ObjectivesTo investigate the effect of Janus kinase inhibitors (Jakinibs) on cardiovascular risk in adult patients with rheumatoid arthritis (RA) via a meta-analysis of randomised controlled trials (RCTs).MethodsPubMed, Embase and Cochrane library were thoroughly searched for RCTs reporting safety issues in patients with RA receiving Jakinibs, from inception to October 2018. The primary and secondary outcomes were all cardiovascular events (CVEs) and major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs). OR and 95% CI were calculated using the Mantel-Haenszel fixed-effect method.Results26 RCTs randomising 11 799 patients were included. No significant difference was observed regarding all CVEs risk following Jakinibs usage in general (OR 1.04 (0.61 to 1.76), p = 0.89), tofacitinib (OR 0.63 (0.26 to 1.54), p = 0.31), baricitinib (OR 1.21 (0.51 to 2.83), p = 0.66), upadacitinib (OR 3.29 (0.59 to 18.44), p = 0.18), peficitinib (OR 0.43 (0.07 to 2.54), p = 0.35) or decernotinib (OR 1.12 (0.13 to 10.11), p = 0.92). Likewise, there was no significant difference for Jakinibs treatment overall regarding occurrence of MACEs (OR 0.80 (0.36 to 1.75), p = 0.57) or VTEs (OR 1.16 (0.48 to 2.81), p = 0.74). Dose-dependent impact of Jakinibs on the risks of all CVEs, MACEs and VTEs was not observed in tofacitinib (5 mg vs 10 mg), upadacitinib (15 mg vs 30 mg), whereas baricitinib at 2 mg was found to be safer than 4 mg in all CVEs incidence (OR 0.19 (0.04 to 0.88), p = 0.03).ConclusionThe existing evidence from RCTs indicated no significant change in cardiovascular risk for Jakinib-treated patients with RA in a short-term perspective, but postmarketing data are sorely needed to ascertain their cardiovascular safety, especially at the higher dose, due to increased risk of thromboembolism events for both tofacitinib and baricitinib at higher dosage.

Background: We aimed to systematically assess a possible association of tofacitinib therapy with cardiovascular events (CVEs) and all-cause mortality. Methods: Systematic searches of PubMed, Embase, and Cochrane Library were conducted from inception through March 2019. Randomized controlled trials in patients with immune-mediated inflammatory diseases (IMIDs) reporting safety data were included. Included studies compared tofacitinib with placebo or 5 mg tofacitinib with 10 mg tofacitinib. The primary and secondary outcome measures were all CVEs [major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs)] and all-cause mortality. Results: 29 studies randomizing 13,611 patients were included. Compared with placebo, there was no significant increased risk of all CVEs (OR = 1.07, 95% CI 0.49–2.34), MACEs (OR 1.54, 95% CI 0.42–5.59), or all-cause mortality (OR = 1.13, 95% CI 0.26–4.95), but a decreased rate of VTEs (OR 0.03, 95% CI 0.00–0.21) in patients with IMIDs initiating tofacitinib. Meanwhile, paired comparison showed 10 mg tofacitinib twice daily was associated with a significantly lower incidence of all CVEs (OR = 0.56, 95% CI 0.33–0.96), MACEs (OR = 0.48, 95% CI 0.22–1.05), or all-cause mortality (OR = 0.47, 95% CI 0.19–1.17), but a trend toward an increase in VTEs risk (OR = 1.47, 95% CI 0.25–8.50), compared with the 5 mg regimen. Conclusion: Compared with placebo, there was no augmented risk of CVEs and all-cause mortality in patients with IMIDs following tofacitinib treatment in a short-term perspective, whereas 10 mg twice daily tofacitinib appeared to be associated with reduction in cardiovascular and all-cause mortality risks, except VTEs, relative to the 5 mg twice daily dose. Long-term studies and postmarketing risk monitoring are increasingly needed to develop a better understanding.

Objectives To explore the risk of new and recurrent cancer in adult RA patients with prior malignancy and subsequently exposed to biologic therapies. Methods Separate searches were performed of PubMed, EMBASE and Cochrane Library and conference proceedings for observational studies reporting cancer incidence or recurrence in patients with RA and prior malignancy treated with biologics and conventional synthetic DMARDs (csDMARDs). Mantel-Haenszel fixed-effects method was conducted to calculate relative risk and 95% CI. Results A total of 12 studies involving 13 598 patients and 32 473 patient-years of follow-up were included (10, 3 and 1 studies for TNF inhibitors [TNFi], rituximab and anakinra, respectively). The crude incidence of new and recurrent cancer per 1000 patient-years were 34.4 for TNFi, 32.3 for rituximab, 32.3 for anakinra and 31.8 for csDMARDs. In the quantitative meta-analysis, biologics were not associated with an increased risk of new or recurrent cancer compared with csDMARDs in patients with RA and prior cancer (TNFi: relative risk = 0.95, 95% CI = 0.83, 1.09; rituximab: relative risk = 0.89, 95% CI = 0.52, 1.53). Secondary analyses of stratification of cancer types, the interval between initiation of TNFi and prior cancer diagnosis, and duration of TNFi exposure, found similar results. Conclusion Compared with csDMARDs, there is no increased risk of developing cancer overall or some specific subtypes in RA patients with a prior cancer receiving biologics. More investigations are warranted to explore the risk of cancer development in individual cancer as well as to determine optimal time to initiate biologic therapy after the diagnosis of cancer or completion of cancer treatment.

