A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases.

OBJECTIVES: Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases. METHODS: A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration. RESULTS: 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman's disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors. CONCLUSION: IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs.

Risk of Clinically Relevant Venous Thromboembolism in Critically Ill Patients With COVID-19: A Systematic Review and Meta-Analysis.

Background: Early during the course of the ongoing COVID-19 pandemic, reports suggested alarmingly high incidences for thromboembolic events in critically ill patients with COVID-19. However, the clinical relevance of these events was not reported in several studies. Additionally, more recent research showed contradictory results and suggested substantially lower rates of venous thromboembolism. Thus, the aim of the present study was to summarize evidence on the incidence of clinically relevant venous thromboembolism (VTE)-defined as VTE excluding isolated subsegmental pulmonary embolism (PE) and distal deep vein thrombosis (DVT)-in adult critically ill patients with COVID-19. Methods: We performed a systematic review of studies reporting the incidence of clinically relevant PE and/or DVT in critically ill patients with COVID-19. Scientific reports published in the English language between January and October 2020 were included. We conducted a random-effects model meta-analysis to calculate incidence estimates of clinically relevant VTE and bleeding events. We also performed exploratory meta-regression and subgroup analyses of different diagnostic approaches and additional factors that possibly influenced the incidence of these outcomes. Results: Fifty-four articles (5,400 patients) fulfilled the predefined inclusion criteria, of which 41 had a high risk of bias. The majority of included patients were male, > 60 years, and overweight. Twenty-one studies reported the use of prophylactic doses of heparin. Pooled incidences for clinically relevant PE were estimated at 8% (95% CI, 4-11%), for proximal DVT at 14% (95% CI, 9-20%), and-after exclusion of studies with a high risk of bias-for the composite outcome of VTE at 18% (95% CI, 13-24%). Clinically relevant bleeding occurred at a rate of 6% (95% CI, 2-9%). Conclusions: We summarized currently available data on the rate of clinically relevant VTE in critically ill patients with COVID-19. Pooled incidence estimates were lower than those reported by previous review articles. In the absence of evidence-based anticoagulation guidelines for critically ill patients with COVID-19, the results of our study provide clinically important information for an individual risk-benefit assessment in this context. Registration: The study protocol was prospectively registered in PROSPERO on June 22, 2020 (CRD42020193353; https://www.crd.york.ac.uk/prospero).