BACKGROUND AND AIMS: Recent studies raise concern for increased risk of major adverse cardiovascular events (MACE) with Janus kinase inhibitors (JAKi) used to treat immune-mediated inflammatory disorders (IMIDs). We aimed to examine MACE risk with licensed biologics and small molecules used commonly between IMIDs: inflammatory bowel disease, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis.
METHODS: Data were obtained from systematic searches (from inception to May 31, 2022) in PubMed, Embase, Ovid Medline, Scopus, Cochrane Central, and Clinicaltrials.gov. Studies that assessed a pre-defined MACE (myocardial infarction, cerebrovascular accident, unstable angina, cardiovascular death, or heart failure) risk in those ≥18 years with IMIDs treated with anti-interleukin (IL)-23 antibodies, anti-IL-12/23, anti-tumor necrosis factor-alpha antibodies (anti-TNF-α) or JAKi were included in a network meta-analysis using a random-effects model with pooled odds ratios (ORs) reported with 95% credible intervals (CrIs) by drug class and disease state.
RESULTS: Among 3,528 studies identified, 40 (36 randomized controlled trials [RCTs] and 4 cohort studies) were included in the systematic review, comprising 126,961 patients with IMIDs. Based on network meta-analysis of RCTs, regardless of disease state, anti-TNF-α (OR, 2.49; CrI: 1.14-5.62), JAKi (OR, 2.64; CrI: 1.26-5.99), and anti-IL-12/23 (OR, 3.15; CrI: 1.01-13.35) were associated with increased MACE risk compared with placebo. There was no significant difference in the magnitude of the MACE risk between classes or based on IMID type.
CONCLUSIONS: Anti-IL-12/23, JAKi, and anti-TNF-α were associated with higher risk of MACE compared with placebo. The magnitude of the increased MACE risk was not different by IMID type. These results require confirmation in larger prospective studies.
OBJECTIVE: To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in rheumatoid arthritis (RA) in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar).
METHODS: The PubMed, EMBASE, Cochrane, databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the American College of Rheumatology (ACR) 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% confidence intervals (95%CI), pooled using random-effects models and then compared using a meta-regression model.
RESULTS: We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95%CI, 66-74) compared with 59% (95%CI, 55-62) in the reference-pbo group (p= 0.001). A significant difference was also found for ACR 50 [44% (95%CI, 39-50) vs 35% (95%CI, 31-39) respectively, p< 0.01].
CONCLUSION: Effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the Lessebo effect.
Introduction: Peficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are lacking. We indirectly compared peficitinib, tofacitinib, and baricitinib for rheumatoid arthritis treatment. Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congress archives up until February 12, 2019, for randomized controlled trials of peficitinib, tofacitinib, and baricitinib. Efficacy (American College of Rheumatology responses, disease activity scores, modified total Sharp score, Simplified Disease Activity Index [SDAI]) and safety outcomes were compared using a Bayesian network meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results. A network meta-regression assessed the impact on outcomes of proportions of patients receiving concomitant methotrexate or of Asian ethnicity. Results: The network meta-analysis included 21 randomized controlled trials. At 12 weeks, all evaluable efficacy outcomes were comparable or improved with peficitinib 150 mg and 100 mg once daily, versus baricitinib 2 and 4 mg once daily and tofacitinib 5 mg twice daily. At 24 weeks, efficacy outcomes were comparable or improved for each peficitinib dose versus baricitinib and tofacitinib. Risk of adverse events and serious adverse events at 12 weeks were similar with peficitinib 100 and 150 mg versus baricitinib and tofacitinib. The proportion of patients receiving concomitant methotrexate had no effect on any outcome analyzed, but Asian ethnicity had a positive effect on multiple efficacy outcomes. Conclusions: Peficitinib had comparable efficacy versus tofacitinib and baricitinib for reduction in disease activity as measured by SDAI, and for reduction in progression of joint damage as measured radiographically. No notable differences in safety outcomes were observed. Further studies are required to better characterize the impact of ethnicity on the efficacy of JAK inhibitors.
