Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider

Abstract

ObjectiveTo summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.MethodsAs part of a European League Against Rheumatism (EULAR) taskforce, a systematic literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools.ResultsOf the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results.ConclusionAlthough there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR ‘points to consider’ on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.

Interleukin-1- Receptor Kinase 4 Inhibition: Achieving Immunomodulatory Synergy to Mitigate the Impact of COVID-19

“…Certain agents are being used to target individual mediators of the inflammatory pathway to mitigate CRS; for example, tocilizumab, which is a monoclonal antibody against the receptor for IL-6, has shown some potential benefit for improving lung function and decreasing length of hospitalization in a large single-center trial (15,16). Other studies have shown conflicting results with little to no benefit for tocilizumab in mortality of patients with COVID-19 (15,(17)(18)(19).…”

Risk of reactivation of hepatitis B virus (HBV) and tuberculosis (TB) and complications of hepatitis C virus (HCV) following Tocilizumab therapy: A systematic review to inform risk assessment in the COVID era

“…For this reason, TCZ has appeal as a therapeutic agent, and multiple studies have set out to determine its role in COVID patients. The literature is currently heterogeneous [7] ; several clinical studies have reported a benefit (e.g. [8][9][10][11] ), or find modest improvements in length of hospital stay without reducing deaths [12] , while others do not find significantly improved outcomes [13] or even identify possible harm [14] .…”

“…TCZ half life is dose-dependent and estimated at 8-14 days [19] ; some recommendations suggest a repeat dose after 12-24 hours if there has not been sufficient clinical improvement [20] . Due to small overall numbers of COVID patients treated, limited prospective follow-up, and lack of concordance in reported clinical outcomes, guidance recognises the low certainty of the evidence and the pressing need for more data [7,21] .…”

“…To date, the safety profile of TCZ in COVID patients is deemed good [7,13] , albeit based on small numbers, delivery of treatment only in selected clinical settings, and limited periods of follow-up. However, based on experience from the pre-COVID era, TCZ carries a black box warning for serious infection events (SIEs; Figure 1B) caused by a range of opportunistic bacterial, mycobacterial, viral and fungal pathogens that may lead to hospitalisation or death.…”

Rheumatology and COVID-19 at 1 year: facing the unknowns

“…From the outset, we believe these authors recognised that their mission to provide real-time analysis in a timely and reflective manner was a Sisyphean task, as at the time of this writing, over 113 635 publications have been posted on PubMed and MedRxiv alone, largely in the past 12 months (search date 14 February 2021). To their credit, the systematic review process in the accompanying literature search 2 even included a ‘hand search’ of the ever increasingly quoted ‘grey literature’ consisting of the torrent of press releases on new drugs and therapies. These types of sources in the COVID-19 field are of particular importance as they are often amplified by social media, creating what some may refer to as ‘epistemic chaos’, and posing an increasing threat to the iterative method of science (eg, the early embrace of hydroxychloroquine).…”