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IntroductionSome COVID-19 patients evolve to severe lung injury and systemic hyperinflammatory syndrome triggered by both the coronavirus infection and the subsequent host-immune response. Accordingly, the use of immunomodulatory agents has been suggested but still remains controversial. Our working hypothesis is that methylprednisolone pulses and tacrolimus may be an effective and safety drug combination for treating severe COVID-19 patients.Methods and analysisTACROVID is a randomized, open-label, single-center, phase II trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) versus SoC alone, in patients at advanced stage of COVID-19 disease with lung injury and systemic hyperinflammatory response. Patients are randomly assigned (1:1) to one of two arms (42 patients in each group). The primary aim is to assess the time to clinical stability after initiating randomization. Clinical stability is defined as body temperature ≤ 37.5°C, and PaO2/FiO2 > 400 and/or SatO2/FiO2 > 300, and respiratory rate ≤24 rpm; for 48 consecutive hours.DiscussionMethylprednisolone and tacrolimus might be beneficial to treat those COVID-19 patients progressing into severe pulmonary failure and systemic hyperinflammatory syndrome. The rationale for its use is the fast effect of methylprednisolone pulses and the ability of tacrolimus to inhibit both the CoV-2 replication and the secondary cytokine storm. Interestingly, both drugs are low-cost and can be manufactured on a large scale; thus, if effective and safe, a large number of patients could be treated in developed and developing countries.Trial registration numberNCT04341038 / EudraCT: 2020-001445-39

Highlights • Dexamethasone, or alternative steroids, are recommended in severe COVID-19. • The use of tocilizumab in COVID-19, with or without steroids, is still controversial. • Risk for mortality was assessed in 186 COVID-19 patients receiving tocilizumab. • Mortality was associated with older age, chronic heart failure and liver disease. • In tocilizumab-treated patients, the additional use of steroids was beneficial., Objectives To assess the characteristics and risk factors for mortality in patients with severe COVID-19 treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS). Methods From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality. Results A total of 1,092 COVID-19 patients were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186, 155 (83.3 %) patients were receiving non-invasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (± 4.3) and 4.3 days (± 3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p

Background Infliximab (IFX) trough levels vary markedly between patients with inflammatory bowel disease (IBD), which is important for clinical response. The aim of this study was to evaluate the performance of previously developed population pharmacokinetic models in patients with IBD for dose individualization for Crohn disease (CD) and ulcerative colitis in our clinical setting. Methods The authors collected 370 trough levels prospectively from 100 adult patients with IBD who were undergoing IFX treatment between July 2013 and August 2016. The external evaluation included prediction- and simulation-based diagnostics [prediction-corrected visual predictive check, prediction- and variability-corrected visual predictive check, and normalized prediction distribution error tests]. Results In prediction-based diagnostics, the authors observed a nonsignificant overall mean relative bias of -6.87% and an acceptable imprecision of 8.45%. Approximately 100% of the prediction error was within ±30%, indicating satisfactory predictability. Simulation-based diagnostics indicated model misspecification; thus, the model may not be appropriate for simulation-based applications. Conclusions While simulation-based diagnostics provided unsatisfactory results, the prediction-based diagnostics demonstrate that the population pharmacokinetic model developed by Fasanmade et al for CD can be used to predict and design individualized IFX dose regimens that meet the individual needs of patients with CD and ulcerative colitis.

Background HLA-DQA1*05 Carriage is associated with development of anti-drug antibodies to infliximab in patients With Crohn’s Disease (Sazonovs et al. Gastroenterology 2019). Our group has shown that the presence of this allele is also an independent predictor of secondary loss of response to infliximab (Guardiola J, ECCO 2019) and adalimumab (Guardiola J ECCO 2020). However, the impact of the HLA-DQA1 * 05 allele on the initial response and persistence of IFX in the first months of treatment is unknown. Methods This is a retrospective cohort study from a prospectively maintained data base at the Hospital Universitari de Bellvitge (third level teaching hospital) Patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) who initiated IFX to induce remission and who had been followed up for failure or a minimum of 6 months were included. Failure at IFX was defined as the need of escalation or change treatment, surgery, or hospitalization for the first 6 months. Results 99 patients (65 MC, 34 CU) were included. In 63 (63.63%) IFX failed. 39 (39%) were carriers of the HLA-DQA1 * 05 allele. In multivariate analysis, HLA-DQA1*05 carriage (HR 1.9, 95% CI 1.14–3.31 p=0.015), the use of immunomodulators (HR 0.38, 95% CI 0, 23–0.66 p = 0.001) and suffering a CU vs. MC (HR 1.72, 95% CI 1.02–2.89 p = 0.041) were independent predictors of IFX failure. HLA-DQA1 * 05 was also associated with non-persistence of treatment (HR 2,4,95% CI1.45–3.99 p = 0.001). Figure A Conclusion HLA-DQA1*05 carriage is common in patients with IBD and it’s associated with a marked increase in the risk of loss of response to infliximab. Testing for HLA-DQA1*05 would allow treatment to be tailored according to the risk of loss of response.

