Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

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Azathioprine (AZA) is used to maintain remission in autoimmune hepatitis (AIH), but up to 18% of patients are unresponsive. AZA is a prodrug, and the formation of active thioguanine nucleotide (TGN) metabolites varies widely. We aimed to assess the relationship between AZA metabolite concentrations (i.e., TGNs and methylmercaptopurine nucleotides [MeMPNs]), thiopurine methyltransferase (TPMT) activity, therapeutic response, and toxicity in adult patients with AIH prescribed a stable dose of AZA for the maintenance of remission. Red blood cell (RBC) TGNs and MeMPNs were measured in serial blood samples over a 2-year period. The average TGNs (avTGNs) and MeMPNs (avMeMPNs) concentrations for each patient were used for analysis. Therapeutic response was defined as the ability to maintain remission, defined as a normal serum alanine aminotransferase (ALT) level (ALT <33 IU/mL). Patients who maintained remission (n 5 53), compared to those who did not (n 5 17), tended to be on lower doses of AZA (1.7 versus 2.0 mg/kg/day; P 5 0.08), but had significantly higher concentrations of avTGN (237 versus 177 pmol/8 3 10 8 RBCs; P 5 0.025). There was no difference in MeMPN concentrations or TPMT activities between the two groups. There was a negative correlation between ALT and avTGN (r s 5 20.32; P 5 0.007). An avTGN concentration of >220 pmol/8 3 10 8 RBCs best predicted remission, with an odds ratio of 7.7 (P 5 0.003). There was no association between TGN, MeMPN, or TPMT activity and the development of leucopenia. Two patients developed AZA-induced cholestasis and the avMeMPN concentration was higher in those patients, compared to those who did not (14,277 versus 1,416 pmol/8 3 10 8 RBCs). Conclusion: TGN concentrations of >220 pmol/8 3 10 8 RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA-induced cholestasis was associated with increased MeMPN concentrations. (HEPATOLOGY 2012;56:1401-1408 A utoimmune hepatitis (AIH) is a chronic inflammatory liver disease, characterized by a relapsing and remitting course and a high mortality if left untreated. Azathioprine (AZA), a potent immunosuppressant, is commonly used as a ''steroid sparing'' agent for the induction and maintenance of remission in autoimmune hepatitis. Approximately 10% of patients with AIH experience AZA-related side effects necessitating drug withdrawal, 1 and a further 18% of patients are unable to maintain remission with AZA alone. 2AZA is a prodrug that undergoes extensive intracellular activation by a multienzymatic process to form the active metabolites, 6-thioguanine nucleotides (TGNs) (Fig. 1). The immunosuppressive mechanism of action of AZA metabolites is not fully understood. TGN metabolites act as purine antagonists. Incorporation of TGN into DNA is the primary mode of overt