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Risk of Infections and Cardiovascular and Venous Thromboembolic Events Associated with JAK Inhibitors in Rheumatoid Arthritis

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Risk of Infections and Cardiovascular and Venous Thromboembolic Events Associated with JAK Inhibitors in Rheumatoid Arthritis Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2020-041420 on 31 December 2020. Downloaded from Risk of infections and cardiovascular and venous thromboembolic events associated with JAK inhibitors in rheumatoid arthritis: protocols of two systematic reviews and network meta- analyses Carlos Alves ,1,2 Ana Penedones ,2 Diogo Mendes,2 Francisco Batel- Marques1,2 To cite: Alves C, Penedones A, ABSTRACT Strengths and limitations of this study Mendes D, et al. Risk of Introduction Janus kinases (JAK) inhibitors demonstrated infections and cardiovascular to be effective in the treatment of adult patients with ► The Preferred Reporting Items for Systematic and venous thromboembolic moderate- to- severe active rheumatoid arthritis (RA) but events associated with JAK Review and Meta- Analysis for Network Meta- have been associated with serious cardiovascular and inhibitors in rheumatoid Analysis statement and the Centre for Reviews and serious events. Two systematic reviews and network meta- arthritis: protocols of two Dissemination’s guidance will be followed. analyses will be carried aiming to compare the relative systematic reviews and network ► The relative risk of cardiovascular and thrombo- safety of the different JAK inhibitors with regard to the risk meta- analyses. BMJ Open embolic events will be assessed for the first time of (1) cardiovascular and thromboembolic events and (2) 2020;10:e041420. doi:10.1136/ among the Janus kinases (JAK) inhibitors class. bmjopen-2020-041420 serious infections in patients with RA. ► Although an increased risk of herpes zoster was Methods and analysis PUBMED, Embase, Cochrane ► Prepublication history and identified for baricitinib in a previous network meta- Controlled Register of Trials and ClinicalTrials. gov will supplemental material for this analysis, further randomised controlled trials have be searched in order to identify randomised controlled paper are available online. To been published, which can provide new evidence view these files, please visit trials evaluating the efficacy and safety of JAK inhibitors regarding the differential risk of infections among http://bmjopen.bmj.com/ in patients with RA. The following events will be the journal online (http:// dx. doi. JAK inhibitors. org/ 10. 1136/ bmjopen- 2020- assessed: (1) any cardiovascular event; major adverse ► The rare nature of serious cardiovascular events and 041420). cardiovascular events and venous thromboembolism opportunistic infections may limit the number and and (2) any infection; serious infections; herpes zoster type of sensitivity analyses that can be conducted. Received 05 September 2020 infection and tuberculosis. Search terms will comprise RA Revised 29 October 2020 and drugs names, including the thesaurus terms and the Accepted 09 November 2020 International Nonproprietary Names. The assessment of the methodological quality of the included studies will be effective conventional synthetic (cs) disease- performed through the RoB 2 tool: a revised Cochrane risk modifying antirheumatic drug (DMARD) on September 30, 2021 by guest. Protected copyright. of bias tool for randomised trials. Network meta- analyses 2 will be performed using STATA V.13.0. For each outcome, and it is the first- line treatment option. If treatments will be ranked according to the probability of the disease activity remains moderate to being the safest (best) alternative using the surface under high, additional treatment with csDMARDs, the cumulative ranking curve. biological DMARDs (bDMARDs) or targeted Ethics and dissemination Ethical approval is not synthetic DMARDs (tsDMARDs) should be required as no primary data are collected. This systematic considered.2 © Author(s) (or their review will be disseminated through peer- reviewed Janus kinases (JAK1–3 and tyrosine kinase employer(s)) 2020. Re- use publications and at conference meetings. permitted under CC BY-NC. No 2) inhibitors are tsDMARDs that target the commercial re- use. See rights JAK–STAT pathway with proven efficacy in the and permissions. Published by BMJ. INTRODUCTION treatment of adult patients with moderate- to- For numbered affiliations see Rheumatoid arthritis (RA) is an inflammatory severe active RA, who have not responded 3 end of article. autoimmune disease, causing symmetrical or are intolerant to either cs or bDMARDs. polyarthritis, typically resulting in swollen, Though two main safety concerns have been Correspondence to 1 associated with the use of JAK inhibitors, Dr Carlos Alves; stiff and painful joints. The pharmacolog- carlosmiguel. costaalves@ gmail. ical treatment of RA should start