Background and aims Treating patients based on a treat-to-trough approach has been shown to be a cost-effective strategy for inflammatory bowel disease (IBD) patients who have become unresponsive to infliximab (IFX). However, the documented evidence for this is limited, and some controversy remains regarding the use of routine proactive therapeutic drug monitoring (TDM). To support routine TDM of IFX and regimen optimization in IBD patients, more in-depth knowledge of the covariates that affect the pharmacokinetic (PK) variability of IFX is needed. The aim of this study was to identify the characteristics of the patient, disease, and treatments that influence IFX PK and exposure in our cohort of IBD patients using a repeated-measures design. Methods We performed a prospective observational study of adult IBD patients who received IFX between July 2013 and March 2017. We obtained repeated IFX trough concentration (Cmin) measurements and implemented a previously described population pharmacokinetic model to estimate individual clearance (CL). From the individual primary parameters, the area under the curve (AUC), half-life (t1/2), and central elimination rate constant (K10) were estimated. We performed a repeated-measures analysis to evaluate whether patient characteristics, disease status, concomitant immunosuppressive therapy, and immunogenicity are associated with IFX Cmin and PK parameters. Results We collected 429 Cmin measurements from 112 patients. The median of the Cmin values was 3.62 mg/L (1.47-6.02). Antibodies to IFX (ATI) were detected in 14 patients. The predicted median AUC was 28,421 mg/h/L (22,336-36,903). The median individual predicted CL, K10, and t1/2 values were 4.77 mL/kg/day (3.88-5.90), 0.09 days (0.08-0.12), and 12.22 days (9.49-14.87), respectively. IFX Cmin, AUC, CL, and K10 were significantly influenced by ATI and serum albumin concentrations. Moreover, body weight was significantly associated with AUC, CL, and K10. Patients receiving concurrent immunosuppressive therapy had higher Cmin and AUC values and lower CL and K10 values than those treated with IFX monotherapy. We also observed high intrapatient variability in Cmin values during the study period. Conclusions In this repeated-measures study in a population of IBD patients, we observed significant associations between ATI, serum albumin concentration, concomitant immunosuppressive therapy, body weight and gender, and IFX Cmin, and CL. The high PK variability observed in this study supports the need for proactive TDM to optimize the use of IFX as early as possible in IBD patients.

Background AntiTNF therapeutic drug monitoring is currently performed at trough, immediately before drug administration. However, in clinical practice when subcutaneous medications are used, blood extractions often do not coincide with that moment. The aim of this study was to know if adalimumab levels measured between injections are sufficiently similar to trough levels to be used in clinical practice in a similar way. Methods 295 adalimumab level determinations performed at different time points of 99 injection cycles in 55 patients with inflammatory bowel disease (IBD) were included in the study. 51 patients received 40mg every 2 weeks and 4 patients received 80mg every 2 weeks. Results Median adalimumab levels (IQR) at trough, between days 1–4, 5–8 and 9–13 were 10.6 (6–12), 12.3 (7–18), 13 (7–19) and 10.8 (8–12), respectively. The median differences between trough level and days 1–4, 5–8 and 9–13 were 1.7 (IC 95% 1–2.3) (p < 0.001), 2.3 (IC 95% 1.5–3.1) (p < 0.001), 0.6 (IC 95% –0.2–1.3) (p = 0.13), respectively. Conclusion Adalimumab levels between days 9 and 13 from drug injection are very similar to trough level and could be interpreted clinically at the same way. Adalimumab levels between days 1 and 8 are significantly higher, although, differences are small.