Background Numerous preclinical studies have revealed a critical role of cysteine-rich 61 (Cyr61) in the pathogenesis of rheumatoid arthritis (RA). But there is little literature discussing the clinical value of circulation Cyr61 in RA patients. The aim of our study is to investigate the serum Cyr61 level and its association with disease activity in RA patients. Methods A training cohort was derived from consecutive RA patients who visited our clinic from Jun 2014 to Nov 2018. Serum samples were obtained at the enrollment time. To further confirm discovery, an independent validation cohort was set up based on a registered clinical trial. Paired serum samples of active RA patients were respectively collected at baseline and 12 weeks after uniformed treatment. Serum Cyr61 concentration was detected by enzyme-linked immunosorbent assay. The comparison of Cyr61 between RA patients and controls, the correlation between Cyr61 levels with disease activity, and the change of Cyr61 after treatment were analyzed by appropriate statistical analyses. Results A total of 177 definite RA patients and 50 age- and gender-matched healthy controls were enrolled in the training cohort. Significantly elevated serum Cyr61 concentration was found in RA patients, demonstrating excellent diagnostic ability to discriminate RA from healthy controls (area under the curve (AUC) = 0.98, P <  0.001). In addition, the Cyr61 level in active RA patients was significantly lower than that in patients in remission/low disease activity, and it was inversely correlated with composite disease activity scores and almost all of the components in statistic. Further study in the validation cohort ( n = 77) showed a significant increase of the Cyr61 level at 12 weeks in ACR responders (ACR20/50/70), while no significant change of the Cyr61 level from baseline was observed in non-responders. Conclusions Serum Cyr61 levels were remarkably increased in RA patients compared with those in healthy controls. The Cyr61 concentration was inversely correlated with RA disease activity and upregulated in those therapeutic responders. Trial registration Combination Therapy Prevents the Relapse of RA, NCT02320630 . Registered 19 December 2014, Electronic supplementary material The online version of this article (10.1186/s13075-019-1906-y) contains supplementary material, which is available to authorized users.

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BackgroundNumerous preclinical studies have revealed a critical role of Cysteine rich 61 (Cyr61) in the pathogenesis of rheumatoid arthritis (RA). However, little is known about the potential value of circulation Cyr61 in clinical RA patients.ObjectivesTo compare serum Cyr61 level in patients with RA and healthy controls, and to characterize the potential association between Cyr61 and RA disease activity.MethodsIn training cohort, serum samples were obtained from 177 patients with definite RA and 50 age- and gender- matched healthy controls. Medical records were collected and serum Cyr61 concentration was detected by enzyme-linked immunosorbent assay. Correlations between Cyr61 levels with clinical disease activity were analyzed. Furthermore, a validation cohort consisting of 77 active RA patients who received uniform biologic therapy for 12 weeks was set up (ClinicalTrials.gov identifier: NCT02320630). Paired serum samples were collected at baseline and after 12-week treatment for each individual and prepared for detection of Cyr61. Comparisons between groups were made using Mann-Whitney U test or Wilcoxon matched-pairs signed rank test, as appropriate.ResultsSignificant elevation of serum Cyr61 concentration was found in RA patients, demonstrating excellent diagnostic ability to discriminate RA with healthy controls (area under the curve (AUC) = 0.98, P < 0.001). In training cohort, Cyr61 level in active RA patients was significantly lower than that in inactive RA, and it was inversely with measures of clinical disease activity in statistic. Findings were further confirmed in our validation cohort. Active RA patients who had a reduction in disease activity showed a significantly increase of Cyr61 level after effective treatment (in terms of achieving ACR20/50/70 improvement criteria). RA patients who did not achieve ACR response showed no significant difference of Cyr61 level before and after treatment. Multivariate logistic regression analysis revealed that increase of Cyr61 level as well as younger age were independent indicators for achieving ACR20 response.ConclusionSerum Cyr61 levels were remarkably increased in RA patients compared with healthy control. More intriguingly, the level of Cyr61 was inversely associated with RA disease activity and increased after effective treatment.References[1] Zhang Q, Wu J, Cao Q, Xiao L, Wang L, He D, et al. A critical role of Cyr61 in interleukin-17-dependent proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis & Rheumatism. 2009;60(12):3602-12.[2] Chen CY, Su CM, Hsu CJ, Huang CC, Wang SW, Liu SC, et al. CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angiogenesis by Inhibiting miR-126 Expression in Rheumatoid Arthritis. J BONE MINER RES. 2017 2017-01-01;32(1):34-45.[3] Barranco C. CCN1, a novel RA target? NAT REV RHEUMATOL. 2016 2016-08-19;12(10):561.Conflict of interestThe authors declare that they have no competing interests.Disclosure of InterestsNone declared

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