Objective: To evaluate the comparative efficacy and safety of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to at least one disease-modifying antirheumatic drug (DMARD). Methods: PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to April 2020. The active drugs included three JAK inhibitors and eight bDMARDs while the control drugs included placebo or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Outcomes include American College of Rheumatology 20% response (ACR20), Disease Activity Score in 28 joints (DAS28), Health Assessment Questionnaire–Disability Index (HAQ-DI) and discontinuations for adverse events (AEs). We estimated summary odds ratios (ORs) and weighted mean differences (WMDs) using network meta-analysis with random effects. Results: Eighty-eight RCTs with 31,566 patients were included. All JAK inhibitors and bDMARDs were more effective than placebo in ACR20 (ORs ranging between 3.05 and 5.61), DAS28 (WMDs ranging between −1.91 and −0.80) and HAQ-DI (WMDs ranging between −0.34 and −0.21). Tocilizumab, certolizumab pegol and upadacitinib showed relatively good efficacy in these three outcomes according to their relative ranking. Notably, tocilizumab was more effective than other active drugs in DAS28 (WMDs ranging between −1.11 and −0.49). Compared with the lower recommended doses, increasing the doses of JAK inhibitors (baricitinib 4 mg versus 2 mg, tofacitinib 10 mg versus 5 mg and upadacitinib 30 mg versus 15 mg) cannot provide significant additional benefits. In terms of discontinuations for AEs, all active drugs showed no significant difference compared with placebo except certolizumab pegol [OR 1.65, 95% credible interval (CrI) 1.06–2.61] and rituximab (3.17, 1.11–10.80). Conclusions: Tocilizumab, certolizumab pegol and upadacitinib may have relatively good efficacy in patients with RA after treatment failure with csDMARDs. RA patients taking a JAK inhibitor may have a preference for a lower recommended dose.
OBJECTIVES: Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs).
METHODS: A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library. Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation.
RESULTS: 3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13). Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated. Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included. Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn's disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA). Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events. No increased malignancy rates or major adverse cardiac events were observed.
CONCLUSION: JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence.
BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis.
METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990 through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events.
RESULTS: We identified 973 studies; of these 82 were included in the final analysis, comprising 66159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of and serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared to patients given placebo or active comparator (relative risk 0.72; 95% CI, 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% CI, 1.04-2.37).
CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.
Background: With a 'treat to target' approach in RA, guidelines recommend tailored monitoring of disease activity using validated composite instruments, such as the disease activity score (DAS) 28. While response assessment at 24 weeks is the standard in clinical trials, assessment as early as 12 weeks is recommended. There is limited evidence assessing the relative efficacy of TIMs following a 'treat to target' strategy. Objectives: To evaluate the relative efficacy of intravenous (IV) and subcutaneous (SC) tocilizumab plus a conventional disease modifying antirheumatic drug (cDMARD) to other TIMs plus a cDMARD in TIM-naïve or mixed (<20% TIM-experienced) adults with moderate to severe RA. Efficacy was defined as achieving remission according to a DAS28 score <2.6 at 12 and 24 weeks. Methods: Randomized controlled trials (RCTs) were selected from a recent systematic literature review conducted by the Institute for Clinical and Economic Review (ICER), as well as from trials for upadacitinib (SELECT-NEXT, SELECT-COMPARE), which were not included in the ICER 2017 report. RCTs that compared TIMs to each other or placebo were included. Treatments included Janus kinase (JAK) inhibitors (upadacitinib, baricitinib, and tofacitinib), tumor necrosis factor alpha inhibitors (TNFi; adalimumab, certolizumab pegol, golimumab, and infliximab), and other non-TNFis (rituximab, sarilumab, tocilizumab, and abatacept). A Bayesian NMA was performed in OpenBUGS and R using a fixed effects model. Model selection was based on deviance information criterion. Forest plots of odds ratios (OR) are presented. Results: In the 12-week analysis, 15 trials were included with a pooled study population of 9,154 patients. Populations were similar across trials and predominantly female (mean 78%, range 39-87%), with a baseline mean age of 52 years (range 47-56), mean disease duration of 8 years (range 2-11), and mean DAS28 score of 6 (range 5-7). In the 12-week analysis, compared to cDMARD, all TIMs were more likely to achieve remission (statistically significant), but tocilizumab IV showed a substantially greater magnitude of effect (OR=19.3, 95% Crl=10.99, 37.22) which was consistent with raw trial results (Figure 1). In pair-wise comparison, tocilizumab IV was associated with a greater likelihood of achieving remission compared to abatacept IV (OR=7.47, Crl=2.53, 20.89), abatacept SC (OR=4.29, Crl=1.96, 9.94), baricitinib (OR=3.39, Crl=1.74, 7.09), adalimumab (OR=5.10, Crl=2.68,10.42), tofacitinib (OR=5.44, Crl=1.26, 20.57), upadacitinib 15mg (OR=3.23, Crl=1.72, 6.54), and upadacitinib 30mg (OR=4.05, Crl=1.97, 8.85). In the 24-week analysis, 21 trials were included in the analysis with a pooled study population of 12,180 patients. Patient characteristics were the same as the 12 week analysis. Compared to cDMARD, all TIMs were more likely to achieve remission (statistically significant), with tocilizumab IV and SC showing a greater magnitude of effect (OR=12.08, Crl=8.09-18.30 and OR=11.98, Crl=5.17-35.86, respectively) (Figure 2). In pair-wise comparison, tocilizumab IV and SC were associated with a greater likelihood of achieving remission compared to abatacept IV, adalimumab, baricitinib, infliximab, upadacitinib 15 mg, and sarilumab. Conclusion: Results of this NMA demonstrate that tocilizumab is associated with a greater likelihood of remission (DAS28 <2.6) at 12 and 24 weeks compared to most other TIMs including new JAK inhibitors, when used in combination with a cDMARD among TIM-naïve/mixed patient populations. (Figure Presented).
