The additional data from the tocilizumab arm of the RECOVERY trial, the post hoc analysis of the CORIMUNO-19 TOCI-1 and the meta-analysis of RCTs published in the JAMA helped clarifying the scenario. not mounting normal anti-SARS-CoV-2 antibody responses. Conclusion This new SLR confirms that some immunomodulators (tocilizumab and JAK inhibitors) have a role for treating severe and critical COVID-19. Although better evidence is available compared with the previous SLR, the need of RCT with combination therapy (glucocorticoids+anti-cytokines) versus monotherapy with glucocorticoids still remains alongside CADD522 the need for standardisation of CADD522 inclusion criteria and outcomes to ultimately improve the care and prognosis of affected people. This SLR informed the 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19. were evaluated at unclear RoB. One study was underpowered and therefore results are not detailed.17 The evidence regarding sarilumab is scarcer as the search retrieved two RCTs at unclear RoB; one comparing sarilumab to SOC,19 and the other comparing sarilumab to PBO.23 The REMAP-CAP trial19 included a small arm comparing sarilumab (n=44 patients) to SOC (n=402); most patients in the sarilumab arm were receiving NIV (48%) at baseline. The study showed a reduction in death and CV and respiratory organ support-free days (RR 1.76, 95% CI 1.17?to 2.91).18 The other RCT23 compared two dosages of sarilumab (200 and 400?mg) to PBO, and showed no efficacy on death (Sari 200: RR 1.13, 95% CI 0.5?to 2.4; Sari 400: RR 0.98, 95% CI 0.5?to 2.1), progression to MV (Sari 200: RR 1.06, 95% CI 0.6?to 1 1.9; Sari 400: RR 1.2, 95% CI 0.7?to 2.2) or admission to ICU (Sari 200: RR 0.83, 95% CI 0.3?to 2.1; CADD522 Sari 400: RR 1.2, 95% CI 0.5?to 2.7). Of note, there is a high heterogeneity among trials in terms of the proportion of patients receiving GCs as part of SOC. An important difference was observed between trials starting before and after the positive results of the GC arm of the RECOVERY trial.24 It is noteworthy that while in two positive RCTs, a high percentage of patients were receiving GCs (82% to 93%),19 20 in an important negative trial, COVACTA,18 which failed to show efficacy in reducing death or improving clinical status, only up to 50% of patients were receiving GCs. In addition, a recent RCT meta-analysis published in JAMA concluded that TCZ reduced all-cause mortality (OR 0.83, 95% CI 0.72?to 0.94) and progression to MV, ECMO or death (OR 0.74, 95% CI 0.66?to 0.82) at day 28.25 Of interest, when analysing the subgroup of patients receiving GCs compared with those who did not, death at day 28 was only significantly reduced in the TCZ group receiving GCs (RR 0.77, 95% CI 0.68?to 0.87) p=0.008) but neither in the TCZ group not receiving GCs (RR 1.06, 95% CI 0.85?to 1 1.33) nor in the SARI group regardless of their GCs status (RR 0.77, 95% CI 0.64?to 1 1.31, p=0.34). IL-1 inhibitors As far as anakinra in concerned, only one study at high RoB was retrieved by the search update. This corresponded to a preprint that was subsequently published during the preparation of this manuscript.26 This study included patients with COVID-19 pneumonia and soluble urokinase plasminogen activator elevations at 6? ng/mL or above, which is considered as a predictor CADD522 of unfavourable outcome. In this population, anakinra 100?mg subcutaneous for 7C10 days increased the number of patients recovered (RR 1.9, 95% CI 1.5?to 2.5), according to the WHO 11-point clinical progression ordinal scale, and decreased mortality at day 28: 3.2% vs 6.9% (HR=0.45, p=0.045). Regarding canakinumab, no RCT was retrieved by the search update but while writing this manuscript the CAN-COVID study was published27 and it demonstrated that PIK3CA the addition CADD522 of canakinumab to SOC did not provide any benefit on survival at 29 days. Colchicine The SLR.