Background Loss of response (LOR) to tumour necrosis factor antagonists (anti-TNF) occurs in up to 50% of patients with inflammatory bowel disease (IBD). The ability to predict which patients are likely to lose response would allow therapies to be tailored to the patient’s characteristics. Immunogenicity is a common cause of LOR. Recently, a GWAS performed using the PANTS cohort demonstrated that carriage of one or more HLA-DQA1*05 alleles confers an increased risk of immunogenicity to anti-TNF therapy (Sazonovs et al. Gastroenterology 2019). We found that HLA-DQA1*05 carriage also identified patients at increased risk of clinical LOR to infliximab (Guardiola et al. ECCO 2019). The aim of our study was to know if carriage of a HLA-DQA1*05 allele is also associated with secondary LOR to adalimumab (ADA) in patients with Crohn’s disease (CD). Methods This is a retrospective cohort study from a prospectively maintained data base. Patients were included if they had achieved response to ADA. LOR was defined as recurrence or worsening of IBD-related symptoms that required a change or intensification in treatment, hospitalisation or surgery. Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Results We included 53 patients with Crohn’s disease, followed up to LOR (n = 31, 58%) or a median of 51 months (IQR 35–74). Forty-five per cent were carriers of an HLA-QA1*05 allele. HLA-DQA1*05 carriage was associated with LOR both, upon univariate analysis (HR 2.1 (95% CI 1.1–4.3), p = 0.04) and upon multivariate analysis, after adjusting for immunomodulators use, smoking status and BMI (HR 2.74 (95% CI 1.2–6.2), p = 0.02) (Figure 1). The cumulative persistence rates of ADA after adjusting for immunomodulators use was significantly lower in HLA-DQA1*05 carriers compared with non-carriers (HR 4 (95% CI 1.2–15.5), p = 0.02) (Figure 2). Conclusion HLA-DQA1*05 carriage is frequent and it is associated with a marked increase in the risk of LOR to ADA. HLA-DQA1*05 may become a clinically meaningful genetic marker that could allow for treatment to be tailored according to the risk of LOR, which is a step towards personalised medicine.

BACKGROUND: A large variability in biopharmaceutical kinetics exists between patients and even within a patient over time. Also, adequate thorough concentrations are linked to response in psoriasis. Therapeutic drug monitoring of biopharmaceuticals (i.e. infliximab–IFX) together with clinical response allows targeted cost-effective dose-adjustments. PURPOSE: The aim of the present study was to evaluate the real-life association between IFX exposure and clinical outcomes in patients with psoriasis. MATERIAL AND METHODS: Prospective study in psoriatic patients receiving IFX, between October 2013 and November 2016. We measured C(min) and antibodies towards IFX (ATI) using an enzyme-linked immunosorbent assay (ELISA) kit. Data on demographic, analytical and pharmacological variables and Psoriasis Area Severity Index (PASI) were recorded. Mixed models were estimated to evaluate association between IFX through concentrations (C(min)) and clinical response. Statistical analysis was carried out using R. RESULTS: We used a total of 155 C(min) values and ATI from 33 patients (33% females). Weight: 88.2 Kg (±23.5), BMI: 31 Kg/m(2) (±2.2), PASI at blood sampling: 2.2 (±3.2), PASI score reduction:% (±) (normal weight: 79% (±32.4), overweight: 78.2% (±35) and obese: 76.3% (±31)). Percentage of PASI 75, 90 and 100 response: 78.8%, 60.6% and 54.5%, respectively. The median C(min) was 2.4 mg/L (±2.2) (normal weight: 1.64 mg/L, overweight: 2.68 mg/L and obese: 2.68 mg/L). Six patients tested ATI positive and had undetectable C(min). Patients achieving PASI 75 had a significantly higher C(min) than non-responders (2.86 vs 1.58 mg/L, p

BACKGROUND: Serum infliximab (IFX) trough levels (Cmin) have been associated with clinical response. Therapeutic drug monitoring of IFX has been shown to be clinical and cost effective in inflammatory bowel disease (IBD) patients. However, some patients present clinical symptoms while IFX Cmin >3 mg/L. Activity markers such as faecal calprotectin (FCP) in combination with IFX Cmin could be of clinical utility to optimise therapy in IBD patients. PURPOSE: To evaluate the relationship between FCP and IFX Cmin, in IBD patients receiving maintenance IFX. Secondary analysis: to determine the use of IFX Cmin as a clinical predictor of FCP