Background: Objectives: Objetive: To assess the incidence of Herpes Zoster (HZ) infection in patients with Rheumatoid Arthritis (RA) treated with JAKi. Methods: Method: We conducted a systematic literature review searching in Medline, Embase and Cochrane. The final date was set on December 31, 2019, and only articles in English were included. See the following terms: rheumatoid arthritis, herpes zoster and the different JAK kinase inhibitors studied: tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib and decernotinib. Conference abstract, case series and clinical practice records were excluded. Only phase II and phase III clinical trials were included, as well as extension studies, with the following criteria:-Patients diagnosed with RA according to the American College of Rheumatology Criteria and /or EULAR criteria.-Drugs evaluated: tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib or decernotinib, all of them compared with placebo.-Safety data on HZ infection. The search included a total of 2521 publications of which 504 were duplicated, leaving 2017. After screening by title and abstract 1874 studies that did not meet the criteria were eliminated and there were 143 fully reviewed. At the end 42 papers were included in the review. The main objective of our study was the number of HZ infections depending on the doses of the drug administered, as well as with placebo. Data collected from each study was: Author and year of publication of the study, study design and population included, number of patients treated, treatment administered and percentage of patients treated for HZ in each treatment arm. Results: Results: In clinical trials of these drugs, a greater number of opportunistic infections due to varicella zoster virus have been identified compared to placebo, which leads to the appearance of HZ. The role of different JAKs in the immune response may suggest differences in safety profiles between these drugs, which could have clinical implications. Therefore, we analyze the results separately for each JAKi. Tofacitinib Of the 14 selected works, 4 are phase II, 8 phase III and 2 extension studies. We observe that the incidence of HZ ranges between 1% and 11%, the latter being the case of the Wollenhaupt extension study with a data collection period of nine and a half years. It is remarkable that in some of the studies included in this review there was no case of HZ and in others this information was not even collected. Baricitinib Two phase II studies, 6 phase III studies and one extension study were analyzed, with an incidence of HZ between 1% and 9%, data similar to those obtained with tofacitinib. Upadacitinib. An incidence of HZ between 1% and 4% was observed according to the 6 clinical trials (two phase II studies and four phase III studies) published as clinical product development. Filgotinib Data similar to upadacitinib, with frequencies between 1% and 4% of HZ according to the studies (three phase II studies and one phase III study). Peficitinib The incidence of HZ ranged between 4% and 7.5% (three phase II studies, two phase III studies, and one extension study). Decernotinib There are only published three phase II trials, of short duration and with only four cases collected from HZ. Conclusion: Conclusions: Opportunistic HZ infection have been reported between 1% and 11% in JAKi clinical trials. The results of the included studies seem to suggest that selective JAK1 inhibitors (Upadacitinib and Filgotinib) develop HZ as a treatment complication less frequently than other JAKi, but more studies are needed to support this conclusion.
OBJECTIVES: To 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).
METHODS: PubMed, 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.
RESULTS: 26 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).
CONCLUSION: The 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.
Recent studies raise concern for increased risk of major adverse cardiovascular events (MACE) with Janus kinase inhibitors (JAKi) used to treat immune-mediated inflammatory disorders (IMIDs). We aimed to examine MACE risk with licensed biologics and small molecules used commonly between IMIDs: inflammatory bowel disease, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis.
METHODS:
Data were obtained from systematic searches (from inception to May 31, 2022) in PubMed, Embase, Ovid Medline, Scopus, Cochrane Central, and Clinicaltrials.gov. Studies that assessed a pre-defined MACE (myocardial infarction, cerebrovascular accident, unstable angina, cardiovascular death, or heart failure) risk in those ≥18 years with IMIDs treated with anti-interleukin (IL)-23 antibodies, anti-IL-12/23, anti-tumor necrosis factor-alpha antibodies (anti-TNF-α) or JAKi were included in a network meta-analysis using a random-effects model with pooled odds ratios (ORs) reported with 95% credible intervals (CrIs) by drug class and disease state.
RESULTS:
Among 3,528 studies identified, 40 (36 randomized controlled trials [RCTs] and 4 cohort studies) were included in the systematic review, comprising 126,961 patients with IMIDs. Based on network meta-analysis of RCTs, regardless of disease state, anti-TNF-α (OR, 2.49; CrI: 1.14-5.62), JAKi (OR, 2.64; CrI: 1.26-5.99), and anti-IL-12/23 (OR, 3.15; CrI: 1.01-13.35) were associated with increased MACE risk compared with placebo. There was no significant difference in the magnitude of the MACE risk between classes or based on IMID type.
CONCLUSIONS:
Anti-IL-12/23, JAKi, and anti-TNF-α were associated with higher risk of MACE compared with placebo. The magnitude of the increased MACE risk was not different by IMID type. These results require confirmation in larger prospective studies.