as soon as namely cardiovascular adverse events and com the diagnosis is made.2 Methotrexate is an serious infections.4–7 Alves C, et al. BMJ Open 2020;10:e041420. doi:10.1136/bmjopen-2020-041420 1 Open access BMJ Open: first published as 10.1136/bmjopen-2020-041420 on 31 December 2020. Downloaded from The cardiovascular risk of JAK inhibitors has been under European Network of Centres for Pharmacoepidemiology scrutiny by regulatory authorities. US Food and Drug and Pharmacovigilance (EUPAS35534 and EUPAS35531, Administration (US FDA) concluded that the benefit– respectively). risk profile of baricitinib was adequate to support the approval of the 2 mg dose, but not the 4 mg dose due to Eligibility criteria 4 an increased risk of thrombosis. Preliminary results from Studies will be considered for inclusion if they fulfil the an ongoing postapproval study revealed an increased following criteria (with the exception of outcomes, the risk of blood clots and death when the approved dose of other inclusion criteria will be the same in both system- tofacitinib was doubled in patients with RA, leading the 8 9 atic reviews): authorities to add warnings to the label. A few cases of ► Study design: Phase II and phase III RCTs. cardiovascular events were further reported in patients ► Population: Studies evaluating patients diagnosed treated with upadacitinib in the Subjects with Moder- with RA based on the American College of Rheu- ately to Severely Active Rheumatoid Arthritis (SELECT) 5 matology/European League Against Rheumatism trials programme. The change in the serum lipid profile criteria will be included.22 seems to be a class effect.3 Despite a previous meta- ► Intervention: Only studies assessing the effects of JAK analysis of randomised controlled trials (RCTs) did not inhibitors (baricitinib, decernotinib, filgotinib, pefi- reveal a significant change in the risks of cardiovascular citinib, tofacitinib, upadacitinib) in the treatment of events and venous thromboembolism in patients with RA will be included. RA treated with JAK inhibitors,6 the relative cardiovas- ► Comparators: Studies comparing the intervention cular safety of JAK inhibitors compared with every other against placebo, active treatment (DMARD) or no remains unclear due to lack of head- to- head comparisons. treatment. Another important safety concern with JAK inhibitors ► Outcomes: (1) any cardiovascular event: angina are serious infections, such as reactivation of herpes pectoris, myocardial infarction, congestive heart zoster, pneumonia, tuberculosis, upper respiratory infec- failure, carotid artery disease, aortic aneurysm, cere- tion and urinary tract infections.7 10 11 In 2013, European bral vascular diseases (stroke and transient ischaemic Medicines Agency (EMA) adopted a negative opinion on attack), venous thromboembolic events (VTEs) and the approval of tofacitinib mainly due to safety concerns, 12 cardiovascular death; major adverse cardiovascular including the risk of serious infections. Tofacitinib was later approved in 2017 but, as baricitinib and upadac- events (MACE): myocardial infarction, cerebrovas- itinib, it was put under additional monitoring.13 14 The cular accident (ischaemic and haemorrhagic strokes) risk of serious infections has also been described for JAK or cardiovascular death and VTEs: pulmonary embo- inhibitors under clinical development (decernotinib, lism and deep vein thrombosis. 7 15 ► Outcomes: (2) any infection; serious infections: events filgotinib and peficitinib). An increased risk of herpes http://bmjopen.bmj.com/ zoster was identified for baricitinib in a network meta- leading to death, hospitalisation or need for antibiotic analysis, but significant differences between the approved therapy; herpes zoster infection and tuberculosis. JAK inhibitors were not found.7 Nevertheless, further ► Timing: No restrictions will be applied to the length RCTs may provide new evidence regarding the differen- of follow- up. tial risk of infections with JAK inhibition.16–18 ► Language: Only studies reported in English will be Two systematic reviews and network meta-analyses included. will be carried out to compare the relative safety of the Information sources different JAK inhibitors with regard to the risk of (1) on September 30, 2021 by guest. Protected copyright. PUBMED (https://www. ncbi. nlm. nih. gov/ pubmed/), cardiovascular and thromboembolic events and (2) Embase (https://www. embase. com/), Cochrane serious infections in patients with RA. Controlled Register of Trials (https://www. cochraneli- brary. com/ central) and ClinicalTrials. gov (https:// METHODS clinicaltrials. gov/) will be searched from the inception The protocols are in accordance with the Preferred until June 2020. Bibliographic references list of all rele- Reporting Items for Systematic Review and Meta-Analysis vant studies, systematic reviews and meta- analyses will be Protocols (PRISMA-
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