Background Due to the large inter-patient pharmacokinetic (PK) and pharmacodynamic (PD) variability of infliximab (IFX), clinical outcomes in patients with inflammatory bowel disease (IBD) exhibit substantial inter-subject variability. An association between the rs1143634 C allele in interleukin 1β (IL1β) and higher serum IL1β concentrations and a lower response to IFX in patients with Crohn’s disease (CD) has been reported. Unravelling the impact of genetic polymorphisms on IFX exposure may help to refine therapy and improve clinical outcomes. Purpose To confirm the effect of the rs1143634 single nucleotide polymorphism (SNP) of IL1β on IFX exposure and PK in CD and ulcerative colitis (UC) patients. Material and methods Patients receiving IFX between July 2013 and December 2014 (n = 67) were genotyped for IL1 β polymorphisms. Associations between this SNP and pre-dose concentrations (Cmin, mg/L), dose adjusted Cmin (Cmin/D, mg/L/mg/month), area under the concentration-time curve (AUC, mg/h/L) and half-life (t1/2, days) at steady state were evaluated. Normalised by dose exposure parameters were statistically compared after log transformation. Pharmacokinetic and statistical analysis was performed using Nonmem 7.2 and SPSSv19, respectively. Results 67 patients were included (56.7% CC, 34.3% CT and 9.0% TT). All patients who developed antibodies against IFX (ATI) were carriers C (15% of carriers C). 60% of carrier C patients had Cmin Conclusion IL1β polymorphisms have a major influence on IFX exposure in IBD patients. The C allele was correlated with lower Cmin and Cmin/D. These results support the importance of IL1 β polymorphisms in IFX dose optimisation but further studies are needed. No conflict of interest.

Background Infliximab (IFX) is a chimeric antitumour necrosis factor α monoclonal antibody used in rheumatoid arthritis (RA). It shows large interindividual variability in serum concentrations during treatment. The use of previously developed population pharmacokinetic (PPK) models might help to guide dosing recommendations to improve response. External validation provides the most compelling evidence for the validity of a PPK model. Purpose To evaluate a previously developed PPK model for IFX in RA patients using an external population dataset. Material and methods RA patients receiving IFX between July 2014 and July 2015 were included. Pre-dose serum concentrations (C min ) (mg/L) and antibodies against IFX (ATI) were determined at steady state by enzyme linked immunosorbent assay (Promonitor). Demographic, biochemical and haematologic covariates, disease activity score (DAS28), tender joints (tender28) and swollen joints (swollen28) were recorded. The PPK model reported by Ternant et al . 1 was implemented in NONMEM v.7.2 and used as a Bayesian predictor. Bias and imprecision were estimated by the median prediction error and the root median squared prediction error, respectively. Prediction errors were calculated for each individual predicted concentration. Results 36 C min values from 17 patients were available (14 women; 6 concomitant psoriasis). IFX was administered at 3 mg/kg/8 weeks (n = 13), 3 mg/kg/10 weeks (n = 2), 3 mg/kg/6 weeks (n = 1) or 5 mg/kg/8 weeks (n = 2). Concurrent immunomodulatory therapy was given to 15 patients. The median C min (range) was 0.29 mg/L (0.01–3.87 mg/L). Median (range) values for the most relevant characteristics were: C reactive protein 3.5 mg/dL (0.5–60.7); serum albumin 43 g/L (38–48); leucocytes 7.15 × 10 9 /L (3.6–12.3); erythrocyte sedimentation rate 10 mm (2–76); DAS28 2.26 (0.63–4.71); swollen28 0 (0–8); and tender28 0 (0–8). Two patients developed ATI. Bias and imprecision estimated values were -0.03 (95% CI −0.53 to 0.43 mg/L) and 0.10 (95% CI 0.01 to 0.67 mg/L, 24%), respectively. Conclusion Acceptable bias and imprecision values were provided by the PPK model of Ternant et al . 1 but a further evaluation using larger datasets will be required to confirm these results. References and/or Acknowledgements Ternant D, Ducourau E, Perdriger A, et al . Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. BJCP 2013;78:118-28 No conflict of interest.

