Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.

AIMSThis study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokineticpharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA). METHODSAdalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated. RESULTSThirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd/F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day −1 (17%); first-order absorption rate (ka) = 0.28 day; CRP input (kin) = 22.0 mg l −1 day −1 (65%); adalimumab concentration leading to a 50% decrease in kin (C50) = 3.6 mg l −1 (88%); baseline DAS28 (DAS0) = 5.5 mg l −1 (11%); and adalimumab concentration leading to 50% decrease of DAS0 (IC50) = 11.0 mg l −1 (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection.

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Background Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). Subcutaneous injections of adalimumab lead to highly variable trough concentrations between patients [1] that may partly explain the variability of response. To date, adalimumab pharmacokinetics (PK) after subcutaneous route has never been described. Objectives The goal of this study is to analyse the quantitative influence of individual factors on adalimumab PK in RA patients. Methods One hundred and twenty seven samples from 30 RA patients were used to measure adalimumab concentration [in a post-hoc analysis]. All patients received adalimumab 40 mg subcutaneously every other week. CRP levels and RA disease activity score (DAS28) were available at baseline, weeks 6, 12, 24 and 52. Adalimumab PK was described using a single compartment model with first-order absorption and elimination rates. A population approach was used. Sex, age, body weight, corticosteroid use and CRP levels were tested as covariates on each pharmacokinetic parameter. Results The following pharmacokinetic parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd/F) = 12.4 L (75%), apparent clearance (CL/F) = 0.31 L/day (17%) and first-order absorption constant (ka) = 0.41 day-1. Apparent clearance increased with body weight and was higher in men. Age, CRP levels, and concomitant treatment with corticosteroid had no effect on pharmacokinetic parameters. Adalimumab concentrations reached steady state after 20 weeks in men and 28 weeks in women. Conclusions Men eliminate adalimumab faster than women and the rate of elimination increases with weight in RA. Monitoring of serum adalimumab concentrations may be useful to avoid underexposure and treatment failure. Time to steady state was long and raises the question of a loading dose of adalimumab at initiation. References Bartelds GM et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007; 66(7):921-926. Acknowledgements Pr Christian Marcelli, CHU Caen. Pr René-Marc Flipo, CHU Lille. Pr Patrice Fardellone, CHU d’Amiens Disclosure of Interest None Declared

Background Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). There is a relationship between adalimumab concentration and clinical response but it has never been quantified individually. Objectives To describe the individual relationship between adalimumab concentration and disease activity in RA patients and to select an adalimumab target concentration necessary to reach either a low disease activity or clinical remission. Methods We measured adalimumab concentration in 127 samples from 30 RA patients who received 40 mg subcutaneously every other week. Disease activity score (DAS 28) were available at baseline, and at weeks 6, 12, 24 and 52. The relationship between adalimumab concentrations and DAS 28 was described by pharmacokinetic-pharmacodynamic (PK-PD) modelling using a direct inhibitory model. Results Median adalimumab concentrations increased over all the year whereas median DAS 28 decreased. At steady state, median adalimumab concentration [min-max] was 7.8 mg/L [1.8-15.0] and median DAS 28 was 2.9 [0.8-6.3]. The concentration-response relationship of adalimumab was well described by the direct inhibitory model. For a typical patient, adalimumab concentration required to decrease baseline DAS28 by 2 was 11.8 mg/L. The relationship between baseline DAS 28 and adalimumab concentration at steady state is displayed in figure 1. It shows that, if baseline DAS 28 is 6, the steady state adalimumab concentration necessary to achieve a low disease activity is 10 mg/L with 25%>75% confidence interval of 5-20 mg/L. To achieve remission, the required adalimumab concentration is 15 mg/L [8-30 mg/L]. Image/graph Conclusions This is the first study describing the individual concentration-effect relationship of adalimumab in RA. This model can be used to select the target concentration of adalimumab when therapeutic drug monitoring is applied. Acknowledgements Pr. Christian Marcelli. CHU Caen, Pr. René-Marc Flipo. CHU Lille, Pr. Patrice Fardellone. CHU Amiens Disclosure of Interest None Declared