of selected studies. Publication bias was assessed using a funnel plot and Egger’s test. The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) assessment was performed to assess the certainty of outcomes presented. Results: We included seventeen relevant studies for systematic review, of which fifteen were eligible for meta-analysis. The meta-analysis results showed that JAK-i is cost-effective compared to csDMARDS/bDMARDs with a pooled INB (INBp) of $19,886 (95% CI, 1,635 to 38,137) but with considerable heterogeneity (I2 = 99.14). As a second-line treatment for csDMARD failed RA, JAK-i is cost-effective than csDMARD/bDMARD with a pooled INB of $23,144 (74.1–46,214) and high heterogeneity (I2 = 99.67). But on a separate analysis JAK-i as second-line treatment is not cost-effective than TNF-a-i (INBp = $25,813, -5,714 to 57,340). However, leave-one-out analysis found that omitting a single outlier makes JAK-i cost-effective. Further, JAK-i is not cost-effective as a third-line treatment for csDMARD-TNF-a-I failed RA, compared to csDMARDs/bDMARDs with INBp $26,157 (-7,284 to 59,598). Conclusion: Meta-analysis suggests that JAK-i is cost-effective when used after csDMARD failure but not cost-effective when used after csDMARD-TNF-a-i failure with low certainty of evidence. Clinical Trial Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021222541, identifier CRD42021222541

Dataset Information

Selectivity of Janus Kinase Inhibitors in Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases: Is Expectation the Root of All Headache?

Publications

Selectivity of Janus Kinase Inhibitors in Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases: Is Expectation the Root of All Headache?

Similar Datasets

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