Background Infliximab (IFX) is a chimeric anti-TNFα monoclonal antibody used in the treatment of psoriasis. Due to the large interindividual variability in IFX, measurement of serum concentrations and correlation with disease activity and different covariables could be useful for psoriasis management. Purpose The primary endpoint was to assess the relation between IFX trough levels (C min ) and treatment efficacy. A secondary endpoint was to identify variables that could affect C min . Material and methods Prospective study of patients with psoriasis treated with IFX between October 2013 and August 2015 at a tertiary level hospital. C min (mg/L) and antibodies against IFX (ATI) were determined at steady state by enzyme linked immunosorbent assay (ELISA) (Promonitor). Data recorded: sex, weight, BSA, PASI, dose regimen and cigarette smoking. Dose adjusted C min values were statistically compared after log transformation. Statistical analysis was performed using SPSS v.19. Results 16 patients (25% women) were included. Median weight (kg) was 83.4 (Q1-Q3 65.5–93.8), median age (years) was 45 (Q1-Q3 38–54) years and median BSA (m 2 ) was 1.96 (1.66–1.96). 40 serum samples were available for analysis. Median IFX dose was 5 mg/kg/8 weeks (range 4 mg/kg/8 weeks to 5 mg/kg/6 weeks). All patients receiving dose intensified IFX had a BSA >1.7 m 2 . Median C min (mg/L) and dose adjusted C min (C min /D) (mg/L/mg/kg/month) were 1.59 (Q1-Q3 0.86–2.63) and 0.66 (Q1-Q3 0.37–1.1), respectively. 3 samples were positive for ATI. All patients who developed ATI had undetectable C min . Patients achieving PASI75 had a 23% higher C min /D compared with those not achieving PASI75. In patients with BSA >1.7 m 2 , median C min and C min /D were 45% and 15% higher, respectively. Only 63% of patients with BSA >1.7 m 2 achieved PASI75 (compared with 100% of patients with BSA ≤1.7, p = 0.026); patients with BSA >1.7 m 2 and achieving PASI75 had a 36% higher C min /D compared with those not achieving PASI75. Median C min was 13.7% lower in cigarette smoking patients. Conclusion Higher C min and C min /D values were associated with better treatment response in all patients. Patients with SC ≥1.7 showed a tendency to lower treatment response. Lower C min was found in smoking patients. More studies with a higher number of patients are needed to define the target levels and assess the influence of covariables. No conflict of interest.

Background The level of adherence to hepatitis C virus (HCV) treatment is associated with response. High adherence throughout the initial 12 weeks is related to better virological outcomes. Several factors can influence adherence. Purpose To assess HCV treatment adherence and to evaluate the relationship between adherence and rapid (RVR), early (EVR) and sustained virological response (SVR). Material and methods Retrospective observational study of HCV-infected patients receiving pegylated interferon (peg-IFN) + ribavirin (RBV) ± protease inhibitor (PI) from January 2011–December 2013. Demographic and clinical data recorded: age, sex, weight, HIV infection, HCV genotype; quantitative HCV RNA; peg-IFN, RBV and PI doses, frequency and quantities dispensed; psychiatric disorders. Results 183 patients (31.1% women); 14.2% HIV co-infected; 71.2% genotype 1. IL28B CT/TT genotype rate: 33/46. 79.8% were treated with peg-INF + RBV and 20.2% with peg-INF + RBV + PI. 11.7% received reduced RBV/peg-IFN doses. 3.3% required growth factor. RVR: 97.4% (mean reduction: 1.91 log IU/ml). EVR: 46.1%. SVR: 57.3% (genotype 1: 47.1% vs. others: 73.8%; p = 0.011). SVR among PI treated patients: 72.7%. Overall adherence according to quantities dispensed and the Morisky-Green test were 97.35% (95.8% with >80% adherence) and 99.56% (100% > 85% adherence), respectively. Mean adherence according to quantities dispensed at 4 and 12 weeks was 100% and 99.8%, respectively. Sex, HIV co-infection or psychiatric diseases were not associated with lower adherence. No relationship was found between RVR and adherence but the EVR was found to be significantly greater with adherence levels >85% (11.1% vs. 48.3%). Adherence ≥80% was associated with (not significantly) higher rates of SVR (57.7% vs. 50%). Conclusion Adherence >80% is associated with higher cure rates and adherence >85% at 12 weeks is related to greater EVR. No relationship was found between HCV-RNA decrease at 4 weeks and adherence. Neither psychiatric disorders nor HIV co-infection influenced adherence. References and/or Acknowledgements Mathes T, Antoine SL, Pieper D. BMC Infectious Diseases 2014;14:203–16 Lo Re V, Amorosa VK, Localio A, et al . Adherence to hepatitis C virus therapy in HIV/hepatitis C-Coinfected patients. CID 2009;48:186–93 No conflict of interest.